What is Parkinsons 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. More here...

The ParkinsonsReversing Breakthrough Summary


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Highly Recommended

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American Parkinson Disease Association

National support group that works to find the cure for Parkinson's disease and to alleviate the suffering of its patients by subsidizing information and referral centers and providing funds for research. The association offers counseling services to patients and their families and maintains information and referral centers. Founded in 1961, the association publishes a quarterly newsletter, an annual report, and a wide variety of informational pamphlets and booklets. For address, see Appendix I.

Parkinson Support Groups of America A

National organization for members are Parkinson's disease self-help groups. The group provides encouragement, companionship, physical therapy, and counseling and offers programs and activities to help people with parkinson's improve the quality of their lives. Members define the needs of support groups and their members, makes recommendations, and supplies resources necessary for and encourages research into the cause and treatment of parkinson's disease.

Structural Alteration of UCHL1 in PD

UCH-L1 is one of the most abundant proteins in the brain (1-2 of the soluble protein in neurons), where it catalyzes the hydrolysis of C-terminal ubiq-uityl esters. This activity is presumed to be critical for cytoplasmic protein degradation and results in the recycling of free Ub during the degradation of polyubiquitinated proteins in the proteasome (2,13). As with Ub, UCH-L1 is a constituent of cellular aggregates (e.g., Lewy bodies) that are hallmarks of neurodegenerative diseases such as PD (14). The UCH-L1 gene was first linked to PD upon identification of an autosomal dominant point mutation (I93M) that was found in two siblings of a PD-affected family, and this gene has been implicated in the development of an inherited form of PD (15). Since the I93M mutation decreases the hydrolytic activity of UCH-L1 in vitro (to 55 of wild-type UCH-L1), this form of PD was proposed to result from a partial loss of UCH-L1 hydrolytic function. However, several lines of evidence suggest that...

Parkinsons Disease and Other Age Related Neurodegenerative Diseases

Parkinson's disease is another age-related neurodegenerative disease commonly seen in older people. Indeed, Parkinson's disease is the second most common neurodegenerative disease, affecting about 1 million Americans over the age of 55. It is also due to degeneration of neurons, but in this case to neurons in a specific midbrain nucleus that innervates a large part of the basal ganglia complex. The basal ganglia are concerned with the initiation and execution of movement. Thus, patients with Parkinson's disease show specific motor deficits. Initially the disease is marked by a rhythmic tremor of the limbs at rest, but then it progresses to a rigidity of limb muscles. Eventually, Parkinson's patients have difficulty initiating movements. They tend to shuffle as they walk and have a mask-like facial expression. Parkinson's disease sufferers can also develop a dementia. The neurons that die in Parkinson's disease release the neuromodulator dopamine in the brain, and a deficiency of...

United Parkinson Foundation 321

United Parkinson Foundation This national support group for patients, family members, and medical personnel publishes reliable information about symptoms, medication, and therapy that is helpful to those with Parkinson's disease and related disorders. The group also supports scientific research, helps patients, and family through medical referrals, education, and other means. Founded in 1963, the group sponsors eight conferences a year. its publications include the quarterly newsletter United Parkinson Foundation Newsletter Patient Experience, One Step at A Time, and Your Questions Answered the foundation also distributes an exercise tape and book. For address, see Appendix i.

Distinguishing Essential Tremor from Parkinson Disease

The prognosis and treatment of tremor depend on careful diagnosis. ET is a monosymptomatic disorder that progresses insidiously over years to decades, if at all. In contrast, PD is a progressive neurodegenerative disorder. Although tremor is the most common presenting symptom of PD, up to one-third of people with PD have no tremor. Distinguishing ET from PD can be accomplished by considering a few clinical characteristics (Table 14.2). During history taking, the physician should determine the patients age at onset, duration of symptoms, part(s) of the body affected by tremor, medications taken, family history, and response of the tremor to alcohol. In preparation for deciding on therapy and assessing its results, the physician needs to know the effect of tremor on the activities of daily living and whether it is a source of psychological distress, primarily embarrassment. Tremor 217 Table 14.2. Parkinson Disease versus Essential Tremor

The Treatment of Parkinson Disease

Many of the principles suggested for the treatment of ET also apply to PD. Since the tremor of PD often attenuates with movement, it tends to cause little functional impairment but can be a source of embarrassment. Generally, the other features of PD, notably bradykinesia, dictate the need for treatment based on the patients functional status. Furthermore, antiparkinsonian medications often have little effect on tremor. Nevertheless, there is often some, albeit modest, improvement with anticholinergics, levodopa, aman-tadine, or dopamine agonists. A full discussion of the treatment of PD is not practical here and is given in the references. A small percentage of people with PD have a disabling tremor that no longer appears exclusively at rest but persists with maintenance of posture and movement, significantly affecting functioning. Sometimes the medications used for ET are helpful in this situation, but when they are not, these patients are candidates for thalamotomy or DBS of the...

Oxidative Modifications and Reduction of UCHL1 Hydrolase Activity in PD

Oxidative stress is another important factor that has been implicated in the pathogenesis of a number of age-related neurodegenerative diseases, including PD and AD. UCH-L1 is a member of the papain-like cysteine protease family, having conserved Cys and His residues within the active site. Certain cysteine proteases are known targets for covalent modification during cellular oxidative stress (32), and several lines of evidence implicate this phenomenon in sporadic PD (33). One of the endogenous factors that is toxic to neurons during oxidative stress is 4-hydroxynonenal (HNE), an aldehyde product of fatty acid peroxidation (34). HNE can induce neuronal death and is thought to form covalent cross-links with proteins via Michael addition to Cys, His, and Lys residues, thus altering the function of cysteine proteases. HNE-modified proteins have been detected in substantia nigra neurons and in Lewy bodies in sporadic PD (35).

Parkin In The Genetics Of Parkinsons Disease

Result in misfolding or excessive production leading to proteolytic stress (22). These observations and implications to PD are discussed in detail in Chapter 12. Parkin, on the other hand, is more directly related to the UPS. Parkin functions as an E2-dependent E3 ubiquitin ligase, catalyzing the addition of ubiquitin molecules to specific substrate molecules (23-25). Mutations in parkin have been linked to an autosomal recessive form of juvenile parkinsonism (AR-JP), a distinct clinical entity from sporadic PD in spite of overlapping clinical symptoms (15,26). An early onset form of PD, AR-JP is characterized by the selective loss of dopaminergic neurons in the substantia nigra and locus coerulus, usually with the absence of Lewy bodies (11,27,28). While sporadic PD and AR-JP have common characteristics such as dystonia, sufficient response to levodopa, lack of dementia and classic parkinsonism symptoms, the two forms can be separated based on sleep benefit for parkinsonian symptoms,...

Parkinsons Disease

Though tremor and other problems with movement are the main features of Parkinson's disease, one-third to one-half of the one million Americans with Parkinson's also have significant cognitive and memory problems. Parkinson's disease, which is most common in people over the age of fifty, involves the loss of neurons in a brain structure called the substantia nigra, which produces dopamine, a chemical messenger that controls movement and helps you form memories. Patients with Parkinson's disease frequently exhibit deficits on tasks of visuospatial analysis and construction (such as assembling puzzles and designs). A small subset of patients develop global dementia with severe deficits in multiple cognitive domains, including memory.

Parkin In Pd

Ubiquitin-positive inclusions in neuropils have been reported in some cases (11,65,67). Although somewhat controversial, some groups have shown that Lewy bodies in sporadic PD patients stain positive for parkin, suggesting that Lewy bodies could isolate parkin from its normal function in the cell, implicating a role for functional parkin in the formation of these characteristic protein inclusions (68,69). This observation is challenged by a report that does not observe co-localization of parkin with a-synuclein in Lewy bodies in a-synucleinopathies, using different antibodies to parkin (60). There is evidence in cell cultures that diminished cellular proteasomal activity results in an accumulation of over expressed parkin in large non-toxic cytoplasmic aggresome-like structures (71,72). Compartmentalization into these structures would preclude parkin from its normal enzymatic activity, resulting in the accumulation of substrates and cell death by the mechanism described above. It is...

Parkinsons Dementia

Parkinson's disease is associated with a loss of striatal dopaminergic neurons, particularly in the pars compacta region of the substantia nigra. Tremor is the best recognized symptom and is present in approximately half of individuals with PD (Martin et al., 1983). Often tremor begins unilaterally, increasing with stress and disappearing in sleep. Other early symptoms include aching, paresthesias, and numbness and tingling on one side of the body that ultimately spread to the other side. Other classic motor symptoms are rigidity, slowness of movement, and alterations in posture. Not all individuals with PD develop dementia, and prevalence estimates vary. Marttila and Rinne (1976), in one of the most comprehensive studies of prevalence, reported it to be 29 . Other investigators have reported similar estimates of dementia prevalence (Rajput and Rozdilsky, 1975 Mindham, Ahmed, and Clough, 1982 Huber, Shuttleworth, and Christy, 1989). Widely debated is the cause of the dementia, with...

Is Aging Of The Brain A Disease

A number of other age-related degenerative diseases such as Parkinson's disease and age-related macular degeneration can occur as people age. What causes these diseases How might we combat them and what types of therapies are possible Here I shall use as a model an inherited retinal degeneration, called retinitis pigmentosa, which typically attacks people in their twenties and progresses until complete blindness ensues by age 60 or so. It might be the best-understood neurodegenerative disease at the moment, and therapies for its cure, at least in animals, look promising.

Retinitis Pigmentosa A Model Neurodegenerative Disease

This form of macular degeneration, then, has characteristics of other neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases in which excess accumulation of protein, either extracellularly or intracellularly, is the defining feature. However, for most cases of AMD, the link with genetics is tenuous. At present, there are no animal models of the disease, because relatively few animals have a fovea like ours. Higher primates, some birds, reptiles, and fish do, although the foveas of these latter animals are somewhat different. Thus, we can do relatively little for most cases of AMD at present and it severely compromises the quality of life of those who suffer from it. The same is true of those who become deaf in old age. They, too, can become quite isolated from their fellow humans. The lesson here is that when seeking therapies for a disease, it is critical to know what specific form of the disease you are dealing with. A therapy might be very effective...

Neurogenesis and Birdsong

Some brain cell transplantation experiments have been carried out in attempts to intervene in Parkinson's disease, and limited success has been reported. In Parkinson's disease, there is a depletion primarily of the cells that release the neuromodulator dopamine (see Chapter 4). The cells transplanted into the brain appear to secrete dopamine and help in that way. The transplanted cells appear to work, at least for a while, although side effects are often a problem. There is no evidence that the transplanted cells incorporate into the circuitry of the brain or replace the dopami-nergic neurons that have died in Parkinson's disease. I shall discuss Parkinson's disease further in the next chapter.

Environment and Neurodegenerative Diseases

The emphasis in the discussion so far has been on the role of predisposing genes in the causes of age-related neurodegenerative diseases. But many cases of these diseases cannot be linked to a genetic factor, so it is believed that environmental factors must be the precipitating cause. Only about 50 percent of the cases of Alzheimer's disease can be linked to one of the five predisposing genes for it. The cause of the other 50 percent is very much up in the air. The genetic links to Parkinson's disease are even weaker. Clearly, brain injury or trauma can lead to excessive brain cell loss and people who have had such injury can show Alzheimer's-like symptoms. People prone to brain injury, like prizefighters, can develop these symptoms and in such cases are described as punch-drunk. Suffering from a prolonged high fever also can cause substantial neuronal death and result in an Alzheimer's-like condition. Such brain cell death might not be distributed evenly throughout the brain, but...

The Etiology of Major Depression

One-quarter of patients hospitalized for acute stroke develop major depression in the weeks after their cerebrovascular accident. These poststroke depressions are more common with left frontal (cortical or subcortical) lesions, and few remit, if untreated, at six-month follow-up, even if there has been significant improvement in the neurologic deficits. Typical major depressions occur in Parkinson disease, human immunodeficiency virus (HIV) infection, and Huntington disease (in which mania can also be seen). All of these symptomatic depressions respond well to antidepressant medication.

The Plasticity Of Proteasome In The

Proteasome plasticity is a relative new concept, and may explain some of the current controversies associated with the role of the proteasome in neurode-generative disorders. In AD, HD, and Parkinson's disease (PD), neurodegeneration likely requires decades. It is unlikely that the proteasome contributes to neurodegeneration in these disorders by undergoing permanent and dramatic decreases in function. Far more likely, in each of these conditions there is a short-term proteasome inhibition that is followed by intracellular changes that allow the cells to recover proteasome-mediated protein degradation in the short-term. Changes in proteasome expression, proteasome complex function, and proteasome localization are very likely to play a direct role in mediating these beneficial short-term adaptations. However, the long-term and cumulative effects of proteasome alterations may ultimately result in cytotoxicity and neurodegeneration.

Commonality of Aggregated Protein Conformations in Neurodegenerative Diseases

Many neurodegenerative diseases and to some extent physiological ageing are characterized by conformational changes and aggregation of specific proteins, resulting in intra or extra neuronal accumulation of amyloid fibrils . Mutations in such aggregate-prone proteins cause inherited forms of disease, as is the case in Alzheimer's, Parkinson's, Huntington's and prion diseases. A common feature of neurodegenerative disorders characterized by protein aggregation is that the aggregate-prone proteins, despite the fact that they are unrelated in size or amino-acid sequence, are detergent-insoluble, and have high P-sheet content and a cross beta structure. These common biochemical features suggest the possibility of a conserved mechanism of pathogenesis in these otherwise phenotypically diverse disorders. The commonality of such aggregate-prone proteins is further supported by the finding that a single antibody can recognize a common conformational epitope displayed by aggregated AP,...

Brain tissue transplants

Medulla can be quickly fatal damage to the reticular formation can result in coma. Likewise, damage to a specific cranial nerve can have particular effects for example, damage to the seventh (facial) cranial nerve will result in facial palsy. Degeneration of the substantia nigra in the midbrain is linked to the development of Parkinson's disease. Rat studies have shown that grafted brain tissue can become effective parts of the animal's brain and can even improve age-related learning impairments. Scientists have also shown improvement in some Parkinson's disease patients after transplanting fetal brain cells to produce dopamine, a key brain chemical lacking in the disease. In 1992, a Swedish team from the University of Lund performed a fetal tissue transplant on two Americans who had destroyed their substantia nigra after injecting themselves with tainted synthetic heroin. For seven years the two had not been able to use their voluntary muscles after receiving brain tissue from more...

Search for the Toxic Species The Protofibril Hypothesis

As the extracellular or intracellular deposits of neurodegeneration-related proteins are the obvious, dramatic hallmarks of the aggregation process, for a long time the idea had been that such end-products of the aggregation process or, at the very least, the fibrillar forms prior to their incorporation in the deposits, may be the toxic species (23). The possibility that oligomeric species and not the fibril itself could be pathogenic arose when oligomers rich in P-sheet structure termed protofibrils where found to be discrete intermediates in the fibrillization of AP and a-synuclein in vitro (24,25). A role for soluble oligomers in neurodegenerative diseases is further supported by the following observations there is no correlation between fibrillar deposits at autopsy and the clinical severity of Alzheimer's or Parkinson's disease (24), transgenic mouse models of these conditions have disease-like phenotypes before fibrillar deposits can be detected (25) and non-fibrillar AP...

Effects of Protein Aggregation on the UPS

It is worth mentioning here studies performed with various forms of a-synuclein, a molecule linked to Parkinson's disease (PD) by its prominent localization in an aggregated conformation within the characteristic Lewy bodies and by the presence of mutations in rare families with autosomal dominant PD (see also chapter on Parkinson's disease by Mark Cookson). We and others have shown that expression in neuronal cell systems of mutant forms of a-synu-clein is associated with a modest UPS inhibition (72-74). In our initial study, we found no evidence for frank aggregation of a-synuclein, as assessed by immunostaining or fractionated Western immunoblotting (72). The immunos-taining pictures shown by Tanaka et al. (73), although not commented upon, also appeared to show a diffuse pattern, with no visible aggregates. This suggests that the form of a-synuclein linked to proteasomal dysfunction is not the frankly aggregated one, but rather the soluble monomeric form, or soluble oligomeric...

Cluster headaches See headaches

Cocaine and the brain Cocaine, an alkaloid derived from the coca plant (Erythroxylon coca), produces its stimulating effects by enhancing the activity of dopamine and norepinephrine neurons. (It is dopamine that also plays a key role in the development of schizophrenia and Parkinson's disease.) Cocaine works by not only increasing the release of norepinephrine and dopamine, but also by blocking their reuptake. This overuse of the two systems takes its toll on the brain areas that normally rely on these neurotransmitter systems for function learning and memory areas, and limbic structures. This is why heavy cocaine use leads to emotional and cognitive disorders.

Inclusion Formation And Composition In Neuronal Cells Following Proteasomal Inhibition

Because of the evidence strongly linking UPS dysfunction with PD in particular (see chapters 12 and 13 in this volume), it was especially critical to establish whether a-synuclein, a main component of the Lewy bodies (LBs) characteristic of PD, was present within the inclusions we had observed in PC12 cells following proteasomal inhibition. We found that a-synuclein was indeed occasionally present within such inclusions, but only about 10 of ubiquitinated inclusions contained a-synuclein. This may be due to the low levels of expression of a-synuclein in this cell type. In any case, these studies established that protea-somal inhibition could lead, in neuronal cells, to the formation of inclusions that contain both basic elements of Lewy bodies, a-synuclein and polyubiquitinated proteins (3). agents led to consistent and reproducible ubiquitinated cytoplasmic inclusion formation, with the same characteristics at the fluorescent microscope level as the PC12 cell inclusions (4). Using an...

Mechanisms Of Inclusion Formation And Elaboration Following Proteasomal Inhibition

Few other studies have examined mechanisms of inclusion formation in neuronal cells following proteasomal inhibition. Fornai et al. (10) presented very interesting data suggesting that dopaminergic metabolism may contribute to such inclusion formation. They showed, in both models mentioned above, that treatment with a-methyltyrosine, an inhibitor of dopamine synthesis, led to a dramatic decrease of inclusion formation following application of proteasomal inhibitors to PC12 cells or to rat striatum. Furthermore, co-application of par-gyline, which blocks dopamine metabolism and therefore increases dopamine levels, or of L-DOPA, the dopamine precursor, with the proteasomal inhibitors, enhanced inclusion formation. Notwithstanding the reservations mentioned above about the characterization of these inclusions, these provocative data suggest a possible explanation for the relatively selective pattern of inclusion formation in dopaminergic neurons in PD.

The Treatment of Noncognitive Symptoms

Behaviors, hallucinations, and delusions. Because these drugs may cause adverse side effects (e.g., parkinsonism, rigidity with falls, tardive dyskinesia), the physician should clearly justify their use in the patients chart. Most clinicians recommend the use of the newer, so-called atypical neuroleptics at low doses because they have fewer side effects. Typical starting doses are risperidone, 0.5 mg po qhs, or olanzapine, 2.5 mg po qd. These agents are expensive (e.g., at 2.5 mg qd, the monthly cost of olanzapine is approximately 150), however, and it is often possible to prescribe less-expensive drugs such as haloperidol, 0.5 mg po qd (monthly cost as low as 6), or thiothixene, 1 mg po qd (monthly cost as low as 10). In general, no more than 3 mg of risperidone, 10 mg of olanzapine, 4 mg of haloperidol, or 6 mg of thiothixene per day should be prescribed. When sleep disorder is present, the neuroleptic should be given all at night. Some physicians recommend spreading neuroleptic...

Cardiovascular and Neurodegenerative Diseases

Apart from cancer and infectious diseases, cardiovascular diseases cause the highest mortality in the Western world. The development of strategies for the prevention of those diseases is, therefore, of high priority. RNAi is currently used to elucidate the underlying mechanisms of cardiovascular diseases (230,240,241) however, therapy is still way out of reach. Likewise, the number of patients with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis is growing with the increasing life-span of humans. Many studies support the therapeutic potential of RNAi-based methods for the treatment of diseases like myotrophic lateral sclerosis (242-244). The search for possible candidate genes responsible for Alzheimer's disease (245-251) and Parkinson's disease (252-254) is proceeding at a rapid pace. However, delivery is even more a problem when the trespassing of the blood-brain barrier is involved.

Harsh Words High Stakes

Actors Harrison Ford and Calista Flockhart read letters from former presidents Gerald Ford, Jimmy Carter, and Bill Clinton supporting Mrs. Reagan's efforts. Also speaking in agreement was Michael J. Fox, a longtime supporter of stem cell research because it could help lead to a cure for Parkinson's disease, with which he was diagnosed in 1991. He noted that, For someone like Mrs. Reagan to step outside of political or ideological groupings and just speak to what she believes can help people is tremendously valuable.

Social And Procedural Context

The majority of neuroimaging studies to date may be classified as brain mapping studies, in which investigators are exploring the patterns of activity elicited by a particular psychological process or condition. Brain mapping has been used to investigate virtually every field of study in human psychology and psychiatry, including (for example) attention, perception, memory, learning, emotion, reward, depression and other mood disorders, psychopathy, and Parkinson's and other neurological disorders. Recently, this trend has broadened to include mapping of social processes such as representations of the self and of others' intentions, economic principles such as expected utility and risk, and emotional self-regulation. Another approach particularly relevant here is the mapping of brain regions that correspond with changes in the autonomic and endocrine systems as measured by heart rate (Critchley, 2003), electrodermal responses (Critchley, 2000), pupil dilation (Siegle, 2003), and...

Inflammation and Ubiquitin Ligases

E3 ubiquitin ligases are the critical components that provide specificity to the ubiquitin conjugation system as they interact directly and specifically with the substrates. E3-promoted ubiquitination is involved in many biological processes, such as receptor down-regulation, signal transduction, protein processing or translocation, protein-protein interaction, gene transcription and proteasome-mediated protein degradation. Searches in gene databases reveal that there are hundreds of E3s and they are divided into two main groups the HECT (homology to the E6-associated protein carboxyl terminus) domain-containing E3s and the RING (really interesting new gene) domain-containing E3s. E3 ubiquitin ligases are involved in many aspects of neuroinflammation. For example, LPS- or IL1-activation of nuclear factor kB (NFkB) requires ubiquitination by specific E3 ligases and subsequent degradation of its inhibitor IkB. Notably, mutations in E3 ubiquitin ligases are linked to neurological...

Learning Disabilities Association of America A

Levodopa Also known as L-dopa, this drug is used in the treatment of Parkinson's disease, a neurological disorder caused by a deficiency of the neurotransmitter dopamine in the brain. L-dopa is absorbed into the brain where it is converted into dopamine. It is usually given together with an enzyme such as carbidopa, in order to boost the amount of L-dopa available to the brain by reducing the amount that is first broken down by the liver. This allows for a lower dose of L-dopa, which can reduce the risk of adverse effects. unfortunately, L-dopa does not permanently cure Parkinson's disease, and there is still no real treatment for Parkinson's.

Aphasia Treatment Pharmacological Approaches

In this brief article, we restrict our attention to the subacute and chronic phases of aphasia, rather than the treatments for acute neurological injury. Much of this work has focused on a class of neurotransmitters, the catecholamines, which occur throughout the brain. Two important catecholamines are dopamine, produced by the substantia nigra, and norepinephrine, produced by the locus coeruleus. Since the catecholamines do not cross the blood-brain barrier, typical therapy involves agents that increase catecholamine concentrations. Dextro-amphetamine is the most popular agent of this sort, acting nonspecifically to increase the concentrations of all the catecholamines at synaptic junctions. In the early studies, a single dose of dextro-amphetamine led to accelerated recovery in a beam-walking task in rats with unilateral motor cortex ablation (Feeney, Gonzalez, and Law, 1982). By contrast, a single dose of haloperidol, a dopamine antagonist, blocked the amphetamine effect. When...

Inflammation And Neurodegenerative Disorders

Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amytrophic lateral sclerosis (ALS), found to be associated with the accumulation of ubiquitinated proteins in neuronal inclusions also exhibit signs of inflammation. For example, neurofibrillary tangle (NFT)-containing and damaged neurons in brains of Down's syndrome and AD patients exhibit high expression of COX-2 (80-82). Furthermore, up-regulation of COX-2 was found to precede the appearance of NFT-containing neurons and neurodegeneration in patients with Fukuyama-type congenital muscular dystrophy, a neurodegenerative disorder transmitted through autosomal recessive inheritance (83). When compared to control brains, the substantia nigra in parkinsonian brains contain higher levels of PGE2, which is symptomatic of an increased COX activity (84 85). Moreover, a marked increase in COX-2 levels was detected in the spinal cord of ALS patients (86).

Method of controlling epilepsy by brain stimulation

Abstract A method of preventing seizures as experienced by persons with Epilepsy. High frequency electrical stimulation pulses are supplied to the subthalamic nucleus thereby blocking neural activity in the subthalamic nucleus and reducing excitatory input to the substantia nigra which leads to a reduction in the occurrence of seizures.

Motor system disease See motor neuron disease

Movement disorders A group of neurological disorders that involve the motor and movement systems. some of the more commonly known movement disorders include Parkinson's disease, tremor, dystonias, Huntington's disease and tourette's syndrome. These disorders are all caused by problems in the basal ganglia, deep in the hemispheres of the brain. The movement disorders are characterized by problems that include the inability to move or by severe, constant, and excessive movements. Most movement disorders, among them parkinson's disease, affect the speed, quality, and ease of movement. Others, such as tremors, dystonias, tics, progressive supranuclear palsy, Huntington's disease, and Wilson's disease, result in excess movements of varying type, slow movements, or abnormal movements that are not under voluntary control. Resting tremor is the type seen in parkinson's disease. It is most obvious when arms and legs are at rest, and often subsides when a patient attempts fine movement, such as...

Components Of The Proteasome System Degraded By Caspases

DUB enzymes are encoded by two gene families the UCH family (ubiquitin C-terminal hydrolases, with molecular weight of 30 kDa, hydrolyzing small C-terminal derivatives) and the UBP family (ubiquitin-specific processing proteases, with molecular weight of 110 kDa, hydrolyzing large derivatives of ubiquitin). UCHL-1 is one of the most abundant enzymes in the brain, comprising up to 2 of total brain proteins (74). A partial loss of UCHL-1 activity, due to a missense mutation, has been implicated in proteasome failure and aggregation of ubiquitinated proteins in familial cases of Parkinson's disease (74). For more details on UCH-L1 and its role in UPS dysfunction and neurodegeneration, see the chapter by Kwon and Wada in this volume. We found that the amount of this enzyme does not change during CGC apoptosis (Nadia Canu, unpublished observation), suggesting that other caspase-mediated modifications of UCHL-1 may account for an impairment of its activity, or, more likely, that other DUB...

Therapeutics Can You Cure Me

Neurologists often consult with neurosurgeons and vascular surgeons to discuss treatment alternatives related to excision and repair of neurologic deficits. However, they also have an extensive array of neuropharmacologic choices in their therapeutic regimen. Whether the presenting disease is a complex pain syndrome, debilitating multiple sclerosis, or Parkinson disease, neurologists use powerful new medications to alleviate symptoms. In addition, they can also counter these diseases with more aggressive therapies, like high-dose steroids, strong acute blood thinners, intravenous immune therapies, plasmapharesis (for cleaning out the blood), vagal nerve stimulators, and many others.

The Doctorpatient Relationship

In many fields of medicine, such as oncology, patients sometimes present with severe disease and die within months to years. In neurology, most of the disorders are not outright terminal. Instead, they generate significant disability over time. If they are mortal, death may take many excruciating years to occur. Sometimes, the neurologic disability presents with an acute, shocking nature other times, it is slowly progressive. More than any other specialty, neurologists are confronted with a wide spectrum of progressive and disabling diseases. The paralyzed, wheelchair-bound young person is a neurologist's patient. The stiff, trembling elderly man with Parkinson disease is a neurologist's patient. The severely demented-grandmother is a neurologist's patient.

Current Controversies In Neurology

The other current topic of heavy debate in contemporary neurology is the question of fetal tissue and stem cell transplants. By placing fetal brain extracts into the brains of patients with debilitating degenerative disorders, such as Parkinson disease, physicians hope to prevent (or reverse) disease progression. The goal is to increase the production of the disease-depleted brain chemical, such as dopamine. Is it ethically appropriate to use several fetal brains for every adult patient Neurologists and neuroscientists are at the forefront of this research debate.

Why carbon monoxide is such a deadly killer

The long-term effects of carbon monoxide poisoning for victims who recover are less clear. Those who recover from exposure to high levels, especially if they have been unconscious, can suffer effects on the memory and the brain and heart which may last some time or even be permanent. Some victims may suffer heart attacks some time after apparent recovery or succumb to pneumonia, especially the elderly. Similarly, despite an apparent full recovery, some weeks after the poisoning the victim may suffer from effects on the brain (for example, encephal-opathy) which can cause symptoms similar to Parkinson's disease or personality changes (irritability, for example) which can persist for some time. Loss of short-term memory is common. Muscle damage sometimes occurs, which can lead to renal failure. This is because the breakdown products of the muscle are excreted into the urine and overload the kidneys. These effects are most likely in those who are victims of severe poisoning.

Effects of Lewy Body Pathology on Communicative Function

Lewy bodies are spherical, intracytoplasmic neuronal inclusions that have a dense hyaline core and a halo of radiating filaments composed of proteins containing ubiquitin and associated enzymes (McKeith and O'Brien, 1999). They were first described in the literature by the German neuropathologist Friederich Lewy in 1912. Lewy bodies are classically associated with Parkinson's disease, particularly in the basal ganglia, brain-stem, and diencephalic nuclei. They may also be widespread in the cerebral cortex. Diffuse distribution of Lewy bodies is associated with dementia, and 10 -15

Neuropharmacology See psychopharmacology

Vascular disease, seizure disorders, neurodegenera-tive diseases (such as Alzheimer's disease or Parkinson's disease), brain tumors, infectious and inflammatory diseases of the central nervous system (CNS), alcohol-induced mental disorders, and developmental disorders involving the brain. EPILEPSY, HEAD INJURY, HYDROCEPHALUS, PARKINSON'S DISEASE, SPINA BIFIDA, SPINAL CORD INJURY, STROKE,

Differential Sensitivity Of Groups Of Neurons

A number of interesting studies suggest that certain types of neurons may be more vulnerable to proteasomal inhibition. An attempt has been made to correlate this selective vulnerability with the specific neuronal subtypes that degenerate in particular neurodegenerative diseases. Cultured motor neurons of the anterior horn were more sensitive to cell death compared to other neurons in spinal cord cultures (64). In two studies, dopaminergic neurons of embryonic or post-natal rat ventral midbrain cultures were more sensitive to lactacystin- or MG132-induced death compared to GABAergic neurons (65, 7). An in vivo study confirmed selective vulnerability of dopaminergic neurons in the substantia nigra following striatal microinjections of a proteasomal inhibitor. Selective toxicity in this model was dependent on the endogenous dopamine content (9). Another recent study reported remarkable selectivity of neuronal death induced by systemic administration of pharmacological proteasomal...

Stereotactic and Functional Neurosurgery Precise Mapping Precise Treatment

To illustrate how this works, consider a procedure known as thalamotomy, which is used in some patients with Parkinson disease. Between the pathway of the striatum and thalamus lie the ventro-oral nucleus the target for hypertonia and rigidity and the ventro-intermediate nucleus the target for tremor. Using stereotactic imaging techniques and depth microrecording, these cell groups are precisely targeted and obliterated. With this innovative procedure, as many as 95 of patients with tremor and rigidity are cured on the operating table with minimal side effects.8 Other procedures utilizing similar principles but different targets in the thalamus and basal ganglia include subthalamic nucleus stimulation and pallidotomy. Functional neurosurgery is not limited to stereotactic techniques. The field is broad and growing at an exponential rate. However, functional is somewhat ambiguous, because it really encompasses many disease processes. This subspe-cialty has a special focus on the unique...

Proteasomal Inhibition And Pcd A Complicated Relationship

The reader who has gone through both the previous chapter and the current one may be somewhat baffled. Is proteasomal inhibition deleterious, as suggested by all the data presented in this chapter, or is it beneficial, as suggested by the seminal work of Sadoul et al. (66), Canu et al. (67) and other studies referenced in the preceding chapter There is no doubt that one important variable is the intensity and timing of the inhibition. As demonstrated first by Lin et al. (68), pro-survival effects occur with low concentrations, whereas pro-death effects occur with high concentrations of pharmacological proteasomal inhibitors, when applied to cultured prostate carcinoma cells. A survey of some in vivo experiments further reinforces this idea. For example, Sawada et al. (69) injected nanomolar concentrations of lactacystin in mouse substantia nigra and observed protective effects on MPP-induced neurodegeneration of dopaminergic neurons, whereas McNaught et al. (70) used micromolar...

Natural Occurring Proteasome Inhibitors

The occurrence of natural occurring proteasome inhibitors has to be considered as a possible causative factor for the etiology of neurological diseases. In a recent paper it was reported that the systemic injection of epoxomycin or the peptide aldehyde PSI over a two week period caused a progressive model of Parkinson's disease (13).

Drugs for Mild Cognitive Impairment

Medications that have been used to boost levels of the neuro-transmitter dopamine in the treatment of Parkinson's disease are also being investigated for treating mild cognitive impairment. Such drugs are used in other countries but are not yet approved for this specific indication in the United States. Clinical trials have

Products For Incontinence Control

Urge incontinence, also called overactive bladder, is an urgent sensation to urinate even when the bladder may not be full. In many cases, the cause of urge incontinence is unknown. However, it can be caused by emotional stress, irritation of the bladder, or neurological conditions such as Parkinson's disease or stroke. Some women suffer from a combination of stress and urge incontinence.

Second Set Of Blueprints

Professor Wallace is a self-admitted evangelist when it comes to the research of mitochondrial DNA, also known as mtDNA. He firmly believes that the genes inside a mitochondrion are the real predictors of disease. Whether a person is predisposed to develop Alzheimer's disease or Parkinson's or other age-related ailments will depend not on the state of their cellular nuclei but the condition of their mitochondria. I think the world is on the wrong track, he said in a prior interview.

ASynuclein Inhibits Proteasome Function In Vitro

One might reasonably assume that any property of a-synuclein that is enhanced by aggregation might contribute to toxicity of this protein seen in PD or experimental models. There have been several recent studies suggesting that recombinant a-synuclein can have an inhibitory effect on net turnover of the proteasome in entirely in vitro systems (7,8). In most of these cases, it is aggregated protein that has the strongest inhibitory effect. For example, monomeric a-synuclein inhibits the proteasome at high micromolar concentrations but a-synuclein that has been pre-aggregated to form fibrils is inhibitory in nanomolar amounts (7). Similarly, oligomeric a-synuclein is also an effective proteasome inhibitor (8). These results imply that when a-synuclein starts to aggregate it can prevent proteasomal turnover of other substrates.

Proteasome Inhibition And Selective Neuronal Loss

These considerations show that whilst a-synuclein in an aggregated form can cause decreased proteasome function, this is not a unique property of this protein and could be related to relatively downstream events that occur long after aggregation. Therefore it is critical to consider whether decreased proteasome activity is a necessary part of the process that leads to cell loss in PD. Several in vitro studies have shown that dopaminergic neurons from cultured from the midbrain are more sensitive than non-dopaminergic cells in the same preparations. For example, in our laboratory tyrosine-hydroxylase positive neurons were more sensitive to proteasome inhibitors in cultures made from the postnatal Several recent studies have addressed the question of whether the neurons affected in PD really are more vulnerable to proteasomal inhibition in vivo. Rats exposed to the relatively specific proteasome inhibitor lactacystin by intranigral injection show loss of nigral neurons with inclusion...

Neurodegeneration and Neuroprotective Agents

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson's disease, Alzheimer's disease (AD), epilepsy, and Huntington's disease. Up to 80 of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intra-luminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments.

Encapsidate To envelop a virus in a protein shell the capsid

Encephalitis lethargica Sleepy sickness vonEconomo's disease. An acute virally induced inflammation of the brain characterized by fever and sleep disturbances and followed by various persisting forms of nervous disorder (e.g. Parkinsonism) or by changes in character. It emerged as a new infectious disease near the end of the First World War, but by 1940 new encephalitis lethargica cases had almost entirely disappeared. Probably only of historical interest.

Clinical Application Of Btx In The Treatment Of Lut Dysfunction

In a portion of patients with DO, neurogenic dysfunction can be identified as the underlying pathology and is therefore classified as neurogenic DO (NDO). Examples of neurological impairment include spinal cord lesions, stroke, multiple sclerosis, Parkinson's disease, and dementia. In other cases, no demonstrable neurological impairment can be identified. Accordingly, the disorder is classified as non-neurogenic or idiopathic DO (IDO). Other defects, such as detrusor myocyte hyperactivity, have been suggested as possible etiologies in these patients who have no underlying neurological dysfunction (25). However, the exact etiology of IDO is currently unknown.

Alzheimers Disease And The Ubiquitinproteasome System

The first connections between the ubiquitin protein and Alzheimer's disease were made some years prior to the observations of van Leeuwen and his co-workers. In the late 1980s, two research groups independently noted that neurofibrillary tangles and plaque neurites stained intensely with antibodies against the ubiquitin protein6-8. The era of ubiquitin immunohistochemistry had begun. Therein followed significant activity in the field of ubiquitin and neurodegeneration, and it soon became clear that immunoreactivity to the ubiquitin protein was not limited to Alzheimer's disease. Inclusions in a range of other neurodegenerative disorders, including (but not limited to) Parkinson's disease, dementia with Lewy bodies, Pick's disease, amyotrophic lateral sclerosis, and Huntington's disease, were subsequently found to stain with antibodies to ubiquitin9-11. Outside of the nervous system, ubiquitin immunoreactivity was detected in mallory bodies in alcoholic liver disease, as well as...

How Do We Get The Gene Into The Cell

Nuclear transfer technologies overlap with gene therapy approaches when we contemplate the following If a nucleus is transferred from one of the patient's cells into a stem cell and the resulting cell is treated to repair the patient's genetic defect, the genetically altered nuclear-transfer cell can be brought through a set of differentiation steps to become the type of cell needed to cure the patient's problem. This complex set of events is not yet feasible for most problems we want to cure, but it is among the foreseeable approaches that we expect to be usable in our lifetime, if its development is allowed. Such approaches could potentially replace brain cells that have died in individuals with Huntington disease or Parkinson disease. Such approaches could potentially replace islet cells in the pancreas of a diabetic or even bone marrow in a patient with leukemia. Currently it looks as if nuclear transfer technology may end up blocked from development under the same laws that block...

Hydroxytryptamine2 Receptors

Realization that it is much more closely related to the 5-HT2 receptor family than to the 5-HTj receptor family. The 5-HT2C receptor is expressed nearly exclusively in the brain, with high levels in the choroid plexus, nucleus accumbens, cortex, amygdala, hippocampus, caudate nucleus and substantia nigra (264-266). The 5-HT2C receptor gene has three introns (148,262,267). Despite the presence of three introns, only a single splice variant of the 5-HT2C receptor has been reported, and this is a truncated nonfunctional variant (148,268). The 5-HT2C receptor generates multiple functional receptor variants through a process called mRNA editing (269). This unique feature will be discussed in Section 3.3.3.

The Classification of Tremor

A tremor is a rhythmic oscillation of a body part. The rhythmic nature of tremor distinguishes it from other involuntary movement disorders, such as chorea, dystonia, myoclonus, or motor tics, which are not rhythmic. Tremor can either be physiologic or pathologic. The differential diagnosis almost always boils down to essential tremor (ET) or Parkinson disease (PD) after a few notable exceptions such as drug-induced tremor, hyperthyroidism, and Wilson disease have been ruled out. There are other much less common types, such as cerebellar tremor, primary writing tremor, and orthostatic tremor. Frequency also aids classification of tremor but less reliably. It is difficult to estimate frequency accurately at the bedside. The cerebellar tremor is slowest, generally 3-5 Hz (cycles per second), overlapping with the slow to medium frequency of the parkinsonian rest tremor, 3-6 Hz. ET is medium to fast in frequency, 6-12 Hz, with the fastest frequencies suggesting enhanced physiologic...

Differential Diagnosis

Multiple disorders may present with blepharospasm as part of their clinical spectrum, including neurological defects such as Parkinson's disease, Huntingtons's disease, Wilson's disease, Creutzfeld-Jacob disease, and postencephalitic syndrome. Psychological causes include habit spasms, Gilles de la Tourette syndrome, and functional spasms. Blepharospasm can occur as a result of medical conditions such as myotonic dystrophy, tetany, tetanus, or seizures. Likewise, it can occur from systemic medications including antipsychotics, antiemetics, anorectics, nasal decongestants, and levodopa. A detailed history and physical exam should help differentiate essential blepharospasm and related dystonias from these other systemic conditions.

Image not available

Figure 14.1. (a) Samples of handwriting demonstrate micrographia but no tremor (patient with Parkinson disease top) and normal size but tremulous writing (patient with essential tremor bottom). Each patient has written Today is a nice day in Baltimore. (b) Typical pattern of rhythmic oscillations of the pen, characteristic of essential tremor.

Stem Cell Transplants

Preliminary findings on the use of stem cells in treating the depletion of dopamine-producing cells in Parkinson's disease have produced mixed results. Clinical trials here and abroad have found the stem cell implants significantly improved symptoms in some patients to the point where they no longer needed dopaminer-gic therapy however, the symptoms worsened in other patients. As with any type of organ transplant or tissue graft, one of the major obstacles to overcome with stem cell transplants is to prevent a rejection response in which the body's natural immune defense attacks the new cells. Early experiments with neural stem cell transplants have yielded a wealth of basic information about stem cells and the work that needs to be done before stem cell transplantation can become a viable therapy. To be effective, the transplanted cells need to be rendered specific to the task at hand. If the therapy calls for an increase in dopamine, for example as in Parkinson's disease then stem...

Mesencephalon See midbrain

The mesencephalon is made up of three main parts the tectum (containing auditory and visual relay stations, called the inferior and superior colli-culi), the tegmentum (containing the midbrain reticular formation that controls attention, the substantia nigra and the red nucleus, both of which are involved in motor control.

Proteasome Function In Human Lewy Body Diseases

There is also evidence of proteasome dysfunction in human diseases that prominently include a-synuclein pathology. McNaught and Jenner were the first to demonstrate that proteasome activity is lower in the substantia nigra of postmortem tissue taken from PD patients compared to controls (37). A difficulty with this study is that tissue from the substantia nigra was used. One can argue that this is the most relevant tissue as it is the region of the brain that is most prominently affected in PD. However, because of loss of neurons and the presence of reactive gliosis, the cellular composition changes between control and disease. We don't know if the activity of the proteasome varies between neurons and glia and thus it is difficult to control for this potential confound. In an attempt to address this problem, McNaught and colleagues have shown that the protein expression of several individual proteasome subunits is decreased in diseased neurons. Using immunocytochemical staining, they...

Repression Inhibition and Defense Mechanisms

One study by Howard Shevrin and colleagues has recently examined the neu-rophysiological underpinnings of repression (Shevrin, Ghannam, & Libet, 2002). More specifically, they addressed the question of whether people with repressive personality styles actually require longer periods of stimulation for a brief stimulus to be consciously perceived. Prior research had established that people hi general vary from 200 ms to 800 ms in how long a stimulus needs to be present before being consciously perceived. The study by Shevrin et al. included six clinical participants between the ages of 51 and 70, all of whom years prior had undergone surgical treatment for motoric problems (mainly parkinsonism). During these surgeries, a procedure had been performed hi which electrodes stimulated parts of the motor cortex, and the length of time it took for the stimulus to be consciously perceived was recorded. The results of this procedure showed that these six participants also ranged from 200 ms to...

Genetic Manipulation of Proteasome Activity in Animal Models

In spite of the existence of excellent mammalian models of neurodegen-erative disorders such as Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis, none address the effect of constitutive proteasome impairment. One line of transgenic mice was developed to address the role of the immunoproteasome in antigen presentation (38). In these transgenic mice expression of the immunoproteasome LMP2 subunit was knocked-out. LMP2 is not a constitutive component of the 20S proteasome as its expression is induced by agents such as y-interferon. LMP2 knock-out mice exhibit impaired inflammatory responses manifested by reductions in the numbers of CD8+ lymphocyte Overall these studies support the notion that alterations or reductions in the activity of the UPS may play a critical role in the etiology of neurodegeneration. Given the current interest in the UPS, the genetic manipulation of protea-some activity in animal models has the potential for opening the doors to new...

Hypocretin Status In Hypersomnia In Various Neurological Conditions


Neurodegenerative Disorders Parkinson's Disease Thirty percent of patients with PD have been reported to have EDS. Sleep problems are often related to the disease itself (e.g., difficulties in maintaining sleep because of motor disabilities), but they can also occur secondary to pharmacological treatment, especially with dopamine D2 3 agonists. Ripley et al. (13) initially reported that CSF hypocretin-1 levels in seven PD subjects were in the normal range, but sleep abnormalities of these subjects were not assessed. Overeem et al. (119) measured CSF hypocretin levels in three PD patients with EDS all were normal. neurons in PD. The sleepiness of the patients was assessed by the Epworth sleepiness scale (ESS). The mean ESS of these PD patients (11 1) was significantly higher than that of controls (4 1), but hypocretin-1 levels were not correlated with ESS among PD subjects. The discrepancy between this study and that of Overeem et al. (119) has not been assessed.

The Use of Proteasome Inhibitors in Animal Models

In a long term study, rats were systemically injected with the proteasome inhibitors PSI and epoxomicin, over a two week period. Two weeks later the animals showed signs of progressive parkinsonism with bradykinesia, tremor, rigidity and abnormal postures. Six weeks after the end of proteasome inhibitor injections, postmortem analysis showed dopaminergic cell death and inflammation in the substantia nigra pars compacta. Neurodegeneration was also observed

Jewish Association for Retarded Citizens JARC

Joseph disease Also called Machado-Joseph disease, this is a genetic disorder of the central nervous system that cripples and paralyzes. it affects all races and many ethnic groups, and is often mis-diagnosed as multiple sclerosis, Parkinson's disease, or spino-cerebellar degeneration. Joseph disease is also known as spino-cerebellar ataxia, type 3, or SCA 3, a common hereditary ataxia.

Tricyclic antidepressants 315

More persistent tremors are caused by trauma, tumors, stroke, or degenerative disease. Coarse tremors (four to five movements per second) that occur during rest, diminishing during movement, are a common sign of Parkinson's disease. Intention tremors (tremors that worsen on movement) are a sign of cerebellum disease. Tremors often accompany such diseases as multiple sclerosis, Wilson's disease, mercury poisoning, thyrotoxico-sis, and liver encephalopathy.

Dysarthrias Characteristics and Classification

Although incidence and prevalence are not precisely known, dysarthria often is present in a number of frequently occurring neurological diseases, and it probably represents a significant proportion of all acquired neurological communication disorders. For example, approximately one-third of people with traumatic brain injury may be dysarthric, with nearly double that prevalence during the acute phase (Sarno, Buonaguro, and Levita, 1986 Yorkston et al., 1999). Dysarthria probably occurs in 50 -90 of people with Parkinson's disease, with increased prevalence as the disease progresses (Logemann et al., 1978 Mlcoch, 1992), and it can be among the most disabling symptoms of the disease in some cases (Dewey, 2000). Dysarthria emerges very frequently during the course of amyotrophic lateral sclerosis (ALS) and may be among the presenting symptoms and signs in over 20 (Rose, 1977 Gubbay et al., 1985). It occurs in 25 of patients with lacunar stroke (Arboix and Marti-Vilata, 1990). In a large...

Voice Disorders of Aging

Elderly patients often exhibit neurological voice disorders, particularly in later stages of old age. Estimates of the incidence of peripheral laryngeal nerve damage in elderly dysphonic patients range from 7 to 21 . Generally, peripheral paralysis in the elderly tends to be associated with disease processes associated with aging (such as lung neoplasm), as opposed to idiopathic peripheral paralysis, which occurs infrequently (Morrison and Gore-Hickman, 1986 Woo et al., 1992). Symptoms of peripheral paralysis include glottic insufficiency, reduced loudness, breathiness, and diplophonia. Voice therapy for peripheral paralysis frequently involves increasing vocal fold adductory force to facilitate closure of the glottis and improving breath support to minimize fatigue and improve speech phrasing. After age 60, central neurological disorders such as stroke, focal dystonia, Parkinson's disease, Alzheimer's disease, and essential tremor also occur frequently. Treatment for central...

Hypokinetic Laryngeal Movement Disorders

Hypokinetic laryngeal movement disorders are observed most often in individuals diagnosed with the neurological disorder, parkinsonism. Parkinsonism has the following features bradykinesia, postural instability, rigidity, resting tremor, and freezing (motor blocks) (Fahn, 1986). For the diagnosis to be made, at least two of these five features should be present, and one of the two features should be either tremor or rigidity. Parkin-sonism as a syndrome can be classified as idiopathic Parkinson's disease (PD) (i.e., symptoms of unknown cause) secondary (or symptomatic) PD, caused by a known and identifiable cause or parkinsonism-plus syndromes, in which symptoms of parkinsonism are caused by a known gene defect or have a distinctive pathology. The specific diagnosis depends on findings in the clinical history, the neurological examination, and laboratory tests. No single feature is completely reliable for differentiating among the different causes of parkinsonism. Idiopathic PD is the...

Overview Of Brainstem And Other Stateregulatory Systems

Pedunculopontine Tegmental Nucleus

The brainstem also contains state-regulating neurons that produce norepinephrine (NE), serotonin (5-HT), and dopamine (DA). NE is synthesized in several brainstem nuclei, but the best understood of these regions is the locus coeruleus (LC). The LC projects extensively to the cortex and hippocampus, as well as to subcortical areas such as the thalamus and hypothalamus (3,4). 5-HT is produced by the median and dorsal raphe (DR) nuclei as well as other regions (5,6). The raphe nuclei project throughout the pons, midbrain, hypothalamus, striatum, hippocampus, and frontal cortex (7). Neurons producing DA are abundant in the substantia nigra and the ventral tegmental area as well as in the posterior hypothalamus and several brain-stem nuclei. These DA neurons innervate specific central nervous system (CNS) regions including the frontal cortex, striatum, limbic areas, and many parts of the thalamus (8,9). Fig. 1. Ascending arousal systems in the brainstem and posterior hypothalamus project...

Csf Hypocretin1 Levels From Typical Narcolepsy To The Narcolepsy Borderland

Hypocretin Narcolepsy Brain

Disseminated encephalomyelitis (51,52), hypothalamic sarcoidosis (53,54) or histiocytosis X, multiple sclerosis (MS) (44,48,55,56), and Parkinson's disease (42,48,57,58). In some cases, lesions of the hypothalamic hypocretin centers have been clearly identified using magnetic resonance imaging, as in bilateral MS plaques in the hypothalamus and tumors of the third ventricle (59-62). Cataplexy may not be present in these cases, and the CSF hypocretin-1 levels may be either in the narcolepsy range (

Conclusion To Memory Disorders

Patients with Parkinson's disease in whom l-DOPA has been withdrawn (Lange, et al., 1992). However, the effects of dopamine agonist (e.g. Elliott et al., 1997 Kimberg et al., 1997) and antagonist drugs (e.g. Green et al., 1996 Mehta et al., 1999) on normal subjects have generally been found to be complex and not marked. Many other neurotransmitters have been proposed as candidates for abnormality in schizophrenia, but the current favourite is glutamate this is based largely on the fact that glutamate antagonist drugs, such as phen-cyclidine and ketamine, can induce schizophrenia-like symptoms in normal individuals, and worsen existing symptoms in schizophrenic patients (see Hirsch et al., 1997). Interestingly, administration of ketamine to normal subjects has been found to produce quite marked impairment on memory, executive and other tests (Krystal et al., 1994 Newcomer et al., 1999).

Secondary forms of HSP

Henoch-Schonlein purpura nephritis (HSPN) has been described in association with hypersensitivity. Indeed, several drugs such as ciprofloxacin, acetyl-salicylic acid, vancomycin, carbidopa levodopa, cocaine, ACE inhibitors, carbamazepine and strep-tokinase have been implicated in HSP induction (Disdier et al., 1992 Moots et al., 1992 Kaneko et al., 1993 Drago et al., 1994 Chevalier et al., 1995 Niedermaier and Briner, 1997 Prajapati and Cas-son, 1997 Sola et al., 1997 Michail et al., 1998).

Inflammation and UCHL1 Activity

UCH-L1 is reported to comprise 1-2 of the total soluble protein in brain (47) and is a neuronal specific UCH (48). Inhibition of UCH-L1 is relevant to neuronal pathology as a missense mutation in the uch-l1 gene, which results in a decrease in UCH activity, was identified in a German family with PD (49). UCH-L1 was also found to exhibit E3 ligase activity (50). Interestingly, a polymorphic UCH-L1 variant (S18Y) with reduced E3 ligase activity is associated with decreased PD risk (50). More recently, UCH-L1 was found to be down-regulated in AD and PD brains and to be a major target of oxidative stress (51), being altered by carbonyl formation as well as methionine and cysteine oxidation (52). In addition, an in frame deletion of exons 7 and 8 in the uch-l1 gene causes a dying back type of axonal degeneration in the gad mouse with gracile axonal dystrophy (53). In this mouse model of neurodegeneration, discussed in another chapter of this book, ubiquitinated proteins accumulate...

Demyelinating disorders

Though there are some reversible cases of dementia, caused by head injury, pernicious anemia, encephalitis, myxedema, syphilis, brain tumor, or alcoholism), by far the majority of cases are more permanent, caused by cerebrovascular disease (including stroke), Parkinson's disease, and from Alzheimer's disease. While it may be possible to alleviate some dementia by treating high blood pressure or heart disease, gradual deterioration usually occurs. Alzheimer's disease is at present incurable.

The Hypocretinorexin System And Narcolepsy

Narcoleptic Mice

Human narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and other abnormal manifestations of REM sleep, such as hypnagogic hallucinations and sleep paralysis (11). Narcolepsy is not a rare disease, affecting approximately 1 in 2000 in the general population, which is equivalent to Parkinson's disease (12) or multiple sclerosis (13). EDS in narcolepsy is overwhelming and is characterized by recurring episodes of sleep during the daytime (11). Patients also experience disturbed nocturnal sleep, although less frequently emphasized (11). The total amount of sleep that narcoleptic subjects have over 24 h does not exceed that of normal subjects (14). Therefore, narcolepsy is not an intrinsic hypersomnia but rather a pathological condition involving instability of the vigilance state (sleep wake fragmentation or problems maintaining wake sleep for longer period).

Aphasia Primary Progressive

The initial symptoms of PPA vary from individual to individual, but anomia is the most commonly reported presenting complaint in patients with both fluent and nonfluent PPA (Mesulam, 1987 Rogers and Alarcon, 1999). Another early symptom, particularly in nonfluent PPA, is slow, hesitant speech, frequently punctuated by long pauses and filler words ( um, ''uh''). Although this may represent simply one of many manifestations of anomia, it also portends the language formulation difficulties that later render the speech of these individuals telegraphic (reduced mean length of utterance consisting primarily of content words). Impaired access to phonologic form is frequently associated with later-emerging spelling difficulties, although partial access to initial letters and syllable structure may be retained for many years (Rogers and Alarcon, 1998, 1999). Difficulties with phonologic encoding have also been reported in cases of fluent PPA. Tyler et al. (1997) described the anomic...

The Atomization of Human Behavior

A mutant gene was identified on chromosome 4 that produces misfolded proteins. As the latter accumulate in the brain, neurons die, neurotransmission is compromised, and tremors and muscle rigidity ensue that are the hallmark of some early onset cases of PD.

Toxins That Attack the Nerve Cell Body

Metals bind to structural proteins and enzymes in neurons. There are multiple binding sites with sulfhydryl groups among the most favored. As a result of this binding the normal structure and activities of the neuron become impossible and the cell body undergoes necrotic changes (see Chapter 18 on metals for more extensive discussion of metal toxicity). A different mechanism may be responsible for the damage caused by manganese to those who work in the mining of this metal. Some of these miners develop a Parkinson-like syndrome (uncontrollable shakes, especially of extremities). Victims of this manganese-induced illness are found to have destruction of some dopaminergic neurons. The loss of such neurons also occurs in idiopathic Parkinson's disease and in this disease it is mainly localized in a brain region called the substantia nigra. One hypothesis states that manganese toxicity is due to its ability to oxidize dopamine. Cell death may follow when the cells cannot be stimulated by...

Multiplicity of GABAa Receptors

P2-subunits are also quite abundant and are present in 50-70 of all GABAa receptors. The Px- and P3-subunits seem to be present in 20-30 and 40-55 of all GABAA receptors, respectively, whereas the y3-subunit seems to be present in only 3-4 of all GABAA receptors (7,8). The a2-5-, and 5-subunits are present in 35, 14, 6, 7-8, and 11 of all GABAA receptors, respectively, but are differentially distributed in various forebrain areas and especially enriched in certain brain regions. Thus, in hippocampus 13 of all GABAA receptors seem to contain a4, and 31 of receptors seem to contain a5-subunits. In thalamus, 20 of all receptors seem to contain a4-subunits, and 16 contain 5-subunits. The a6- and y1-subunits exhibit a quite specific regional distribution. The a6-subunits are more or less exclusively located in cerebellar granule cells (and in the cochlea) and are present in about 56 of all GABAA receptors in the cerebellum. The y1-subunit is a minor subunit that is present in about 3-7 of...

Therapeutic Potential Of Vefg In Neural Disorders

Finally, a link between VEGF and common and complex neurodegenerative disorders, such as Alzheimer's disaese (AD) and Parkinson's disease (PD) has been suggested. In particular, the observation that cerebral hypoperfusion precedes the onset of clinical symptoms in AD indicates that chronic brain hypoxia, which can be caused by reduced VEGF levels, increases the risk for AD 207 . Moreover, the capacity of the amyloid plaques (which represent a typical feature of the disease) to bind VEGF might reduce the availability of the cytokine in the brain of AD patients, thus contributing to cerebral hypoperfusion and aggravating memory decline 207 . The link of VEGF to AD has been further highlighted by the observation that specific polymorphisms in the VEGF gene promoter confer greater risk for AD 209 . Although this association has been recently challenged by a similar case-control study 210 , this discrepancy might possibly be attributable to population differences. Finally, there is some...

Btxa For The Treatment Of Gastroparesis

Gastroparesis is the term used to describe delayed stomach emptying. The pathogenesis of this disorder depends on the underlying etiology, but can be broadly categorized as neuropathic or myopathic. Neuropathic processes involving the stomach are characterized by poorly coordinated contractile activity of the stomach (i.e., non-peristaltic), reduced frequency of gastric contractions, but preserved contractile amplitude. On full thickness biopsy, there is a degeneration of axons, dendrites, and or neurons with preserved circular and longitudinal smooth muscle layers (3). Some neuropathic causes of gastroparesis include endocrine disorders (diabetes mellitus, hypo hyperthyroidism), post-surgical (e.g., resulting from vagotomy), drug-induced (e.g., anticholinergics and narcotics), post-infectious (e.g., Chagas disease), and complications of systemic neurological disorders (e.g., Parkinson's disease and multiple sclerosis).

Of Cataplexy And Excessive Daytime Sleepiness

Jolly Phonics Free Printable

Monoaminergic transmission is also critical for the control of cataplexy. All therapeutic agents currently used to treat cataplexy (i.e., antidepressants or monoamine oxidase inhibitors MAOIs ), are known to act on these systems. Furthermore, whereas a subset of cholinergic neurons is activated during REM sleep, the firing rate of monoaminergic neurons in the brainstem (such as in the locus coeruleus LC and raphe magnus) is well known to be dramatically depressed during this sleep stage (35,36). Using canine narcolepsy, it was recently demonstrated that adrenergic LC activity is also reduced during cataplexy (37). In contrast, dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) do not significantly change their activity during natural sleep cycles (38,39). Indeed, an involvement of the dopaminergic system in intolerable sleepiness is also noted in some pathological conditions, such as Parkinson's disease. Frequent sleep attacks and associations with...

UCHL1 and Ubiquitin Stabilization

Uchl1 Inhibitor

The role of UCH-L1 in neurodegeneration in PD. Unfolded proteins are refolded by molecular chaperones or degraded by the ubiquitin proteasome pathway. Genetic defects such as A53T A30P mutations in a-synuclein and 193M in UCH-L1 may result in a gain-of-toxic-function that leads to PD. A S18Y polymorphic variant of UCH-L1 has been associated with a decreased risk for PD. However, loss of UCH-L1 function in the gad mouse does not appear to cause PD. Thus, the accumulation of a toxic intermediate (oligomer or protofibril) is proposed to precede and promote neurodegeneration.

Postpolio Syndrome Glossary

Amantadine An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. nih Bromocriptine A semisynthetic ergot alkaloid that is a dopamine D2 agonist. It suppresses prolactin secretion and is used to treat amenorrhea, galactorrhea, and female infertility, and has been proposed for Parkinson disease. nih

Dynamic Control Of Behavioral State The Flipflop Switch

The ventrolateral preoptic area (VLPO) contains sleep-promoting neurons. Neurons of the VLPO produce GABA and galanin and inhibit all the arousal systems during NREM sleep. Many of these cells are active during REM sleep as well. All the arousal systems, with the notable exception of pedunculopontine and laterodorsal tegmental areas (PPT LDT), also project to the VLPO. LC, locus coeruleus LH, lateral hypothalamus SN, substantia nigra TMN, tuberomammillary nucleus VTA, ventral tegmental area. (Adapted from ref. 1.) Fig. 2. The ventrolateral preoptic area (VLPO) contains sleep-promoting neurons. Neurons of the VLPO produce GABA and galanin and inhibit all the arousal systems during NREM sleep. Many of these cells are active during REM sleep as well. All the arousal systems, with the notable exception of pedunculopontine and laterodorsal tegmental areas (PPT LDT), also project to the VLPO. LC, locus coeruleus LH, lateral hypothalamus SN, substantia nigra TMN, tuberomammillary...

Parallels Between The Aggresome And Lewy Bodies

Several similarities have been pointed out between aggresomes and Lewy bodies (LB), the hallmark pathologic features of Parkinson's disease and of dementia with LBs. In cellular models, the aggresomes that result from the overexpression of parkin or synphilin-1, for example, accompanied with proteasomal inhibition, have both morphologic and immunocytochemical characteristics of LBs, including the core and halo organization and the presence of vimentin, y-tubulin, a-synuclein, synphilin-1, proteasome subunits, and chaperones (1,9). Additionally, dysfunction of the ubiquitin-proteasome pathway is generally involved in the pathogenesis of PD (10). For example, LBs are rich in ubiquitin and proteasome subunits (11,12), proteasomal activity and expression levels of certain of its components are reduced in the parkinsonian nigra (10,13-15) and a-synuclein, which is an abundant component of LBs (16) and is mutated in rare inherited types of PD (17), is degraded through the...

Language Disorders in Adults Subcortical Involvement

Subcortical structures most commonly purported to have a linguistic role include the basal ganglia, the thalamus, and the subcortical white matter pathways. Some evidence for a role for the cerebellum in language has also been reported (Leiner, Leiner, and Dow, 1993). The basal ganglia comprise the corpus striatum (including the caudate nucleus and the putamen and internal capsule), the globus pallidus, the subthalamic nucleus, and the substantia nigra. Although these nuclei are primarily involved in motor functions, the corpus striatum and globus pallidus have frequently been included in models of subcortical participation in language. In addition, several thalamic nuclei have also been implicated in language, in particular the ventral anterior nucleus, which has direct connections to the premotor cortex and indirect connections to the temporoparietal cortex via the pulvinar. The basal ganglia and the thalamus are linked to the cerebral cortex by way of a series of circuits referred...

William T Greenough and Ann Benefiel

Publication is Richard Smeyne's finding that the drug MPTP, which kills catecholamine neurons in the substantia nigra in humans and in conventionally housed rats, does not result in similar neural damage when rats are housed in an enriched environment. Although this finding, of course, suggests important therapeutic directions, it also illustrates the complications that might be induced in a well-developed paradigm by the sudden insertion of enriched housing procedures.

Clinical And Neuropathological Hallmarks Of Huntingtons Disease

Individuals with HD typically show marked specific neuronal loss and gliosis in a defined region of the basal ganglia, namely, the striatum (caudate nucleus and putamen) as well as in the neocortex (2,4). In the striatum, the most sensitive cells are the GABAergic medium-sized spiny neurons that project to globus pallidus and substantia nigra. Despite remarkable striatal and neocortical atrophy in post-mortem brain of advanced cases of HD, psychiatric and motor symptoms often precede detectable neuronal loss in HD, and many neurological syndromes proceed without obvious cell death (5).

Benefits of Studies in Yeast for Neurodegenerative Diseases

The ubiquitin-proteasome system at the root of neurodegeneration is still a hypothesis, which is difficult to prove in vivo, since appropriate tools are missing. There are promising attempts made, especially by the group of Susan Lindquist, who studies pathological consequences of protein misfolding by using yeast as a readily manipulable organism. For example, the yeast system provides the opportunity to dissect molecular pathways underlying normal alpha-synuclein biology and the pathogenic consequences of its misfolding. Nucleated polymerization processes and recruitment of alpha-synuclein previously associated with membranes to cytoplasmic inclusions were observed in yeast comparable to aging neurons in Parkinson's disease. Small changes in the quality control balance in which the ubiquitin-proteasome system is suggested to be a key player could produce toxic gain of alpha-synuclein function concomitantly with loss of normal function (49,50). Furthermore, I will put studies in...

Specialist Treatment of Essential Tremor

Two surgical procedures are available for the treatment of severe ET of the upper limbs and are equally helpful for parkinsonian tremor stereotactic thalamotomy and deep-brain stimulation (DBS) of the thalamus. Each procedure has advantages and disadvantages, and a full discussion is beyond the scope of this chapter, except to mention that thalamotomy should be avoided in the patient who requires a bilateral procedure because of the risk of dysarthria. Both procedures are highly effective for either curing or substantially reducing tremor contralateral to the operated side, and the risk of a serious complication is low. Unlike thalamotomy, DBS can be performed safely bilaterally. The physician should refer appropriate candidates to a center experienced in surgical treatment of tremor and, ideally, one where there is close collaboration between the neurosurgeon and a neurologist with expertise in movement disorders.

Exploring the Three Pound Universe

Liver Cell Tem Microscope

The varying modes of alert consciousness, dreaming and deep sleep are generated from deeper brain stem centers that have ascending neural pathways that fan out widely across the cortex into specific cortical layers, thus providing long-term modulation of mood and conscious attention, Fig. 13.10. Two pathways lead from the Raphe Nuclei and the Locus Coeruleus to diverse cortical areas and involve the modulating neurotransmitters, serotonin and nor-epinephrine. The onset of dreaming sleep is heralded by activity of cells in the Pons and silencing of cells in the Raphe Nuclei and Locus Coeruleus. Similar dopamine paths spread out from the Substantia Nigra selectively into the frontal lobes and motor centers. The ascending pathways have been implicated in mental illness, addiction and motor syndromes such as Parkinson's disease. Dopamine is sometimes associated with pleasure and nor-adrenaline with anxiety. The hallucinogens psilocin and mescalin are serotonin and catecholamine analogs,...

The Cerebellar Deficit Hypothesis

Nicolson et al. (1995) argued that A search for the underlying cause of deficits in balance, in motor skill and in automatisation would generally point strongly to the cerebellum (p. 43). In this paper, they report research based on previous findings with patients who had damage to the cerebellum. Ivry and Keele (1989) had found that in comparison with Parkinson's disease patients, cerebellar patients were impaired on a task requiring them to judge which of two auditorily presented intervals of time was the longer. Nicolson et al. gave the same task to dyslexic children and found them to be impaired relative to age and IQ matched control children. Like cerebellar patients, the dyslexics were not impaired on a comparable loudness-estimation task.

The Ups In Huntingtons Disease

A recent study by Seo and co-workers analyzes, with fluorogenic substrates, the chymotrypsin and post-glutamyl activities of the proteasome in postmortem brain samples from HD patients and normal subjects (26). The chymotrypsin activity was decreased in the striatum of grade 0-1 and of grade 3-4 HD patients and also in the cerebellum of grade 0-1 HD patients. This activity did not change in cortex or substantia nigra of HD patients. The post-glutamyl activity was decreased in the striatum and cerebellum of grade 0-1 and of grade 3-4 HD patients, in the cortex of grade 0-1 HD patients and in the substantia nigra of grade 3-4 HD patients. For this analysis, individual proteasome activity values from post-mortem patients' brain samples were normalized using the atrophy index hat results from the macroscopic evaluation of ventricular size of the same HD patients' brains. Unfortunately, this study lacks measurement on total protea-some content in the brain samples, what is the key for the...

Further Readings

Ackerman, H., and Ziegler, W. (1991). Articulatory deficits in Parkinsonian dysarthria. Journal of Neurology, Neuro-surgery, and Psychiatry, 54, 1093-1098. Brown, R. G., and Marsden, C. D. (1988). An investigation of the phenomenon of set in Parkinson's disease. Movement Disorders, 3, 152-161. Caliguri, M. P. (1989). Short-term fluctuations in orofacial motor control in Parkinson's disease. In K. M. Yorkson and D. R. Beukelman (Eds.), Recent advances in clinical dysarthria. Boston College-Hill Press. Conner, N. P., Abbs, J. H., Cole, K. J., and Gracco, V. L. (1989). Parkinsonian deficits in serial multiarticulate movements for speech. Brain, 112, 997-1009. Contreras-Vidal, J., and Stelmach, G. (1995). A neural model of basal ganglia-thalamocortical relations in normal and parkinsonian movement. Biological Cybernetics, 73, 467476. Forrest, K., Weismer, G., and Turner, G. (1989). Kinematic, acoustic and perceptual analysis of connected speech produced by Parkinsonian and normal...


It is not only important to design a good model, it is also important to design different kinds of graphical output to make clear how the model behaves. Additionally, an experiment may examine the effects of changing parameters in a model, just as much as changing the inputs. One of the reasons for studying the basal ganglia is to understand Parkinson's disease, in which the basal ganglia are depleted of a substance called dopamine, whose depletion is a prime correlate of Parkinson's disease. The model of figure 1.2 (at a level of detail not shown) includes a parameter that represents the level of dopamine. The normal model, yields two saccades, one each in turn to the positions at which the two targets appeared the low-dopamine model only shows a response to the first target, a result which gives insight into some of the motor disorders of Parkinson's disease patients. The actual model is described in detail in chapter 15. We shall describe the simulation process in more detail in...

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