Alternative Treatment for Parkinson Disease

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. Read more here...

The ParkinsonsReversing Breakthrough Summary

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Parkinsons Disease

Besides the cardinal signs of tremor, bradykinesia, rigidity, and postural instability, patients suffering from Parkinson's disease (PD) may also present many other neurological symptoms and signs, including cognitive, sensory, and autonomic disturbances. The implication of NE in PD is based on the observation that PD is associated with the degeneration of not only dopaminergic neurons located in the substantia nigra but also NE-LC cells. This LC alteration results in a drastic diminution of NE levels in brain areas such as the prefrontal cortex and also in the peripheral system. As for dopaminergic neurons, noradrenergic neurons contain neuromelanin, a pigment that results from oxidative catabolism of catecholamines and that may sensitize noradrenergic cells to oxidative stress. It should be noted, however, that noradrenergic medullary nuclei remain unchanged. The role of NE in PD is not as clear as it is for dopamine. One possibility is that the depletion of noradrenergic cells is...

Preexcitation syndromes Wolff ParkinsonWhite syndrome concealed pathways

Can be classified based on their location along the mitral or tricuspid annulus, type of conduction (decremental or non-decremental), and whether they are capable of antegrade conduction, retrograde conduction, or both. Accessory pathways which are capable only of retrograde conduction are concealed whereas those capable of antegrade conduction are manifest, demonstrating pre-excitation on a standard ECG. The term Wolff-Parkinson-White syndrome is reserved for patients who have both pre-excitation and symptomatic tachyarrhythmias. Among patients with the Wolff-Parkinson-White syndrome, atrioventricular reciprocating tachycardia (AVRT) is the most common arrhythmia, occurring in 75 of patients. AVRT is further subclassified into orthodromic and antidromic AVRT. During orthodromic AVRT the re-entrant impulse utilises the atrioventricular node and specialised conduction system for conduction from the atrium to the ventricle, and utilises the accessory pathway for conduction from the...

Anti Parkinsonian Drugs

Parkinson's disease is caused by a dysfunction within the basal ganglia. The predominant change is a deficit of dopamine with an increase in dopamine D2 receptors but other neurotransmitters are also implicated in the pathology of the disease. Drugs that affect Parkinson's disease may act in any of the following ways Increased dopamine synthesis (levodopa) Levodopa Levodopa is used to increase brain levels of dopamine. Dopamine does not cross the blood brain barrier, and racemic DOPA produces numerous systemic side effects without being effective. DOPA is well absorbed orally and 95 is converted into dopamine by DOPA-decarboxylase. This is then metabolized by monoamine oxidase and catechol o-methyl transferase (COMT). About 1 of the drug enters the brain where it is converted into its active form, dopamine. Levodopa causes an increase in the number of dopamine (D2) receptors in the brain. Used in conjunction with levodopa, carbidopa increases the proportion of the oral dose of...

Drugs used in Parkinsons disease

The discovery that dopamine was depleted in the basal ganglia of patients who suffered from Parkinsonism at the time of death led to the rational development of the therapeutic treatment, namely the use of L-dopa. Since dopamine does not cross the blood-brain barrier, and is rapidly catabolized Approximately 75 of patients with idiopathic Parkinsonism respond satisfactorily to L-dopa therapy with a reduction in their symptoms of at least 50 . In addition to a beneficial change in their motor symptoms, the mood changes associated with the disease also improve. In some patients, L-dopa has an alerting effect and occasionally more disturbing mental symptoms arise. These take the form of hallucinations, paranoia, mania, insomnia, anxiety and nightmares. Older patients being treated with L-dopa appear to be more prone to these effects. In addition, enhanced libido may occur in male patients, which may be socially unacceptable Approximately 15 of patients may show such symptoms, which are...

Origin of STn Overactivity in PD

The STn plays a key role in the basal ganglia circuitry, and its hyperactivity may be a major factor in parkinsonian symptomatology (Marsden and Obeso, 1994). According to the classical PD model, it is the hypoactivity of the GPe that leads to increased STn activity, which in turn (in addition to the diminished influence of the direct striatal GABAergic input) induces the pathological overactivity of GPi (Figure 20.6). However, although stimulation of the STn induces a strong activation of GPe neurons, STn lesions result in a decreased activity of GPe neurons. There is also physiological evidence suggesting that the STn is a driving force for not only the GPi, but also the GPe and even the SNc cells. In experiments in the normal rat, STn stimulation with the same parameters as in PD patients induced a transient but powerful inhibition (Benabid et al., 2002). As a consequence, a strong decrease in activity was recorded in the penducular pontine nucleus (PPN) (the equivalent of GPi in...

Gender Differences In Pd And Clinical Endpoints

Anesthetic agents have also been investigated for gender-based differences in PD and clinical responses (212). Females have 20-30 greater sensitivity to the muscle relaxant effects of vecuronium, pancuronium, and rocuronium (100,101) compared with men in terms of doses. The exact reason for the gender differences in the sensitivity is still unclear. The authors (107) incline to the PK differences (diverse distribution) as the likely explanation. Again, proper PK-PD modeling might help in indentifying the reason for gender diversities in this case. Many psychotropic medications also appear to exhibit gender-mediated differences in PD (43,218-220). Women show greater improvement in psychotic symptoms and more severe side-effects with typical antipsychotic agents than do men (221). For example, women appear to need much lower doses of fluspirilene than men to treat schizophrenia (222). The gender differences in the antipsychotic treatment responses may be at least partially a result of...

Twin Studies to Investigate the Cause of Parkinsons Disease

An example of the use of investigations in twins to understand more about a disease is provided by recent work in Parkinson's disease. Parkinson's disease (PD) is a progressive neurodegenerative disease causing slowness, tremor, and problems with walking and balance. PD is rare before age fifty but becomes more common thereafter, with increasing age. The cause of PD has long been debated. Both genetic and environmental causes have been suggested, but neither has been definitively shown. Researchers turned to studies in twins to determine the relative contribution of genes and environment to the disease. The first studies identified twin pairs by recruiting through physicians and PD patient organizations. Studies in the United States, the United Kingdom, and Germany identified 103 pairs, of which only thirteen were concordant for PD. In Finland, forty-two twins with PD were identified by records linkage, but among these was only one concordant pair a DZ pair. No study had convincingly...

The striatal dopaminergic system and Parkinsonism

The classical studies of Hornykiewicz and colleagues in the early 1960s clearly established that the symptoms of Parkinsonism were correlated with a defect in the dopamine content of the striatum. The pigmented neurons of the substantia nigra contain dopamine as the major neurotransmitter, accounting for 80 of the total dopamine content of the brain, and the principal motor abnormalities of the disease occur when the transmitter has been depleted by about 80 . While it is now established that acetylcholine, gamma-aminobutyric acid (GABA), glutamate and a number of neuropep-tides (e.g. somatostatin, the enkephalins and substance P) also occur in the basal ganglia, so far only dopamine and acetylcholine appear to be of significance with regard to the drug treatment of this disorder. A simple, but useful, model of basal ganglia function suggests that the neostriatum, containing the caudate nucleus and the putamen, normally contains a balance between the inhibitory dopaminergic and the...

Programming Adult Neurological Disease Parkinsons Disease

A long-term effect of fetal neuromotor programming may be an increased predisposition to adult or later onset neurological disorders, for example, Parkinsons disease. Parkinson's disease is a progressive motor pathology characterised by the loss of capacity to initiate and control appropriate voluntary movements. Patients do not become symptomatic until they have lost more than 60-80 of their dopamine-producing neurons in the substantia nigra pars compacta of the basal ganglia, a process that can take over a decade. Nigral dopamine cell numbers decline during normal ageing, but not everyone develops the disease before they die, presumably because the cell loss threshold has not been reached in Parkinson's disease, this rate of cell loss is accelerated significantly by an unknown mechanism. It is possible that individuals born with fewer dopamine-producing nigral cells are more likely to become symptomatic than someone of the same age and sex who starts life with a normal or optimal...

Clinical Trials in Parkinsons Disease The Prototype for Cell Transplantation

Parkinson's disease is characterized primarily by the degeneration of dopaminergic neurons projecting from the substantia nigra to the corpus striatum. Parkinsonian clinical symptoms like rigidity, tremor, and postural imbalance, accompanied by the histopa-thologic findings of nigral distrophy and Lewy bodies, are well-described and correlate with the loss of dopamine production and release in the brain. The importance of cerebral dopamine became apparent in the late 1950s, and since then our knowledge about the neuroanatomy, physiology, and especially pharmacology of this neurotranmsitter has increased immensely. Readers interested in the topic may start by consulting the chapter in the popular neuropharmacology textbook by Cooper, Bloom, and Roth. Logically, the first therapeutic approach in diseases associated with parkinsonian symptoms, for a long time equated primarily with rigidity, was based on replacing the natural neurotransmitter with precursors like levodo-pa. This has...

Xenografts in Parkinsons Disease

Human xenografts have been used in animal models to study principles of neurotransplantation or mechanisms of brain degeneration. More often, xenotransplantation has been tested with the goal to explore alternative sources of mesencephalic fetal tissues for grafting into the degenerating brain. Studies using porcine fetal cells in rats showed that the grafts survived and integrated successfully in the host. Currently, there are several ongoing clinical trials to assess the feasibility of porcine xenografts in PD and HD patients, and the preliminary data suggest that this may be a safe procedure. The efficacy still has to be determined, although initial reports note measurable improvement in some patients. We believe that xenotransplants will not play a significant role in neural restoration if human cells and tissues can be obtained.

Genes And Parkinsonism

Parkinsonism is a syndrome of rest tremor, rigidity, bradykinesia, loss of postural reflexes, and the freezing phenomenon.1-1-1 Most often, it is a manifestation of Parkinson's disease (PD), which is characterized neuro-pathologically by brainstem Lewy bodies. Recent epide-miological and molecular data suggest that this is not one disorder, but is comprised of at least several disorders with genetic, environmental, or mixed etiologies. Genes play a complex role in PD. Most twin studies, which are powerful tools in dissecting genetic from environmental contributions to the disease, have discounted a genetic influence in PD. However, it is difficult to draw solid conclusions from them because of methodological short-comings. 2 The largest of them, an unselected population-based cross-sectional twin study, has shown similar concordance for PD in monozygotic (MZ) and dizygotic (DZ) twin pairs with onset > 50 years, but a striking concordance in MZ pairs with onset < 50 years. 3 This...

Association With Parkinsonism And Other Extrapyramidal Disorders

Findings from various centers suggest the following characteristics. First, parkinsonism may be quite prevalent in RBD second, RBD may be the initial manifestation of a parkinsonian disorder in a substantial number of RBD cases initially considered to be idiopathic third, a high percentage of parkinsonian patients without sleep complaints may have either subclinical or clinical RBD fourth, Lewy body pathology may be quite prevalent in RBD and fifth, similar findings have been reported in various extra-pyramidal disorders. A review of the world literature on RBD identified 280 published cases, of which 149 (53 ) were closely associated with a neurological disorder (Schenck and Mahowald, 1996a). A parkinsonian disorder was the most prevalent neurological condition, affecting 43 (n 64) of neurologically disordered RBD patients (representing 23 of n 280 total cases) narcolepsy was the next most prevalent condition, affecting 25 (n 38) of neurologically disordered RBD patients...

Parkinsons Disease PD

PD is primarily a progressive, extrapyramidal (involving motor systems ofthe basal ganglia rather than the pyramidal tract) disorder with clinical motor features of stooped posture, bradykinesia (slowing of movement initiation), tremor (when the affected limb is at rest, but typically not during movement), cogwheel rigidity (i.e., rigidity that seems to catch and release, much like a cogwheel, when the clinician attempts to passively move the patient's limb), and festinating gait. Dementia has been estimated to occur in approximately 35-40 of persons with PD. The neuropsy-chological impairments manifested in the dementia of PD include psychomotor slowing, impaired cognitive tracking and set-shifting flexibility, visuospatial deficits, diminished learning and retrieval (although, as with HD, often there is evidence of more intact information retention shown by recognition memory tasks), decreased verbal fluency, and abstract reasoning impairment. Neuronal degeneration (with Lewy bodies...

Neuroanatomy of the basal ganglia relevance to Parkinsons disease

There are two main efferent pathways from the striatum to the globus pallidus, the direct pathway, which is a monosynaptic pathway making contact with the internal globus pallidus and to a lesser extent the substantia nigra, and the indirect pathway that indirectly connects to these brain regions via the lateral globus pallidus and the subthalamic nuclei. The internal globus pallidus and, to a lesser extent, the substantia nigra modulate the activity of the circuits via the thalamocortical motor pathways these pathways are mainly inhibitory in nature. Normally, dopamine inhibits the indirect pathway to the external globus pallidus which then inhibits the subthalamic nuclei. This system can therefore no longer stimulate the substantia nigra and globus pallidus, therefore leading to a reduction in the inhibitory output from these regions. Under these conditions, it is assumed that the thalamocortical pathway can function, leading to normal movement. The role of the direct pathway is...

Ldopa and parkinsonian syndrome

The Parkinsonian syndrome has long held the interest of psychologists, psychiatrists, and other behavioral investigators. Lately, the field of cerebral monoamines has received increased attention first with the serotonin hypothesis of Brodie, then the noradrenaline hypothesis of Schildrant, in relation to neuron function, is receiving particular attention. (67). Dopamine is postulated to be the key neurotransmitter responsible for the origin of human intelligence (67). Dopamine, the direct precursor for noradrenaline, has a specific distribution pattern within the brain (Figure 9.3). It is concentrated mainly in the striatum and substantia nigra. It is deficient in patients with Parkinson's diseases (PD). l-DOPA has been studied as a treatment for neurological disorders such as Parkinson's disease (68,69). Parkinson's disease is a common neurological disorder, affecting 1 of the people over the age of 60 years it is a disease with the signs of rigidity, resting tremor, postural...

Paradoxical Effects of Gp Dbs on Distorted Temporal Memory in PD

The STn DBS work was followed up with pallidal DBS (Benabid et al., 1991 Filion et al., 1991 Tronnier et al., 1997). Given the sophisticated DBS technique used by our collaborators, we were fortunate to identify distinct effects related to the altered neural activity in either the globus pallidus external capsule (GPe) or globus pallidus internal capsule (GPi) portions of the globus pallidus in PD, as compared to STn DBS. Details on the technique and clinical electrophysiological and anatomical data for each patient (N 5) included in our study are published by Yelnik et al. (2000). The beneficial effects of the STn DBS were not reproduced when DBS targeted the GPi. Rather, inaccuracies in the form of migrated estimates were worse, whereas slowed encode was found to be highly variable among subjects. When in contrast, the plots

Sudden death in Wolff ParkinsonWhite syndrome

Wolff-Parkinson-White syndrome is one of the most common causes of arrhythmias in childhood, but sudden deaths are rare. The overall mortality risk is very difficult to quantify but may be around 1.5 per 1000 patient-years.w47 Sudden death is probably caused by ventricular fibrillation which, in turn, is precipitated by atrial fibrillation in patients with a very short anterograde accessory pathway refractory period (fig 21.3). Cardiac arrest and sudden death mainly occur in adolescents and young adults and are very rare in younger children.w48 Resuscitation from cardiac arrest is (perhaps not surprisingly) a strong predictor of risk, but syncope and atrial fibrillation have poor predictive value, although they would be indications for catheter ablation in any case. Although a short anterograde refractory period of the accessory pathway is thought to be the best electrophysiological indicator of risk, the predictive value of such a finding is poor.w48 Patients with significant...

Animal Models of Brain Degeneration in Parkinsons Disease

Among the chronic brain degenerative diseases, PD has the best characterized and most consistent models. Although the underlying mechanism of disease in these models may be significantly different from the human condition, they reproduce rather closely the pathology in the final stages of dopaminergic degeneration in PD and constitute a crucial basis to test novel therapies. Due to its well-defined neuroanatomical distribution, the nigrostriatal dopaminergic pathway can be le-sioned or severed at various locations and the benefit of various cell grafting methods can be studied. Because this approach is more labor intensive and sometimes postsurgical complications may interfere with the experimental results, most investigators prefer to use chemical lesioning. The best characterized and most extensively used models are the rat 6-OHDA and the primate and murine (MPTP) models. Both are based on the induction of a cytotoxic lesion in the dopami-nergic neuronal population of the substantia...

Treatment Of Pdpda

Cognitive behavior therapy (CBT) for PD PDA usually follows a manualized approach covering 8-12 structured sessions. Typically, treatment involves (1) psychoeducation, (2) breathing retraining, (3) cognitive restructuring, (4) inte-roceptive exposure, and (5) in vivo (situational) exposures. These intervention strategies address the cognitive, behavioral, and physical components of PD PDA and are designed to help the individual not fear the bodily sensations associated with PD PDA. Therapists present information to clients, model techniques, and provide feedback and reinforcement throughout the treatment period. A brief summary of the intervention techniques follows. Cognitive restructuring addresses cognitive distortions or errors in thinking such as catastrophic misappraisals of somatic sensations (e.g., I'm having a heart attack, I'm going crazy). Individuals are taught techniques to address correct errors in overestimation of risk (e.g., I'm lightheaded, therefore I will faint) or...

Parkinsonism

The delayed emergence of a parkinsonian disorder in RBD has been reported in a group of 29 male patients 50 years of age who were initially diagnosed to have idiopathic RBD (Schenck and Mahowald, 1996c). Of these, 38 ( ) eventually developed a parkinsonian disorder presumably Parkinson's disease (PD) at a mean interval of 3.7 1.4 years after the diagnosis of RBD, and at a mean interval of 12.7 7.3 years after the onset of RBD. Only 7 ( J of those patients had, at the time of publication, developed any other neurological disorder. RBD was controlled with nightly clonazepam treatment in 89 (f ) of patients (both groups). Thus, RBD can be the heralding manifestation of PD (by many years) in a substantial subgroup of older male RBD patients. However, a number of presumed PD patients could eventually be diagnosed with multiple system atrophy (striatoni-gral degeneration subtype). The findings from that report indicate the importance of serial neurological evaluations after the initial...

Amyotrophic Lateral Sclerosis 721 Introduction

Disorders such as Parkinson's disease, Alzheimer's disease and ALS. Transition metals in the organism like Fe are thought to promote the generation of free radicals such as O-, and to cause oxidative stress. On the other hand, there are enzymes called super-oxide dismutase (SOD) that dissociates free radicals. Cu Zn SOD, which is the major SOD in human bodies, utilize coordinated Cu and Zn to dissociate free radicals. This enzyme is encoded by the SOD1 gene and converts O- into H2 O2, which is then metabolized by gluathion peroxidase 3 . The generally accepted mechanism of dismutation involves cyclic reduction and reoxidation of Cu(II) and Cu(I), respectively by single molecules of superoxide 4 .

Connections Between Interval Timing Neuropharmacology And Drug Abuse

Genetic modifications of the dopamine system can be made in various ways, including the deletion of the gene coding for the dopamine reuptake transporter (DAT), which leads to an increase in the synaptic levels of dopamine. The DAT mediates uptake of dopamine into neurons and is a major target for cocaine and amphetamine (e.g., Carboni et al., 2001). Since its cloning, much information has been obtained regarding the structure and function of the DAT. Binding domains for dopamine and various blocking drugs (e.g., cocaine) are likely formed by interactions with multiple amino acid residues, some of which are separate in the primary structure, but lie close together in the still unknown tertiary structure. The DAT gene is expressed only in the central nervous system within a small subset of neurons (i.e., dopamine-containing neurons) and not in glia cells. DAT expression is more restricted, for instance, than the expression of genes encoding dopamine biosynthetic enzymes (e.g., tyrosine...

Anatomical Changes With

Some areas of the brain do show a decrease in neuronal number, including the hippocampus, thalamus, putamen, cerebellum, and subcortical nuclei such as the substantia nigra, locus coeruleus, nucleus basalis of Meynert (NBM), and inferior olive. The hippocam-pal region is of interest because of its purported role in encoding new memories the earliest neuropathologi-cal changes in Alzheimer's disease occur in parts of this structure and in surrounding tissue. Parts of the basal ganglia (putamen, globus pallidus, and portions of the thalamus), along with the cerebellum and substantia nigra, are key components of the neural system involved with regulating movement. Neuronal death ofthe dopaminergic cells in the substantia nigra causes Parkinson's disease several symptoms of this degenerative disease increase their frequency in the aged. Some studies have reported neuronal loss in the NBM, the source of the cholinergic projection to the cerebral cortex. This nucleus shows a significant...

Smell And Sexual Arousal

Besides purely anatomical similarities, the linkage between olfactory function and sexual function is recognized in a clinical setting. More than 17 of individuals with chemosensory dysfunction develop impaired sexual desire or other sexual dysfunction (28). Genetic disorders can affect both systems for example, those with Kalliman's syndrome have both olfactory deficit and impaired sexual drive and functioning (29). Other diseases impair olfactory ability and sexual functioning concomitantly, including cerebral vascular disorders (18,30), Parkinson's disease (31,32), senile dementia of the Alzheimer's type (33), hypothyroidism (34,35), and vitamin deficiency states including B12 deficiency (36). Alternatively, odors may act to enhance sexual arousal by actually acting directly on areas of the brain that induce sexual arousal (eg, the septal nucleus), by acting directly, almost as a drug, influencing them through dopaminergic, cholinergic, or serotinergic mechanisms (70). Odors induce...

Edmund A Bermudez Md Mph and Ming Hui Chen MD MMSc

Stress Echo Protocol

Stress echocardiography is indicated in the diagnosis of coronary artery disease in those with an intermediate likelihood of coronary artery disease and an abnormal electrocardiogram (Fig. 1, Table 1). Those individuals with left bundle branch block, Wolff-Parkinson-White syndrome, left ventricular hypertrophy, digoxin use, or more than 1 mm ST segment depression on electrocardiogram should undergo imaging with stress as interpretation of ST segments are an unreliable marker of ischemia in these settings. If the patient is able to exercise, treadmill stress, or bicycle stress (supine or upright) should be performed. When this is not feasible, dobutamine stress may be used. In the United States, vasodilator stress is an uncommon modality for stress echocardiography.

Anatomical Distribution In The Central Nervous System

Metabolic Pathway For Dopamine

There are several dopamine-containing pathways in the CNS. The nigrostriatal dopamine pathway accounts for approximately 70 of the dopamine in the brain. Cells bodies in this pathway are located in the substantia nigra pars compacta and project to the caudate, putamen, and the globus pallidus (Fig. 1). An interesting characteristic of these dopamine neurons is that they contain extensive dendritic trees, which extend ventrally into the substantia nigra pars reticu-lata. Dopamine release occurs from these dendrites in addition to the axon terminals. Deterioration of the nigrostriatal pathway underlies Parkinson's disease (PD). The substantia nigra and VTA dopamine cell bodies are often referred to as the A-9 and A-10 nuclear groups, respectively, following the original designation of Dahlsstrom and Fuxe from their pioneering rodent studies using a novel technique that made dopamine neurons fluorescent. However, more detailed immunohistochemical studies suggest that the A-9 and A-10...

Neurological Abnormalities

Ing dysfunction include CVEs, cauda equina syndrome or spinal cord compression, Parkinson's disease, Shy-Drager syndrome (multisystem atrophy), multiple sclerosis (MS), and motor neuron disease (MND). Spinal cord injury also causes long-term voiding dysfunction, but rarely AUR. Most patients are, however, managed with an in-dwelling catheter after the initial injury, until the period of spinal shock has passed when a better idea of long-term bladder function can be ascertained.

Synaptic Transmission

Synaptic Knobs

There are many other neurotransmitters. Many hormones serve this function, including epinephrin (adrenaline), ADH, oxytocin, insulin, and glucagon. The amino acids glycine, glutamine, and aspartic acid are neurotransmitters, as are the gases carbon monoxide and nitric oxide. A group of compounds called endorphins modifies the effect of neurotrans-mitters and may be involved in mood and pain reduction. They are similar in structure to morphine. It is thought that exercise produces a natural release of endorphins. Dopamine is a central nervous system neurotransmitter that can be inhibitory or excitatory, depending on the receptor. A decline in dopamine production produces Parkinson's disease, in which the inhibitory action of dopamine is missing. As a result, the neurons that control muscle tone become overstimulated. All movement requires overcoming the tension of the opposing muscle. Dopamine cannot cross the blood-brain barrier, but the drug L-dopa can, and it is converted to...

Neuromuscular Control

Electromyographic Olympic Snatch

Recruitment is the activation of different motor units within a muscle. Physiological research has determined three important properties of recruitment of motor units. First, motor units tend to be organized in pools or task groups (Burke, 1986). Second, motor units tend to be recruited in an asynchronous fashion. Different motor units are stimulated at slightly different times, staggering the twitches to help smooth out the rise in tension. There is evidence that some motor unit synchronization develops to increase rate of force development (Semmler, 2002), but too much synchronous recruitment results in pulses of tension tremor that is associated with disease (Parkinson's) or extreme fatigue (final repetition of an exhaustive set of weight lifting). The recruitment of motor units is likely more complex than these general trends since serial and transverse connections between parallel architecture muscles allows active fibers to modify the tension and length of nearby fibers (Sheard,...

The Caudal Diencephalon

Ventrobasal Schema

The pretectum (alar p1) is the caudalmost forebrain region. It is characterized by the posterior commissure, whose fibers cross the pretectal dorsal midline and then course transversally through the alar plate, just in front of the diencephalomesencephalic limit, before spreading longitudinally in the basal plate (pc in Fig. 3). The function of the posterior commissure is unclear. This region contains various pretectal nuclei involved in visual processing, including the centers for the pupillary and optokinetic eye reflexes. The subcommissural organ is a dorsal midline specialization that secretes glycoprotein (Reissner's fiber) into the ventricular fluid. The basal plate has dopamine-containing neurons that form part of the substantia nigra in addition to diverse reticular cell populations involved in motor circuits, like the parvocellular nucleus ruber (origin of the rubroolivary tract) and the interstitial nucleus of Cajal. The latter is a rostral source of descending preoculomotor...

Anomia In Alzheimers Disease

Alzheimer's disease (AD) is the most studied of the dementia-producing diseases that can have anomia as a salient symptom. Dementia (see the article on it in this volume) may be defined as a progressive cognitive decline resulting from a number of diseases. Such a cognitive decline characteristically may include more language disturbance (as in Alzheimer's disease in all but very-late-onset instances) or less language disturbance (as in the dementia associated with perhaps one-third of the individuals with Parkinson's disease). When a language disturbance is evident, anomia is invariably a part of it. The naming problems associated with the dementias may or may not be termed anomia by different scholars however, the phenomenon is quite similar to that found in the aphasias. What underlies the problem, however, appears to be different. First, the cognitive problems underlying the dementia regularly include a variety of memory problems, so one may argue that the difficulty with...

Peripheral Agraphias

Where Angular Gyrus Axial

Figure 3 (A) Errors of letter morphology in the writing produced by a patient with apraxic agraphia following left parietal lobe damage. (B) Micrographia in Parkinson's disease. Note overall reduction of letter size. Progressive reduction of writing amplitude is seen with repeated attempts to write the same word or letter. (C) Afferent dysgraphia in a patient with right parietal lobe damage. Duplications occur mostly in words with double letters and when writing letters that contain repeated stroke cycles. Figure 3 (A) Errors of letter morphology in the writing produced by a patient with apraxic agraphia following left parietal lobe damage. (B) Micrographia in Parkinson's disease. Note overall reduction of letter size. Progressive reduction of writing amplitude is seen with repeated attempts to write the same word or letter. (C) Afferent dysgraphia in a patient with right parietal lobe damage. Duplications occur mostly in words with double letters and when writing letters that contain...

Sensorimotor Examination

Cjd Morbidity Rates

The sensorimotor neurological examination does not contribute to making a diagnosis of dementia per se. However, the pattern of neurological abnormalities often point to likely underlying diseases that may be contributing to the dementing process. For example, a clinician should look for evidence of upper motor neuron signs (e.g., hemiparesis, asymmetric deep tendon reflexes, extensor plantar responses) that would suggest the possibility of stroke or structural lesion. Extrapyramidal signs would raise the question of Parkinson's disease, progressive supranuclear palsy, or Lewy body dementia. Abnormalities of gait may be associated with cerebrovascular disease, Parkinson's disease, and normal pressure hydrocephalus. Dysarthria would alert the clinician to possible extrapyramidal disorders, bilateral strokes, de-myelinating disease, and motor neuron disease. Sensory abnormalities (e.g., peripheral neuropathy) may be associated with B12, other vitamin deficiency states, thyroid disease,...

Major Hypothalamic Connections

The medial forebrain bundle (MFB) is another prominent fiber tract associated with the hypothalamus. The trajectory of this projection system brings it through the full rostrocaudal extent of the lateral hypothalamus. This pathway is more diffusely organized than the postcommissural fornix and carries both ascending and descending fibers. Many of the axons that pass through the MFB are simply traversing the hypothalamus in transit to other forebrain targets. The prominent dopaminergic projections from the substantia nigra and ventral tegmental area fall into this category. Brain stem noradrenergic and cholinergic neurons also project through the MFB to both diencephalic and telencephalic targets. Thus, whereas the MFB is an important conduit for axons innervating the hypothalamus, it is also a major projection pathway for axons projecting to and from forebrain nuclei. Loss of function in response to lesions that interrupted these fibers of passage confounded the interpretation of...

A EEG Arousal Is Controlled by Interconnections between the NMTs Thalamus and Cortex

Cortical Arousal Eeg

Figure 1 (A) Early model of arousal systems, circa 1972. The RF was considered a unitary structure that modified processing in sensory thalamic relay structures, nonsensory diffuse nuclei, and the cortex. The two groups of thalamic nuclei were mutually interconnected. (B) Contemporary view of arousal systems. Each NMT (bottom) sends influences to both the RT and the TRN. The RT contains oscillatory circuits (dotted line) that produce the rhythmic activity of the brain. (C) Electrical activity recorded in the cortex and the effects of electrical stimulation (tetanus) of the cholinergic NBM. The EEG switches from high-voltage slow waves to low-voltage fast activity. Individual cells show burst activity prior to tetanus and single spike activity for several seconds after tetanus reproduced with permission from Metherate et al., (1992). J. Neurosci. 12, 47014711. Copyright Society for Neuroscience . RF, reticular formation NBM, basal nucleus of Meynert PPT, peduncolopontine tegmental...

Extrapyramidal Disorders

Akathisia is a condition wherein patients demonstrate motor restlessness with corresponding anxiety it can be mistaken for a worsening of the underlying psychiatric disorder. This assumption may lead to increasing the dose of the offending agent, thus making the symptoms worse. Administration of diphenhydramine or related agents may be diagnostic and therapeutic a reduction in dose of the antipsychotic, or a switch to a less potent agent, is a possible long-term solution. 23 Bradykinesia, or drug-induced parkinsonism, is another extrapyramidal side effect of this drug class and should be treated in a similar fashion. 12

Preexcitation Syndromes

Kent bundles are composed of myogenic tissue and directly link the atria to the ventricles, completely bypassing the AV node and infranodal system. This is the most common form of preexcitation and is the anatomic basis for the Wolff-Parkinson-White (WPW) syndrome. On ECG, this appears as a shortened PR interval and with an initial distortion of ventricular activation (delta wave). Sometimes the bypass tract does not conduct an atrial impulse in the antegrade direction and the QRS complex is entirely normal. However, these concealed bypass tracts may conduct retrograde and be able to sustain reentrant SVT. FIG. 24-39. Type A Wolff-Parkinson-White syndrome. FIG. 24-39. Type A Wolff-Parkinson-White syndrome. FIG. 24-40. Type B Wolff-Parkinson-White syndrome.

Antimuscarinic Effects

TCAs frequently produce antimuscarinic symptoms. They are competitive inhibitors of acetylcholine at central and peripheral muscarinic receptors. This action is commonly referred to as being anticholinergic, but the term antimuscarinic is more precise because TCAs do not antagonize acetylcholine at nicotinic receptors. Central antimuscarinic symptoms vary from agitation to delirium, confusion, amnesia, hallucinations, slurred speech, ataxia, sedation, and coma. Peripheral antimuscarinic symptoms include dilated pupils, blurred vision, tachycardia, hyperthermia, hypertension, decreased oral and bronchial secretions, dry skin, ileus, urinary retention, increased muscle tone, and tremor. Antimuscarinic symptoms are especially common when TCAs are combined with other medications that also have antimuscarinic activity. Examples include antihistamines, antipsychotics, antiparkinsonian drugs, antispasmodics, and some muscle relaxants.

Potential cardiotoxicity of antipsychotic drugs

In CONCLUSION, the use of the classical neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutyl-piperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side effects such as akathisia, Parkinson-ism, tardive dyskinesia and the all too frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulties encountered when attempting to reduce their frequency and severity by concurrent medication, has stimulated the development of atypical neuroleptics such as clozapine and risperidone which, hopefully, will combine efficacy with a reduction in side...

Class I Antidysrhythmic Agents

Common Emergency Department (ED) Indications Procainamide is a second-line agent generally used to treat and prevent recurrence of ventricular dysrhythmias, specifically stable ventricular tachycardia (VT) and premature ventricular contractions (PVCs) that are unresponsive to lidocaine. It is infrequently used in ventricular fibrillation (VF) or pulseless VT because it takes so long to achieve therapeutic concentrations. Procainamide may also be used for slowing or converting supraventricular tachycardias (SVT) including atrial flutter and fibrillation especially in Wolff-Parkinson-White (WPW) syndrome , paroxysmal supraventricular tachycardia (PSVT), paroxysmal atrial tachycardia (PAT), and paroxysmal atrioventricular (AV) junctional rhythm. Contraindications include complete AV heart block, second- or third-degree heart block (without an electrical pacemaker present), long QT intervals, and torsades de pointes. The drug should be used cautiously in patients with systemic lupus...

Epidemiology and clinical significance

Atrial flutter is most often a nuisance arrhythmia. Its clinical significance lies largely in its frequent association with atrial fibrillation, its previously little appreciated association with thromboembolism, especially stroke,14 15 and its frequent association with a rapid ventricular response rate (fig 24.2). The association of atrial flutter with a rapid ventricular rate is important because the rapid ventricular rate is principally responsible for many of the associated symptoms. And, in the presence of the Wolff-Parkinson-White syndrome or a very short P-R interval (< 0.115 s) in the absence of a delta wave, it may be associated with 1 1 atrioventricular (AV) conduction, sometimes with dire consequences. Furthermore, if the duration of the rapid ventricular response rate is prolonged, it may result in ventricular dilatation and congestive heart failure.

Costeffective Treatment Options For Generalized Dystonia

Historical issues not typically associated with idio-pathic generalized dystonia include the presence of tremor or other movement disorders, possible birth injury, developmental milestones, and exposure to neuroleptic medications, as well as a family history of dystonia, parkinsonism, or other movement disorders. Identification of any of these risk factors may mean major differences in symptom progression, and may require different types of interventions. Evidence of other conditions known to produce dystonia but associated with other neurologic dysfunctions (e.g., cogni Treatment of generalized dystonia in a setting in which the use of botulinum toxin, a baclofen pump, or surgical intervention are not options will rely heavily on assistive devices and oral medications. While physical and occupational therapy have not been demonstrated to alter the progression of ITD, daily range-of-motion sessions done by a caregiver will be helpful in reducing limb contracture. In some settings, the...

Deficits In Other Kinds Of Proceduralimplicit Memory

In contrast to amnesics, patients with Huntington's disease (HD), who have neostriatal damage, have been found to show impaired acquisition and retention of skills such as reading mirror-reversed words and relatively normal performance at verbal recognition tests. Similarly, Parkinson's patients, whose substantia nigra pathology also disrupts neostriatal function, have shown impaired acquisition of cognitive skills despite being normal at some explicit memory tasks. with degenerative damage in the region. However, impairments are not always found because preserved acquisition of mirror-reading skill has been found in Parkinson's disease patients. Whether cerebellar damage impairs perceptual and cognitive skill acquisition is uncertain because although deficits have been reported, there is strong evidence that patients with selective cerebellar degeneration do not show deficits in learning to read mirror-reversed text or solving the tower of Hanoi difficulty. The difficulty is that...

TABLE 2182 Segmental Innervation of Muscles

RESISTANCE TO PASSIVE MOVEMENT The early parkinsonian patient may present with rigidity or with a cogwheel phenomenon. Alteration in resistance to passive movement may occur in some demented patients where the amount of resistance is proportional to the amount of force applied (gegenhalten). The spastic catch, with a clasp-knife character from spasticity, is seldom present in an acutely developing lesion. Flaccidity results from denervation, which may be peripheral, as well as from deep coma. TREMOR AND INVOLUNTARY MOVEMENTS Involuntary movements are usually seen when the limbs are at rest, such as the rhythmic tremor of parkinsonism, but may be more obvious during movement, as in chorea or the distal, rhythmic, sometimes rotatory, essential tremor (T ble , 218.-.3). Most involuntary movements represent slowly developing neurologic disorders and do not require emergent intervention. An exception is the abrupt, constant while awake, proximal, swinging movements of hemiballismus, a...

The process of consciousness

On one hand, the activation system is centered upon the dopamine cells of the tegmentum and substantia nigra. Its activity produces a redundancy bias that maintains focused attention and routinizes action. It produces an analytic cognitive mode. The activation system is believed to be central to the experience of negative affect, such as anxiety. On the other hand, the arousal system is regulated by norepinepherine cells of the locus ceruleus. This system produces a habituation bias so that novel events capture attention. The cognitive mode of this system is holistic. Its activity is believed to be central to the experience of positive affect, such as elation (for a detailed description see Tucker and Williamson, 1984).

Use of brain transplants

Foetal mesencephalic tissue has been implanted in the striatum of patients with the juvenile form of Parkinson's disease and has been shown to develop functional axons this has enabled the dose of L-dopa to be reduced. Both imaging and pharmacological studies have now shown that functional dopaminergic neurons can develop in the brain of the patient following tissue transplantation. However, a major ethical objection has been raised to such transplants as six to seven foetal brains are required to obtain sufficient tissue. In addition, only about 20 of neurons survive transplantation. The ethical problem may be overcome by using brain transplants from domestic animals such as pigs. Such xenotransplants have been shown to survive in the human brain but the main problem with the extensive use of such transplants is the possible spread of viruses and prion infections. There is evidence that trophic factors, which are essential for the development of neurons and their maintenance in the...

Twin Studies and Concordance

The data in the last column indicate the relative risk (RR) and 95 percent confidence interval (CI) for concordance of Parkinson's disease in MZ twins. The risk to the second twin is much higher if the first is diagnosed before age fifty, indicating a strong genetic component in early-onset PD.

What Do Genes In Autosomal Dominant Pd Tell Us About Pathogenesis

Autosomal recessive parkinsonism, which have occurred in parallel with the finding of dominant genes and are outside the scope of this article. The subject has been recently reviewed. 26,27 Derangements in protein handling seem to be central in the pathogenesis of PD (Fig. 1). a-Synuclein is a small protein characterized by imperfect repeats (KTKEGV) distributed through most its amino-terminal half of the polypeptide that also includes a hydrophobic middle region and an acidic carboxy-terminal region. Its function is not established but it is believed to modulate synaptic vesicle turnover and synaptic plasticity. In vitro, it polymerizes into 10-nm fibrils, which are a major component of nigral Lewy bodies and Lewy neurites in PD and other forms of parkinsonism. It is unfolded in its native state but becomes structured on binding to lipid membranes. In the unfolded form, it is degraded by proteosomes in a ubiquitin-independent manner. In diseases where it aggregates, it forms a...

Microglial Responses in Degenerative CNS Diseases

A pathogenic role of microglia has been suggested in degenerative CNS diseases, such as Alzheimer's disease (AD) and Parkinson's disease, that are characterized by selective loss of neurons in distinct regions of the brain. These conditions lack an overt inflammatory response, but microglia are activated at sites of neuronal degeneration. AD is characterized pathologically by the presence of insoluble structures in the cerebral cortex that represent either extracellular plaques consisting of amyloid-b protein (Ab) deposits or neurofibrillary tangles within nerve cell bodies. In AD brain microglial cells accumulate in the center of

Clinical Presentation

Progressive respiratory muscle weakness causes dyspnea with mild activity, until dyspnea at rest occurs. Dementia and parkinsonism also may be seen in up to 15 percent of patients, especially those with fALS. Other cognitive problems such as apathy, poor attention and motivation, and altered social skills may be noted in patient with ALS.

Additional Reading

Arch Phys Med Rehabil 1979 60 155-158. Jankovic J, Fahn S. Dystonic disorders. In Jankovic J, Tolosa E, (eds.) Parkinson's Disease and Movement Disorders. 3rd ed. Baltimore Williams & Wilkins 1998. Jankovic J. Post-traumatic movement disorders central and peripheral mechanisms. Neurology 1994 44 2006-2014. Karp BI, Cole RA, Cohen LG, Grill S, Lou JS, Hallett M. Long-term botulinum toxin treatment of focal hand dystonia. Neurology 1994 44(1) 70-76.

Clinical Diagnosis

Of neurologic disorders, a prior history of encephalitis or other CNS infections, concurrent drug use, and any exposure to toxins or street drugs. The symptoms of PD also can be seen in postencephalitis patients and those with other infections such as neurosyphilis, subacute spongiform encephalopathy, and AIDS. Parkinsonism also can occur as a result of street drugs, toxins, neuroleptic drugs, hydrocephalus, head trauma, and with more rare and complex neurologic disorders such as progressive supranuclear palsy, striatonigral degeneration, and corticobasal ganglionic degeneration. Although thought to be a common cause of parkinsonism, cerebral infarction is now considered an unusual cause of these symptoms. In drug-induced PD, akinesia is the most common sign, with resting tremor less commonly observed. Other characteristics of drug-induced parkinsonism include a history of drug ingestion known to interfere with central dopamine activity, short interval between symptom onset and...

Emergency Diagnosis and Management

Psychiatric complication can occur with dopaminergic therapy, including sleep disturbances, vivid nightmares, auditory and visual hallucinations, paranoia, and frank psychosis. The severity of psychiatric side effects, especially visual hallucinations, is related to the treatment dose and duration and can be improved by a drug holiday or a reduction in drug dosage. Psychotropes that are known to cause tardive dyskenesia, such as haloperidol, must be used cautiously in patients with PD due to an increased risk of this complication.

TABLE 2273 Viral Pathogens Causing Encephalitis in North America

Signs of meningeal irritation and increased intracranial pressure should be sought. Neurologic findings reflect the areas of involvement. A careful assessment of cognition is crucial. Sensorimotor deficits are not typical. Encephalitides may show special regional tropism. Herpes simplex virus (HSV) involves limbic structures of the temporal and frontal lobes, with prominent psychiatric features, memory disturbance, and aphasia. Some arboviruses predominantly affect the basal ganglia, causing choreoathetosis and parkinsonism. Involvement of the brainstem nuclei that control swallowing leads to the hydrophobic choking response characteristic of rabies encephalitis.1 I5

Implantable CNS Stimulators

The pathogenesis of Parkinson's disease is thought to involve unregulated activity of the subthalamic nucleus and globus pallidus intermedius. Neurophysiologists have shown that high-frequency stimulation can reversibly inactivate nerve conduction in these areas. 1112 High-frequency stimulation with implantable CNS devices are being used for suppression of parkinsonian and essential tremors. This neurostimulation is typically used if drug therapy has failed to control tremors. Neurostimulation is as efficient at controlling tremors as classic thalamotomy, but is less invasive.

LDoPA from Natural Sources

L-DOPA is present in certain food, and l-DOPA glycoside has been extracted from the broad bean (fava bean) Vicia faba (83). The fava bean is one of the best plant sources of l-DOPA clinical studies have shown that seed sprouts have antiParkinson's effects without any of the side effects seen from the pure synthetic form (74). Fava beans are a widely cultivated legume and commonly consumed in the Mediterranean region (37). l-DOPA was identified in the seedling, pods, and beans of broad bean (fava bean) initially by Guggenheim in the early 1930s (37,69,74). Fava bean ingestion correlated with a significant increase in levels of l-DOPA in plasma and with an improvement in motor performance (35). As discussed earlier, exogenously synthesized l-DOPA is not effective in all PD patients and has side effects (37). The mechanism of efficiency of the natural source of l-DOPA may be due to the amino acid milieu generated in broad fava beans that may favor the selective transport of l-DOPA across...

Treatments For Specific Forms Of Dystonia

DRD is associated with a deficiency of guanosine-5'-triphosphate (GTP) cyclohydrolase 1 or tyrosine hydroxylase activity in nigrostriatal terminals. Levodopa is the most appropriate treatment to restore the lack of dopamine. Most patients improve with low doses (< 500 mg day) of levodopa combined with a peripheral decarboxylase inhibitor. Rarely, higher dosages are required. Levodopa provides symptomatic relief that compensates for the causative metabolic defect and must be continued for life. Unlike Parkinson's disease, levodopa-related side effects such as nausea, constipation, orthostatic hypotension, confusion, and hallucinations are uncommon in DRD patients, and resolve with dose reduction. Fluctuations or dyskinesias similar to those occurring in Parkinson's disease are also observed in DRD, particularly when high doses of levodopa are prescribed, and usually resolve with dose reduction. Genetic testing for DRD allows for identification of patients who carry the

Catheter ablation of supraventricular arrhythmias

The therapeutic options for patients with supraventricular arrhythmias include pharmacologic treatment, arrhythmia surgery, and catheter ablation. The optimal management of an individual patient depends on many factors, including the type of arrhythmia, asscociated symptoms, frequency and duration of episodes, concomitant disease, and patient preference. With the exception of the Wolff-Parkinson-White syndrome, supraventricular arrhythmias are generally not life threatening. Thus, the inherent attractiveness of catheter ablation as a curative approach is tempered by the cost and potential complications associated with an invasive procedure. From the perspective of catheter ablation, supraventricular arrhythmias can be classified into atrial tachycardia, atrial flutter, atrial fibrillation, accessory pathways Wolff-Parkinson-White syndrome, and atrio-ventricular nodal re-entrant tachycardia (AVNRT). Catheter ablation of the atrioventricular junction is also used to control the...

An estimated 2 million cases of traumatic brain injury TBI

Occur in the United States every year, with around 500,000 sufficiently serious to require hospitalization. Additionally, a large number of cases of mild TBI remain unreported or undiagnosed each year. Therefore, TBI, with its estimated incidence of 100 per 100,000 persons, occurs more often than many of the better known diseases affecting the central nervous system tissue (e.g., Parkinson's disease, Alzheimer's disease, multiple sclerosis). Epidemiologically, TBI is most often associated with motor vehicle, bicycle, or pedestrian-vehicle accidents followed by falls and violence- and sports-related incidents, occuring primarily in people 15-24 years of age. Estimates for the lifetime cost of care for a severely injured person range from 600,000 to 1,875,000 and add up to a yearly cost of 9-10 billion for rehabilitation for new cases in the Unites States alone. Although the development of

Current and Future Controversies

The abortion issue remains among the most politically explosive and unresolved issues in bioethics. Provision of abortion services has endangered funding for other family planning services and endangered the lives of providers and consumers alike. Concerns of political conservatives and anti-abortion groups have affected policy debates as diverse as end of life decision-making in New York State and Federal regulation of embryonic stem cell research. In August of 2002, George Bush revealed his decision on stem cell research. Had it not been for the terrorist attacks that occurred shortly thereafter, stem cells might have been the defining issue of his presidency. Bush allowed future work with stem cell lines already produced, but his policy did not allow for the development of additional cell lines. By sitting on the fence, Bush did not satisfy either side in the debate. Anti-abortion forces were not happy that the existing cell lines, obtained from aborted fetuses, would still be...

Brain Mechanisms in Combined RBDExtrapyramidal Disorders

What brain mechanisms may be involved in subclinical and clinical RBD associated with various extrapyramidal disorders The pedunculopontine nucleus (PPN) is likely to be prominently involved in the disruption of the REM-atonia circuitry, for at least three reasons. First, there is a strong reciprocal connectivity between the PPN and the substantia nigra (Garcia-Rill, 1991), the main site of pathology accounting for the cardinal signs of PD (Koller, 1992). Second, the neuropathology of PD includes prominent neuronal loss within the PPN (Jellinger, 1992). The retrorubral nucleus is located near the substantia nigra, and appears to be implicated in the linked PD-RBD pathology (Lai and Siegel, 1990). The retrorubral nucleus projects to the caudate and putamen (extrapyramidal motor system) experimental lesions to the retrorubral nucleus in cats releases abnormal motor activity during both sleep and wakefulness, ranging from myoclonic twitches to rhythmic leg movements and locomotion (Lai...

Positron Emission Tomography Studies

Although secondary depressions have not been extensively studied using functional imaging techniques, PET studies have been conducted in patients with depression associated with stroke, Parkinson's disease, or Huntington's disease. A study of metabolic activity in patients with basal ganglia stroke demonstrated that patients with basal ganglia lesions not involving motor pathways (i.e., lesions of the head of the caudate, anterior internal capsule, or anterior or dorsal medial thalamus) had focal ipsilateral hypome-tabolism involving regions of frontal, temporal, or cingulate cortex. In contrast, patients with lesions of the motor pathways (putamen and posterior internal capsule) had widespread ipsilateral hypometabolism. When these patients with subcortical lesions were classified as having no mood disturbance, mania, or depression, patients with either depression or mania demonstrated hypometabolism in the temporal lobe. Patients with mania showed temporal hypometabo-lism in the...

Monoamine Oxidase Inhibitors

Secondary to the inhibition of monoamine oxidase (MAO) enzymes. There are two isoenzymes (i) MAO type A, which degrades mostly NE, epinephrine, and 5-HT, and (ii) MAO type B, which degrades mostly phenylethylamine, phentylamine, benzylamine, and phenylethanolamine. Tyramine and dopamine are nonselective substrates. The MAO inhibitors (MAOIs) can be classified according to the type of MAO inhibition they cause and whether the inhibition is reversible or irreversible. The available MAOIs in the United States are the hydrazine derivatives that are non-selective and have an irreversible action on the MAO enzyme. Moclobemide is a nonhydrazine MAO-A-selective and reversible compound, and deprenyl is useful in the treatment of Parkinson's disease because it increases the levels of dopamine in the CNS due to its MAO-B-selective effect in low doses. MAOIs have significant side effects and interactions. The increased availability of biogenic amines in the CNS causes an overstimulation with...

Muscle Afferent Reflexes

Disorders of Long-Loop Stretch Reflexes in Parkinson's Disease Normally, people can voluntarily suppress the long-loop component of the stretch reflex. In Parkinson's disease, however, patients appear to lose this ability. Regardless of the instructions given to them, stimulation of primary muscle spindle afferents produces a large response. In Huntington's disease, by contrast, there can be a complete loss of the long-loop stretch reflex. The relation between the basal ganglia and control of these reflexes remains unknown, but it probably involves its influence over the motor cortex. Recent research suggests that loss of the long-loop reflexes accounts for the jerky movements characteristic of Hunting-ton's disease.

Economic considerations

The cost of catheter ablation procedures compares favourably with that of arrhythmia surgery or lifelong antiarrhythmic treatment. In one US study, the cost of surgery in patients with Wolff-Parkinson-White syndrome was estimated to be 53 000, compared with 15 000 for catheter ablation.19 Another study, which compared the cost of medical management before catheter ablation with the cost of the procedure in patients with AVNRT, found total costs of 10. Jackman WM, Wang X, Friday KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med 1991 324 1605-11. 11. Calkins H, Sousa J, El-Atassi R, et al. Diagnosis and cure of the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardias during a single electrophysiology test. N Engl J Med 1991 324 1612-18.

Biochemical and Disease Control Outcomes with Low Dose Rate LDR Brachytherapy

Grimm et al. 14 reported the outcome of 125 patients treated between 1988 and 1990 with TPI using I-125 and followed for a median of 81 months. A PSA relapse in that report was defined as three consecutive PSA elevations above the nadir PSA level. Among patients defined as having low-risk disease (PSA < 10ng ml, Gleason score < 7, and clinical stage < T2b) the 10-year PSA relapse-free survival (RSF) outcome was 87 . Improved long-term outcomes were noted for both favorable- and intermediate-risk patients who were treated after the physicians' initial learning curve was achieved compared with the outcome for the initial patients treated at the center 43 . Blasko et al. 15 reported the outcome of 230 patients treated with Pd-103, with a median follow-up of 41 months. Most patients in this report had favorable risk features, whereas only approximately 30 and 20 , respectively, of the patients had Gleason scores > 6 and PSA levels > 10ng ml. The seven-year PSA RFS (with relapse...

Mouse Models Of Tauopathies

Erative disorders characterized by filamentous tau inclusions have been identified. These disorders, collectively termed tauopathies, include sporadic and familial frontotemporal dementia with parkinsonism linked to chromosome 17, progressive supranuclear palsy, and Pick's disease. In humans, six tau isoforms (three isoforms with three microtubule-binding repeats and three isoform with four microtubule-binding repeats) are generated by alternative splicing of the tau gene in adult brain. In rodents, there are three four-repeat isoforms. To model neurodegenerative tauo-pathy, investigators have developed transgenic mice expressing high levels of wild-type tau isoforms. Overexpression of either the shortest or the longest tau human isoform in the brain and spinal cord of transgenic mice using either the Thy1 or the prion protein promoter, respectively, resulted in an age-dependent phenotype characterized by insoluble, hy-perphosphorylated tau and intraneuronal inclusions composed of...

Review Of Existing Studies

Time production studies in this time span that have involved patients with either cerebellar lesions or Parkinson's disease (PD) are summarized in Table 19.1. The PD patients have been generally viewed as a model for studying basal ganglia dysfunction. Most of these studies have used a continuation task introduced by Wing and Kristofferson (1973). Trials begin with the presentation of a periodic signal, usually an auditory metronome. After an initial synchronization phase, the metronome is terminated and the participants are asked to continue tapping, attempting to separate each response by the interval specified by the metronome.

Reaction of Catechol OMethyltransferase

The steady-state kinetic studies show that the action of soluble COMT follows an ordered binding mechanism (fig. 15-7B). SAM binds first, followed by Mg2+ and then the methyl acceptor (Lotta et al., 1995). COMT is a drug target, primarily to depress its activity against l-DOPA, which is the leading therapeutic agent prescribed for Parkinson's Disease. Very potent, slow-binding inhibitors bind with Mg2+-dependence (Bonifacio et al., 2002). The most efficacious inhibitors can suppress the tissue activity of COMT by more than 75 when administered to mice.

Panicogenic Effects of Lactate

That systemic alkalosis caused vasoconstriction of cerebral vessels, which in turn induced cerebral ischemia, with an increase in the intracellular lactate -pyruvate ratio. Furthermore, infused lactate resulted in a rapid passive elevation in the lactate pyruvate ratio in localized brain regions outside the blood-brain barrier, such as the chemoreceptor zones. These two mechanisms lowered the intracellular pH in medullary chemoreceptors. In PD patients there is dysregulation (greater sensitivity to alterations in pH) in this region thus, a panic response is triggered. This theory predicts that panic could be triggered in any subject if medullary pH was changed sufficiently. Alternatively, panic attacks can be provoked by breathing only one or two deep breaths of 35 CO2. Hyperventilation and increased CO2 hypersensitivity have also been posited as an explanation for symptoms of PD. According to the model, elevated levels of CO2 lead to activation of the vagus nerve, which through the...

Nerve Cells And Memory

Procedural memory refers to the acquisition of skills, characterized by the ability to perform a specific task or habit. Such memories include, for instance, knowing how to ride a bike or more explicit knowledge of sequences or grammatical rules. Studies of amnesic patients have revealed that, although unable to explicitly remember past experiences, these patients can gradually acquire new perceptual, motor, or cognitive skills. These studies suggest that the acquisition of procedural knowledge is independent of the medial temporal lobe. Instead, procedural memory seems to depend heavily on corticostriatal systems, e.g., patients with Huntington's disease or Parkinson's disease may have difficulty in acquiring new motor skills without having any deficits in explicit memory. Functional imaging studies have suggested that both the motor cortex and the basal ganglia are involved in procedural learning. Interestingly, the cerebellum also appears to be involved in procedural memories, as...

Pk Differences Between Males And Females

Although the FDA mandated in 1998 that new drug applications must include data on safety and effectiveness by gender, a 2001 U.S. General Accounting Office investigation revealed that over one-third of the FDA-approved drugs in the preceding two years failed to provide such gender-specific information (36). Although women may be increasingly represented in clinical trials, failure to analyze gender-related differences in PK, side-effects, and efficacy limits the generalizability of such data to women. The importance of studying gender-based differences in PK, PD, and efficacy safety is demonstrated by the increasing data on gender-related variation in basic processes involved in linking drug administration to clinical response. Gender-based differences in the major processes that contribute to interindividual PK variability (bioavailabil-ity, distribution, metabolism, and elimination) are theorized to stem from variations between men and women in factors such as body weight (BW),...

Exogenous Gene Expression

The overexpression of developmentally important genes is currently being used as a means of achieving directed differentiation. Several regulatory genes have been introduced in various mouse experiments. Hepatocyte nuclear factor 3 (HNF3) transcription factors -a and -p induced differentiation of mouse ES cells toward the early endodermal lineage. Ectopic expression of HoxB4, a homeotic selector gene, has enabled the use of mouse ES cells for the repopulation of myeloid and lymphoid lineages in immune-deficient mice. Similarly, the expression of the nuclear receptor related-1 (Nurr1) transcription factor generated a highly enriched population of midbrain neural stem cells that have been shown to ameliorate the phenotype of a mouse model of Parkinson's disease.

Applications of Microarray Analysis

Microarrays are new enough that their applications are still being developed. Microarray expression analysis can be used to help study complex, multigenic diseases such as Parkinson's disease (PD). The great challenge in understanding the genetics of such disorders is identifying susceptibility genes, which are genes that increase a person's risk of developing the dis-linkage analysis exami- ease. Frequently, the first step in discovering a susceptibility gene is linkage analysis. This technique can identify regions of a chromosome that harbor such a gene, but the regions that are identified are frequently very disease genes large, containing hundreds of genes. Screening through all of these genes Brain tissue can be collected through anatomical donations from patients with Parkinson's disease and from unaffected individuals, for example. Regions of the brain that are especially affected in Parkinson's patients can be compared to the same regions from unaffected individuals. Genes...

The Nigrostriatal Pathway

It projects from the substantia nigra to the caudate and putamen, and its effects are mediated by the neurotransmitter dopamine. In essence, dopamine facilitates the motor loop in two ways. First, it provides tonic, excitatory drive to the direct (stimulatory) pathway through the neostriatum, and, second, it inhibits the indirect (inhibitory) pathway. The additive effects of this pathway provide an excitatory bias to the basal ganglia loop and allow the overall level of cortical activity to funnel through the motor loop and provide positive feedback to motor areas. Yurek DM, Sladek JR, Jr. Dopamine cell replacement Parkinson's disease. Annu Rev Neurosci 1990 13 415-440. FIGURE 5 Effects of Parkinson's disease, Huntington's chorea, and hemiballismus on output of the basal ganglia motor loop. (A) In the hypokinetic condition of Parkinson's disease, cells of the substantia nigra degenerate. In the absence of the nigrostriatal pathway, there is increased inhibitory control of...

Cellular Circuits Of The Cerebellum

FIGURE 1 Comparison of connections of the basal ganglia (A) and cerebellum (B). The basal ganglia and the cerebellum have many commonalties and influence motor function in similar ways. Excitatory input from broad areas of the cerebral cortex drive spiney neurons in the neostriatal region of the basal ganglia (A) and also relay nuclei in the pons, which then excite Purkinje cells of the cerebellar cortex (B). Both spiney neurons and Purkinje cells release y-aminobutyric acid (GABA) to inhibit relay neurons in the globus pallidus substantia nigra (A) or in the deep cerebellar nuclei (B). In turn, these relay nuclei project to the thalamus, where they modulate thalamic inputs to specific motor areas of the cerebral cortex.

Huntingtons Disease

The rationale for intrastriatal grafting in HD patients in many ways is similar to that for, PD but the methodological challenges could be greater due to the more complex neurophysiological substrate. Nevertheless, extensive efforts are under way to establish a series of large-scale clinical trials, and the preliminary data are currently under evaluation. More promising are the studies analyzing the benefits of cell grafts in primate models of HD. Like in PD, much hope is invested in developing neuronal cells that can be manipulated in vitro to promote their in vivo functional integration into the degenerating striatum of HD patients.

Brain Derived Neurotrophic Factor

BDNF has been proposed to have an autocrine effect on dopaminergic neurons that express abundant trkB, and if these results are confirmed in humans, new hypotheses may be formulated about the mechanisms of disease in parkinsonism. Supporting this theory, several studies showed reduced BDNF protein in the substantia nigra of PD patients. In this context, BDNF treatments (similar to GDNF, discussed later) pre- and posttransplantation may serve a dual purpose stimulate the growth of a functional dopaminergic population within the graft and promote the regeneration of dopaminergic pathways in PD.

Glial Derived Neurotrophic Factor

In general, GDNF has similar or even enhanced trophic functions on dopaminergic neurons and their precursors. In vivo, GDNF was also shown to be relatively potent in animal models of dopaminergic protection or regeneration, but human clinical trials have not been so encouraging. Nonetheless, its potential use in PD has made GDNF the prime candidate for NTF treatments in association with fetal mesencepha-lic transplants of dopaminergic neurons. GDNF, a related member of the TGF-b family, was first identified and characterized in 1993 by Lin et al. From the beginning, it was evident that GDNF has a potent but specific-selective activity on dopaminergic neurons, inducing their differentiation in the absence of overt neuroglial proliferation. Shortly after, in vivo studies demonstrated that GDNF injected into the substantia nigra produced a significant decrease in the motor deficits associated with 6-OHDA lesioning in rats. When GDNF was injected in developing or mature mesencephalic...

Neuronal Cell Lines

One of the most studied neuronal cells is the NT2 line derived from a human teratocarcinoma that can differentiate in vitro, following treatment with retinoic acid, into cells with a mature neuronal phenotype known as hNT (or the older designation NT2N) cells. In vivo, grafted hNT cells aquired a mature phenotype (including growth of neuritic processes and synaptic contacts) and could survive for more than a year in the mouse CNS. Interestingly, later studies showed that in vitro treatments of NT2 cells are not critical to their in vivo differentiation. One of the most convincing applications of using these cells in transplantation comes from experiments using a rat CNS ischemic model, in which hNT cells induced a more robust recovery than fetal rat striatal grafts. In the rat 6-OHDA parkinsonian model, hNT cells grafted into the striatum and substantia nigra were shown to survive in the host parenchyma and generate TH immunoreactivity when pretreated with LiCl. When made for human...

Polymer Encapsulation

As discussed earlier, one of the major challenges to graft survival in the CNS is modulation of the host immune response. Most neuroglial cells (including in vitro adapted lines like PC12) could, at least theoretically, benefit from protection against the host immune response and rejection by using an encapsulating physical barrier. Though many grafted cells can survive, the connectivity between the host and implanted neurons is limited and a significant number of donor cells die. In an early study by Jaeger et al., dopaminergic cell lines survived within a semipermeable membrane. Shortly after, Winn et al. proposed that polymer-encapsulated cells may provide a means of neurotransmitter and growth factor delivery in vivo. This approach was proposed early on as an alternative treatment in PD, and its feasibility was demonstrated in animal models. In MPTP monkeys that showed clinical improvement after grafting, encapsulated cell implants were shown to be able to uptake and metabolize...

Suggested Reading

Implantation of human fetal ventral mesencephalon to the right caudate nucleus in advanced Parkinson's disease. Arch. Neurol. 48(8), 822-827. Kordower, J. H., et al. (1995). Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease see comments . N. Engl. J. Med. 332(17), 1118-1124. Mendez, I., et al. (2000). Enhancement of survival of stored dopaminergic cells and promotion of graft survival by derived neurotrophic factor in patients with Parkinson's disease. Report of two cases and technical considerations. J. Neurosurg. 92(5), 863-869.

SET and the PD Timing Deficits

The encode-decode design combined with the ON-OFF method of determining whether performance is DA dependent has revealed two timing deficits in PD patients with distinct, well-documented psychophysical profiles. Those findings were novel and forced a rethinking of the theoretical account that has framed this research, i.e., the classical temporal information-processing model based on the SET framework, which is a largely linear stochastic system described by Gibbon et al. (1984).

Assessment of Motor and Sensory Functions

Neurological examination of motor functioning assesses the functional integrity of neurons in the cerebral cortex as well as their connections with subcortical, brain stem, cerebellar, and spinal cord pathways and the effector muscles that produce observable actions. Dysfunction in the motor cortex (upper motor neurons) results in weakness and spasticity of the limbs that are contralateral (i.e., on the opposite side of the body) to the site of the lesion. Basal ganglia dysfunction alters muscle tone and speed of response, causing bradykinesia (i.e., slowness of movement). Midbrain and brain stem structures control the coordination of cranial nerve functions such as conjugate eye movement, articulation of speech, and swallowing. Impaired cerebellar functioning results in ataxia of gait and tremulous trunk, head, and outstretched extremities. Tremors resulting from cerebellar and vestibular dysfunctions appear during actions and increase upon intention, whereas the tremor associated...

Diagnostic Classification

Fewer studies have examined the ability of functional imaging to differentiate AD from other dementias. Similar patterns of temporoparietal hypome-tabolism hypoperfusion have been reported in Parkinson's disease with dementia (PDD) (49-51). The overlap between AD and PDD may reflect the high incidence of Alzheimer's pathology found in patients with PDD (52). Two recent studies (53-54) demonstrated a distinct pattern of reduced occipital glucose metabolism in patients suspected to have dementia with Lewy bodies (DLB) as compared with AD. Parkinson's disease without dementia shows a metabolic pattern similar to normals (55).

Modeling the Effects of PD

The curvilinear psychophysics of the pacemaker-accumulator model gives rise to the finding relevant to the duration-dependent timing effects stemming from PD. As can be seen in Figure 20.3, the high-gain-high-decay function crosses the low-gain-low-decay function. Consider a timing task where there are two target intervals, the durations of which fall on either side of the crossover point between the two functions. Now consider the case where the low-gain-low-decay function represents the psychophysical function associated with encoding time intervals in the OFF-medication state by PD patients, and the high-gain-high-decay function is associated with PD patients' decoding temporal memories in the OFF state. Such a mismatch between encoding and decoding will yield migration of mean production times because the memory of the shorter interval is now compared to a relatively slower clock, while the longer interval is compared to a relatively faster clock. The association of different...

Apoptosis May Have Important Contributions To Neurodegenerative Disorders In Humans

It has been discovered that the degeneration of neurons in ALS is a form of apoptosis (Fig. 7). Vulnerable brain and spinal cord regions in ALS (Table I) have abnormalities in the balance of Bcl-2, Bax, and Bak proteins and abnormalities in their interactions (Table IV). However, the initial molecular pathology and upstream signals for motor neurons to engage PCD mechanisms are not known, although we suspect DNA damage. Furthermore, it is still unknown whether the neuronal degeneration in other age-related neurological disorders such as AD, Parkinson's disease, and Huntington's disease is related causally to an abnormal activation of PCD pathways in selectively vulnerable neurons.

Association Of Rapid Eye Movement Sleep Behavior Disorder With Specific Human Leukocyte Antigen Haplotypes

Arnulf, I., Bonnet, A.-M., Damier, P., Bejjani, B.-P., Seilhean, D., Derenne, J.-P., and Agid, Y. (2000). Hallucinations, REM sleep, and Parkinson's disease a medical hypothesis. Neurology 55 281-288. Boeve, B. F Silber, M. H Petersen, R. C., Kokmen, E., Parisi, J. E., and Olson, E. J. (1997). REM sleep behavior disorder and degenerative dementia with or without parkinsonism A syndrome predictive of Lewy body disease Neurology 48 A358-A359. Cornelia, C. L., Tanner, C. M., and Ristanovic, R. K. (1993). Polysomnographic sleep measures in Parkinson's disease patients with treatment-induced hallucinations. Ann. Neurol. 34 710-714. Datta, S., Dossi, R. C., Pare, D., Oakson, G., and Steriade, M. (1991). Substantia nigra reticulata neurons during sleep-waking states Relation with ponto-geniculo-occipital waves. Brain Res. 566 344-347. Eisensehr, I., Linke, R., Noachtar, S., Schwarz, J., Gildehaus, F. J., and Tatsch, K. (2000). Reduced striatal dopamine transporters in idiopathic rapid eye...

DBS in the STn of DADepleted PD Patients Corrects Migration

The finding of separable storage and retrieval mnemonic deficits restricted in the temporal domain in PD was followed up by a new set of experiments asking whether distinct neural pathways underlie those deficits. To this end, we applied the same encode-decode design in a series of studies testing PD patients OFF levodopa undergoing deep brain stimulation (DBS) either in the subthalamic nucleus (STn) or the pallidum. The effect of DBS is reversible, and the stimulation parameters (principally site and voltage) can be varied to achieve the optimal therapeutic result (Benabid et al., 1991, 1998). Moreover, the reversibility of DBS means that patients' cognitive performance can be assessed both with (ON) and without (OFF) DBS. This in turn presents the possibility of identifying specific patterns of impairment, including cognitive ones, associated with the stimulated basal ganglia substructures. DBS in the STn, which alleviates parkinsonism (akinesia, bradykinesia) quite dramatically,...

Effects of PD Stimulation on Distorted Temporal Memory

Our findings, in accordance with other recent cognitive research, support the view of the models' inadequacy to explain cognitive deficits seen in PD and the way they are affected by stimulation (Pillon, 2002), consistent with recent studies suggesting that functional surgery in PD could influence cognitive and affective processes (Malapani et al., submitted). The cognitive and behavioral outcome might depend on the exact location of the stimulation (Lombardi et al., 2000), suggesting that it may be crucial to evaluate changes between off and on stimulation on more specific behavioral and cognitive research tools (Ardouin et al., 1999 Jahanashi et al., 2000 Pillon et al., 2000 Saint-Cyr et al., 2000). The model predicts that high-frequency stimulation in the STn would mimic the effects of DA replacement therapy overall (Bejjani et al., 1997 Limousin et al., 1995a, 1995b), which is not the case here (the encode deficit is alleviated by levodopa, but not by STn DBS). Moreover, if the...

Mechanisms of Action of DBS

A second important consideration relates to the mechanism of DBS in the parkinsonian brain that still remains unknown (Benabid et al., 2002). With the advancing use of DBS as the primary surgical tool not only in PD, but also in other basal ganglia diseases (i.e., dystonia, Huntington's disease) (Lenz et al., 1998), there is increasing interest in the mechanisms underlying its effects from both clinicians and researchers. The STn stimulation is regarded as essentially correcting (attenuating) the abnormally high neural activity of this nucleus associated with the parkinsonian state (Dostrovsky and Lozano, 2002 Limousin et al., 1998). One could say that DBS induces a functional inhibition of a nucleus it targets, as its effects mimic what is functionally obtained when the nucleus is destroyed. Yet there are data suggesting that rather than inhibition, the stimulated site is activated (Benazzouz and Hallett, 2000 Vitek, 2002).

Virtual Reality in Rehabilitation

Physical rehabilitation has obvious VR applications, but VR can also reach people with specific attention and movement disorders. Paradoxical walking or the diminished ability to walk voluntarily is a condition suffered by patients with Parkinson's disease. The difficulty of walking can be overcome if only stationary objects can be placed along the walk paths. VEs can be used in presenting the virtual images to the nondominant eye and scrolling the objects toward the subject along a virtual ground plane. Perception of the objects stabilizes appropriately as the subject walks over them. The VE can create images of such stationary objects with the use of special glasses and can superimpose these images onto the real environment, enabling people with paradoxical walking disorder to walk again (Weghorst, 1997). Attention deficit disorder and visual impairments are other domains in which VR rehabilitation is believed to be effective as the VR provides users with visual cues of objects in...

Mitochondrial Genetics And Animal Modeling

Cytoplasmic-based traits in domestic animals have included growth, reproduction, and lactation. In addition, mitochondrial restriction fragment-length polymorphisms (RFLPs) were identified and associated with specific lactational characteristics in a number of dairy cattle lineages. The matrilineal inheritance of mammalian mtDNA has also been used to advantage in studies exploring the timing and geography of domestication events, as recently demonstrated for horses, where multiple domestication events appear to have occurred in the Eurasian steppe. 2 In addition, metabolic and cellular abnormalities in humans were correlated to mutations arising exclusively within the mitochondrial genome. Indeed, various diseases have been associated with mtDNA point mutations, deletions, and duplications (e.g., diabetes mellitus, myocardiopathy, and retinitis pigmentosa) as well as age-associated changes in the functional integrity of mitochondria (as seen in Parkinson's, Alzheimer's, and...

Directed differentiation of cES cells induced by coculture

Neuroectodermal categories (dorsal and ventral) is produced by cES cells, as well as by mES cells, in vitro (24). Thus, it is inferred that in the absence of exogenous patterning signals, SDlA-treated cES cells generate naive precursors having the potential to differentiate into the full dorsal-ventral range of neuroectodermal derivatives, (24). The implications and relevance of this differentiation system for neurodegenerative diseases (such as Parkinson's disease, and retinitis pigmentosa) are highlighted.

Uses Of Stem Cells In Therapeutic Applications

The most obvious use of stem cells is in replacement therapies where compromised tissues are replaced with functional equivalents. This had been envisioned as the goal in several disease processes, most commonly in diseases where a specific known cell type is compromised, such as diabetes, spinal cord injury, myocardial infarctions, Parkinson's disease (PD), and some blood cancers reviewed in (Daley et al., 2003 Shizuru et al., 2005). While initial impetus for the field of therapeutic transplantation was given by bone marrow transplantations for blood-related malignancies (Shizuru et al., 2005), it is now being contemplated for several of the somatic stem cells including NSCs and MSCs and, in the longer term, ESCs as well when the processes of uncontrolled differentiation and tumorigenesis in these latter cells is understood better. Amelioration of disease phenotypes in animal models have been attempted with various stem cells including hESCs, NSCs, HSCs, and MSCs (Kim et al., 2002...

Gas6 and Other Vitamin KRequiring Gla Proteins

A Gla protein that is associated with the central nervous system, rather than with liver or bone, was discovered in 1993. In tissue culture models it had the properties of a growth arrest-specific (GAS) cell-signalling gene product. It acts as a ligand for a number of receptor protein kinases it potentiates the growth of vascular smooth muscle cells, Schwann cells, and the neurons that synthesize gonadotropin-releasing hormones and it can prevent apoptotic cell death. Knockout mice in which three Gas6 receptors are mutated had major neurological and spermatogenic abnormalities. There is interest in potential roles for Gas6 in Alzheimer's disease and Parkinson's disease. Clearly, these properties and emerging roles have helped to confirm the growing suspicion that vitamin K-dependent Gla proteins possess key functions beyond blood clotting and even bone remodelling. Gas6 has a MW of 75,000 with 11 or 12 Gla residues, and its structure is partly homologous with protein S.

Brief clinical history

Clinical xenotransplantation began again with a heart transplant from a baboon to 'Baby Fae' in 1985. Since then there have been two baboon-ro-human liver transplants, a series of islet transplants from fetal pigs to humans, transplantation of fetal pig neural cells to patients with Parkinson disease, and at least one bone marrow transplant from a baboon to a patient with the acquired immune deficiency syndrome (AIDS). In addition, livers from pigs and other species have been used to maintain patients with fulminant hepatic failure by intermittent ex vivo perfusion of an animal organ, and there has been at least one effort at 'bridge' transplantation in which a pig liver was transplanted to a critically ill human patient as a first step toward subsequent replacement by an allogeneic organ. At this point, however, no clinically successful xenotransplant has been reported in the sense of achieving patient survival for one year based on the ongoing physiologic function of the...

Macrostructure And Connections Of The Basal Ganglia

Model Process Photosyntese

Despite the fact that they share the same name, the medial and lateral globus pallidus differ in terms of connectivity and function. The medial globus pallidus is in fact frequently considered a homologous structure to the substantia nigra pars reticulata. Even though the putamen and globus pallidus are adjacent and can be referred to with a collective label, they are neither structurally nor functionally homologous. The internal structures of the caudate nucleus and the putamen are quite similar. Although their connectivity is not overlapping, it can be considered to be parallel this parallelism of connections will become evident when we discuss the connectivity of the basal ganglia. Collectively, the caudate nucleus and the putamen are referred to as the neostriatum or, often, as just the striatum. Figure 4 Diagram showing the relationship between components of basal ganglia loops. As conceptualized by Alexander et al., both anterior and posterior...

Prevalence of Specific Dementia Types

Enlarged Brain Ventricles Dementia

Although not typically resulting in symptom reversal. Among the more common potentially reversible causes are those due to prescription and nonprescription drug toxicity, metabolic disorder, brain tumors, subdural hematoma (a collection of blood under the outermost meningeal covering of the brain), and depression. The more common dementia types that are presently irreversible include Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, Huntington's disease, frontotemporal dementias, vascular dementia, and traumatic brain injury. Lewy body disease has only relatively recently been recognized as a significant cause of dementia, and earlier autopsy studies typically did not include it. Lewy bodies are microscopic intracellular abnormalities seen in the brain stem structures of patients with Parkinson's disease but are also found distributed Other causes, including Huntington's disease, Parkinson's disease, corticobasal degeneration (all considered among the...

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