Cure for Parkinsons

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...

The ParkinsonsReversing Breakthrough Summary

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Author: Matt Traverso
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My The ParkinsonsReversing Breakthrough Review

Highly Recommended

I usually find books written on this category hard to understand and full of jargon. But the author was capable of presenting advanced techniques in an extremely easy to understand language.

All the modules inside this book are very detailed and explanatory, there is nothing as comprehensive as this guide.

Clinical Features of Parkinson Disease

The four cardinal signs of Parkinsonism include resting tremor, rigidity, bradykinesia, and postural instability. Tremor in PD usually occurs at rest, with the hand in a pronating-supinating (pill-rolling) manner at approximately 4-7 Hertz frequency. The tremor in PD may also involve the chin, jaw, tongue, and legs. In addition, symptoms of PD usually present unilaterally, and will almost always maintain some asymmetry in severity of symptoms. Video Segment 1 Most of the other signs in PD are manifestations of these cardinal characteristics either alone or in combination lack

Pharmacological Treatment of Parkinson Disease

Pharmacological therapies in PD may be classified into two main categories presynaptic strategy (levodopa car-bidopa, catechol O-methyltransferase COMT -inhibitors, selegiline, and amantadine) attempts to maintain physiological nigrostriatal synaptic concentrations of dopamine, and post-synaptic strategy (pergolide, bromocriptine, pramipex-ole, ropinirole, cabergoline, and apomorphine) bypasses degenerating nigrostriatal neurons by stimulating striatal neurons directly. In addition anticholinergics may help modify acetylcholine neurotransmission, which counteracts the dopaminergic transmission system (Stacy 2000a). Levodopa, a dopamine precursor, is converted to dopamine by the enzyme dopa-decarboxylase. Ingestion and bloodstream metabolism of levodopa to dopamine leads to activation of the area postrema, potentially causing nausea and even vomiting. Carbidopa or benserazide, dopa-decarboxylase inhibitors, do not cross the blood-brain barrier and when given with levodopa, block the...

Classification Of Atypical Parkinsonian Disorders

Atypical parkinsonian disorders can be caused by primary or secondary diseases (see Fig. 1). The primary causes consist of neurodegenerative processes such as PSP, CBD, MSA, DLB, and PDD. Interestingly, one of the earlier historical cases thought to have the typical features of PSP was recently found to have a midbrain tumor through autopsy examination. As discussed in Chapter 23, secondary causes also include drugs, infections, toxins, or vascular disease (21,23,39-44). Classification of Atypical Parkinsonian Disroders West-French Indies parkinsonian disorder Frontotemporal dementias with parkinsonism Parkinson's disease Multiple system atrophy Dementia with Lewy bodies Parkinson disease and dementia Neurodegeneration with brain iron PSP and DLB PDD are the most frequent neurodegenerative primary cause of an atypical parkinsonian disorders (31,45-47). A good history and physical examination will rule out drug-induced atypical parkinsonian disorders and supports the diagnosis of these...

Early Concepts Of Atypical Parkinsons Disease

Nineteenth-century neurologists recognized three basic categories of parkinsonism that were suitably different from typical Parkinson's disease to merit designation cases without typical tremor, those with atypical postures (extension rather than flexion), and those with marked asymmetry in the form of seeming hemiplegia. Within these categories, modern neurologists will find characteristics that typify progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration, though these latter diagnoses were not defined specifically until clinical-pathological studies distinguished them as distinct from Parkinson's disease itself. Each of these clinical categories is described from the perspective of 19th-century neurology and then followed by a specific discussion of the history of progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration.

Idiopathic Parkinsons Disease

Although there is some controversy as to the most appropriate use of the term (14), Parkinson's disease is most often used to denote idiopathic parkinsonism associated with the pathological finding of neuronal loss and Lewy bodies in the substantia nigra. External examination of the brain is generally unremarkable, although PD patients who develop dementia may have mild to moderate cerebral atrophy. On cut sections, there is usually loss of pigment from the substantia nigra and locus ceruleus (Fig. 1A). The caudate, putamen, globus pallidus, thalamus, and other brainstem structures appear normal. The histopathological hallmark of PD is the loss of dopaminergic neurons from the substantia nigra associated with the presence of intraneuronal inclusions called Lewy bodies (LBs). Cell loss in the substantia nigra occurs in a region-specific manner, with the lateral ventral tier of the pars compacta being most affected (15). It is estimated that at least 50 of the nigral neurons must...

Motor Complications in Primate Models of Parkinson Disease

Chronic levodopa treatment of Parkinson disease (PD) patients ultimately produces motor response complications (MRCs) that include response fluctuations and dyskinesias. Similarly, in MPTP-lesioned nonhuman primates, administering dopaminomimetics produces many of the features of the human motor complication syndromes. Recent nonhuman primate studies suggest that MRCs from the pulsatile nonphysiological stimulation of dopaminergic receptors on striatal spiny neurons increase the sensitivity of corticostri-atal glutamatergic synaptic transmission. Changes to the glutamatergic signaling pathways and adenosinergic and serotonergic pathways both intrinsic and extrinsic to the stri-atal dopaminoceptive medium-spiny neurons also may contribute to the pathogenesis of motor dysfunction in advanced PD. As a result of these alterations, basal ganglia output changes in ways that favor the appearance of Parkinsonian signs and motor complications. Conceivably, safer and more effective therapies...

Eye Movements In Other Disorders Causing Parkinsonian Syndromes Differentiation From Psp Table

The clinical challenge often posed to neurologists is to diagnose parkinsonian patients with abnormal eye movements. As noted above, most patients with PD have normal eye movements for their age, whereas as most patients with PSP do not. In fact, a number of other parkinsonian disorders have been reported to produce abnormal eye movements, and it is those disorders that we review in this section, noting features that help to differentiate from PSP. Comparison of Findings in Some Parkinsonian Syndromes

Postencephalitic Parkinsonism

Following the pandemic of encephalitis lethargica (von Economo's disease), in the early part of the 20th century, a large proportion of individuals who survived the acute encephalitic phase developed parkinsonism, after a latency of several years or decades. PEP was therefore common in the 1940s and 1950s but is now rarely encountered. Although a viral etiology (possibly influenza A) has long been suspected, this remains to be proven (164,165). Most detailed accounts of the neuropathology of PEP were published several decades ago (166,167). There may be mild cerebral atrophy and the substantia nigra and locus ceruleus show loss of pigmentation (Fig. 10A). There is severe chronic degeneration of substantia nigra with neuronal loss and gliosis. The histopathology is characterized by the presence of numerous NFTs (Fig. 10B). The tangles may be either flame-shaped or globose (164) and have the same immunohistochemical and ultrastructural features as those seen in AD (168,169). NFTs are...

Other Unusual Causes Of Secondary Parkinsonism

Parkinsonism was reported after a wasp sting resulting in a progressive syndrome of frequent freezing, rigidity, and bradykinesia, in addition to dystonia in the left arm (98). The patient was reported to have had emotional lability and bilateral frontal release signs. The brain MRI showed marked destruction of the striatum and pallidum bilaterally, and enlargement of the lateral and third ventricles. There were circulating antibodies against the basal ganglia and cerebral cortex. The patient responded to immunosuppressive therapy with plasma exchange and intravenous immunoglobulin. Multiple sclerosis (MS) has also been reported to cause parkinsonism (99). One patient presented mainly with gait difficulty, with slowness, short steps, and unsteadiness. She also developed rest tremor, hypomimia, and hypophonia. There were other features suggestive of multiple sclerosis in the form of diplopia, brisk reflexes, and sensory loss. The patient improved with steroids. So far in the literature...

Developmental Forms Of Parkinsonism

Developmental forms of parkinsonism include syndromes induced by in utero or perinatal viral (or other) infection, such as maternal influenza during pregnancy or in utero or perinatal trauma or maternal stress. In utero influenza has been reported to be a cause of parkinsonism in a young child (85). Parkinsonism was reported in children born to mothers with encephalitis lethargica (85). Asphyxia during delivery, prenatal disturbances, premature birth, or early-childhood meningoen-cephalitis, often in combination with a complicated pregnancy, were all described to predispose to parkinsonian syndromes. The clinical symptoms included rigidity, hypokinesia, and in a small percentage, tremor. These children also had other neurological abnormalities including cognitive problems, behavioral difficulties, headaches, and strabismus. Treatment with levodopa was reported to be effective. Dyskinesia was noted to be a side effect 8-30 months after therapy, and by 3 years levodopa Secondary Causes...

Toxic And Metabolic Parkinsonism

A long series of toxic and metabolic disorders, acquired or inherited, may cause parkinsonian symptoms and signs (72). Many times the diagnosis is straightforward, known from the medical history, but the support of imaging studies may be useful in defining at least the extent of damage. This is the case of post-anoxic encephalopathy or carbon monoxide intoxication, in which the lesions involve the white matter and the basal ganglia where they are prevalent in the pallida (73,74). The same prevalent pallidal location is seen in cyanide intoxication (75). In other conditions, such as the unusual parkinsonian presentation of Wilson's disease, the correct diagnosis may be unsuspected and MRI, by demonstrating putaminal and lateral thalamic abnormalities or more extensive basal ganglia and brainstem involvement (25), may orient the diagnostic work-up to a rapid conclusion. One condition in which MRI may suggest the correct diagnosis is manganese intoxication. This is manifested by...

Posttraumatic Parkinsonism

Parkinsomism immediately following a single episode of acute head injury is rare (180) but has been reported with direct penetrating lesions of the midbrain (181) and with subdural hematoma (182). Epidemiologic studies have shown a history of remote head trauma to be a risk factor for PD, however the mechanism is unclear (183-184). Repeated head injury may result in a syndrome that includes psychiatric symptoms, memory loss, and or parkinsonism (dementia pugilistica, punch-drunk syndrome). This most often occurs in professional and amateur boxers, with the onset of symptoms occurring several years after the end of their athletic career. Pathological studies have shown loss of pigmented neurons in the substantia nigra and the presence of widespread AD-like pathology, with numerous tau-immunoreactive NFTs and amyloid p (Ap) containing SPs (185,186). A direct link between these pathological changes and preceding trauma is supported by studies showing Ap deposits in the brains of...

From Man to Mouse The MPTP Model of Parkinson Disease

James Parkinson first described the syndrome that we know today as Parkinson disease (PD) in a paper entitled An Essay on the Shaking Palsy (Parkinson 1817). PD is a debilitating neurological disorder that strikes approximately 1-2 of the adult population older than fifty years of age (new incidence is 20 per 100,000 persons) (de Rijk et al. 1995). Current estimates from the American Parkinson Disease Foundation put the number of American citizens suffering from this disease at greater than one million persons. The costs of treatment of PD can be staggering. At an average per patient cost of 6,000 per year for drugs, physicians, and loss of pay to patient and family members (Whetten-Goldstein et al. 1997), the total cost of the disease may approach 6,000,000,000 per year of which 85 is borne by private and government (e.g., Social Security, Medicare) insurance. In fact, more individuals present with PD than with multiple sclerosis, muscular dystrophy, and amyotropic...

The Impact Of Parkinsonism On Healthrelated Quality Of Life

Parkinson's Disease The only parkinsonian disorder that has been assessed in detail with regard to Hr-Qol is PD. Studies on Hr-QoL of patients with PD have improved our understanding of subjectively experienced difficulties associated with this disease, and we now have a clearer understanding of what aspects of Hr-QoL are most important to patients with PD. A full review of the expanding Hr-QoL literature in PD is beyond the scope of this chapter. However, it has consistently been found that all areas of Hr-QoL are affected by PD, not merely the physical impairment or functioning (23,25,26). The main areas of impairment in PD are in physical functioning, emotional reactions, social isolation, and energy. Other domains of impairment of Hr-QoL in PD, include bodily discomfort pain, self-image, cognitive function, communication, sleep, role function, and sexual function (23,25-27). It has also become clear that in PD, it is not primarily disease severity and presence of the symptoms of...

C elegans Models of Parkinson Disease

C. elegans is a soil-dwelling nematode that measures 1 mm in length. Advantageous features that make it a suitable model organism to study human neurodegenera-tive diseases include its body transparency for direct visualization of neurons, a reproductive cycle of three days, a life span of three weeks, and richness in posture, movement, and behavior. C. elegans has well-developed methods and resources for genetic manipulation including visible phenotypic markers, a completed genome sequence, a library of mutants, and the ability to perform forward and reverse genetics. C. elegans hermaphrodites have eight dopaminergic neurons that modify behaviors as diverse as egg-laying, sexual reproduction, response to drugs, habituation, and muscle movement. Investigators have identified two C. elegans dopamine receptors and studied their role in behavior. Parkinson disease models produced from the wild-type C. elegans can be divided into classes based on genetic mutations, chemical treatments,...

Epidemiology And Implications Of Neuropsychiatric Features In Parkinsonian Disorders

There are few epidemiological studies of neuropsychiatric symptoms in parkinsonian disorders. In one study of a relatively large, representative community-based sample of patients with PD, 61 had a positive score on at least one NPI item, and 45 had a positive score on at least two items. Patients in nursing homes, with more advanced parkinsonism, and with dementia had more frequent and severe neuropsychiatry symptoms (12). Studies of patients with atypical parkinsonian disorders have typically involved small convenience samples from highly specialized movement disorder clinics, and thus may not necessarily be representative of the general population. The exception is DLB, and two studies, both including 98 patients with DLB, showed a high prevalence of neuropsychiatric symptoms (23,24). In one study, 98 had at least one positive symptom as measured by the NPI (24) demonstrating the importance of neuropsychiatric symptoms in this common disorder, which affects 5 of the elderly aged 75...

The Nature Of Apraxia In Atypical Parkinsonisms

CBD patients may not only exhibit spatiotemporal errors when handling objects but in addition may often show impairment in the selection and usage of novel tools in the mechanical problemsolving task (63) on occasion, they may also commit content errors and perform wrongly the sequential arm movement test, displaying errors such as omissions, misuse, mislocations, and intrusions, as well as pantomime recognition deficits (10). Therefore, a consistent production or executive deficit may frequently combine with mechanical problem-solving impairment and less commonly with semantic knowledge breakdown as well (63). However, disruption of conceptual knowledge and IA (content errors or semantic parapraxias) are uncommon in CBD patients this type of praxic deficit is particularly observed in patients with cognitive impairment including aphasia and dementia (10,64), or in the presence of primitive reflexes (10). The combination of several types of limb praxic deficits relevant for object use...

Druginduced Parkinsonism

A discussion of secondary parkinsonism would not be complete without at least a brief review of drug induced parkinsonism. Drug-induced parkinsonism, one of the most common causes of secondary parkinsonism, may coexist with tardive dyskinesia. In a study in patients in the hospital, 51 of the 95 patients had drug-induced parkinsonism (75). The symptoms in drug induced parkinsonism are often bilateral at onset, whereas idiopathic PD is asymmetric at onset, but this clinical observation does not reliably differentiate between the two forms of parkinsonism. Tremor in drug-induced par-kinsonism is generally high-frequency 7- to 8-Hz action tremor rather than a rest tremor as seen in idiopathic PD. Women tend to have drug-induced parkinsonism more frequently than men, the opposite of gender distribution in idiopathic PD. Most of the cases of drug-induced parkinsonism occur in patients over 40 yr of age. Parkinsonian symptoms occur generally 10-30 d after starting the drug. It is important...

Clinical Diagnosis Of Familial Atypical Parkinsonian Disorders

Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 The term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was defined in 1996 during the International Consensus Conference in Ann Arbor, Michigan (3). At the time of this meeting, only 13 families with syndromes linked to the chromosome 17q21-22 locus were known (4-12). Currently, over 80 families with FTDP-17 are known (13). Data indicate that some of these kindreds may share a common founder (14,15). However, distribution is worldwide, with families described in North America, Europe, Asia, and Australia (4-14,16). From Current Clinical Neurology Atypical Parkinsonian Disorders Edited by I. Litvan Humana Press Inc., Totowa, NJ Familial Parkinsonism Associated With Known Gene Mutations or Loci Response to Levodopa

Genetic Testing For Atypical Parkinsonian Disorders

Recent discoveries on chromosomal loci and mutations in familial neurodegenerative conditions have expanded our knowledge about the basic cellular mechanisms involved in neurodegeneration. These have provided us with the option of genetic testing to establish a more precise diagnosis in symptomatic individuals with or without an obvious family history. Presymptomatic (predictive) and prenatal diagnosis are possible for several movement disorders, including some of those discussed here, although a detailed discussion of molecular genetic testing is beyond the scope of this chapter. A recent review on this subject was published by the Movement Disorders Society Task Force on Molecular Diagnosis (88). Molecular genetic testing can be readily performed in affected individuals presenting with parkinsonism with ataxia (SCA2 and SCA3), dystonia (DYT1), and chorea (HD). The genetic tests for these conditions are commercially available. Appropriate genetic counseling can be provided by a...

FDGPET study of the bilateral subthalamic nucleus stimulation effects on the regional cerebral metabolism in advanced

The aim of the study was to evaluate the changes in regional cerebral metabolic rate of glucose (rCMRGlu) induced by bilateral subthalamic nucleurs (STN) stimulation in advanced Parkinson's disease (PD). Keywords Parkinson's disease subthalamic nucleus deep brain stimulation PET 18F-fluorodeoxyglucose. Stimulation of the subthalamic nucleus (STN), especially bilateral stimulation, may improve all cardinal motor signs of the Parkinson's disease (PD), and has become an effective treatment option in advanced medically intractable PD patients. However, the underlying mechanisms are still poorly understood. To elucidate the functional anatomic substrate involved in the clinical effect of STN stimulation, we investigated the changes in regional cerebral metabolic rate of glucose (rCMRGlu) with 18F-fluoro-deoxyglucose (FDG) PET examinations in PD patients under clinically effective bilateral STN stimulation. Five patients with insufficient symptom control by medication of advanced PD, all...

Devising New Treatments For Parkinson Disease Through Research On Animal Models

The current problem for treating PD lies in the lack of therapies that can provide a long-term benefit in the absence of disabling complications. Devising novel efficacious treatments for the future is an important goal for both preclinical and clinical investigators in the Parkinson field. New therapeutic options can be classified in three main categories (1) neuroprotective treatments, which aim at halting the neurodegenerative process at the basis of PD. For example, investigators are attempting to counteract the degeneration of DA neurons through intracerebral delivery of trophic factors (Gill et al. 2003 Grondin et al. 2003) or systemic administration of antioxidants (Shults 2002 Mandel et al. 2003) (2) restorative treatments, which aim at restoring the integrity of the damaged nigrostriatal system by intracerebral transplant of DA-producing cells (Lindvall and Hagell 2000 Bjorklund et al. 2003), or by delivery of viral vectors encoding DA-synthesizing enzymes (Kirik et al....

Peripherally Induced Tremor And Parkinsonism

There are several disorders that have been reported to result from trauma to the peripheral nervous system. These include tremor, dystonia, segmental myoclonus, hemifacial spasm, and in some cases parkinsonism. Among 146 patients with peripherally induced movement disorders, 28 had tremor with or without parkinsonism (81). Eleven patients had tremor-dominant parkinsonism. Clinical features included rest and action tremor, and bradykinesia and rigidity in those with parkinsonism. Onset of movement disorder was temporally related to the injury, and was within 2-5 months after injury. Injuries varied from whiplash to sprain, dental procedure, fracture, overuse, or surgery. Patients had the injury in various areas including arm, neck, lumbar region, and teeth. A majority of patients had injuries in the arms. The condition seemed to spread to the other parts of the body beyond the initial site of injury, and it is unclear if any of them may have had predisposition to parkinsonism, and the...

Note On Laboratory Methods For Studying Eye Movements In Parkinsonian Disorders

Perhaps the most important diagnostic contribution to be made by recording eye movements in parkinsonian disorders concerns tests of vertical saccades (7,8). Reliable measurement of horizontal or vertical saccades requires methods with adequate bandwidth (0-150 Hz), sensitivity (0.1 ), and linear range ( 30 ). DC-amplified electro-oculography (EOG) is adequate to signal horizontal eye position and timing at the beginning and end of a saccade, but is unreliable for measuring vertical movements. Infrared methods provide better bandwidth but inferior range to EOG, and also cannot be used to measure vertical movements. The most reliable method is the magnetic search coil which, in our experience, is well tolerated by frail and elderly subjects, and has the added advantage of being calibrated independently of the patient's voluntary range of movements (1). Fast frame-rate video-based techniques are suitable for measuring dynamic properties of horizontal and vertical saccades (9), but their...

Performance Deficits in Parkinsons Disease

The Psychological Corporation (1997) also reported WAIS-III data for a small sample of 10 patients with Parkinson's disease (mean age 71.2, 80 male, 80 Caucasian), a disease of involuntary movement characterized by resting tremors, reduced initiation of voluntary movements, shuffling gait, plastic rigidity, and impaired posture (p. 152). Like MS, one would hypothesize V > P profiles for patients with Parkinson's disease, and, indeed, they had a 12.3-point discrepancy. Their index profile, though not as extreme as the MS sample concerning the PSI, was as follows VCI (96.9) > WMI (89.6) > POI (84.7) > PSI (81.7). In addition to studying Huntington's patients (and patients with Alzheimer's disease), Randolph et al. (1993) obtained WAIS-R data on 59 patients with Parkinson's Disease (mean age 46), demonstrating a V > P IQ discrepancy of 14.9 points, similar to the value reported for the small WAIS-III sample of patients with Parkinson's disease.

Neurophysiological Tests In The Assessment Of Atypical Parkinsonian Disorders

Table 1 summarizes the observations made in patients with parkinsonism regarding facial movements and brainstem reflexes. Although many brainstem circuits are dysfunctional in patients with APDs, the examination of brainstem reflexes and functions yields more interesting results in patients with PSP than in any other form of parkinsonism. Some of the most striking features differentiating PSP from other disorders presenting with parkinsonism regard facial expression and gaze disturbances (42). A list of abnormalities reported so far regarding eye or eyelid movements in these patients is shown in Table 2. The resting blink rate, of 24 per minute in normal controls, was found to be reduced in most patients with parkinsonism (43), but significantly more so in patients with PSP, whose mean blinking frequency can be reduced to as little as 4 blinks per minute. Blinking rate may be an expression of the level of dopamine activity. Clinical evidence of eye movement abnormalities is not always...

Specific Issues That Can Be Addressed By Future Research Of Visuospatial Cognition In Parkinson Disease And In Atypical

Does unilateral neglect in CBD patients have a different qualitative pattern than in PD patients 5. Which is the role of the dopaminergic system in controlling visuospatial exploration in PD patients Can dopaminergic drugs improve directional attention deficits in PD patients 7. Can a careful assessment of visuospatial skill help diagnostic accuracy in the early stage of parkinsonian diseases 8. Is there any role of impairment in size discrimination in determining freezing episodes in PD patients

Followup of bilateral subthalamic deep brain stimulation for Parkinsons disease

To demonstrate the effects of bilateral subthalamic deep brain stimulation (STN-DBS) in the treatment of Parkinson's disease (PD) after 4-45 months' follow-up. Method. Between 04 01 and 12 04, 46 PD patients were operated on with bilateral STN-DBS. All of them were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) parts II-V before surgery and 4-45 months after surgery. The amelioration of miscellaneous symptoms and decrease of medication dose, respectively, were compared. Main side effects were observed. In the past few years, deep brain stimulation (DBS) has become an accepted treatment modality for Parkinson's disease (PD) patients who experience disabling motor fluctuations and dyskinesia as a result of dopaminergic therapy, and some follow-up data have been published, including short-term follow-up for 3-6 months and long-term follow-up for up to 5 years. The selected targets varied from subthalamic nucleus (STN) to globus pallidus internus (GPi) 2, 4, 12,...

Neurophysiological Correlate Of Parkinsonism

Patients with APDs usually present with the main clinical signs characteristic of parkinsonism, i.e., bradykinesia and rigidity. Although clinicians identify bradykinesia and rigidity with no need for neurophysiological recordings, these are convenient for quantitation of the dysfunction. Bradykinesia and, specially, rigidity are present with varying degree and localization in patients with parkinsonism. They may not be observed at all in patients at early stages of the cerebellar variant of multiple system atrophy (MSA-C), though they will eventually appear during the course of the disease. Rigidity in patients with parkinsonism manifests as a difficulty of complete muscle relaxation, with often permanent tonic background EMG activity (11). Several neurophysiological tests have been used to assess rigidity, although direct clinico-neurophysiological correlations have proven more difficult than with bradykinesia. Rigidity has been considered to be the cause of some neurophysi-

Familial Parkinsons Disease

At the time this manuscript was being prepared, at least 11 different genetic loci had been linked to familial PD, including mutations in four specific genes (47,48). The pattern of inheritance includes both autosomal dominant and recessive and the clinical phenotypes vary from typical PD to families with juvenile or early onset and others with atypical clinical features. For most of these, information about the pathological findings is not yet available. Families with autosomal dominant PD and mutation of the gene for a-synuclein have changes similar to sporadic PD, with nigral degeneration and LBs (23). Cases of autosomal recessive, juvenile-onset PD and parkin mutations have neuronal loss in the substantia nigra and locus ceruleus, but only one report has described finding LBs (49). A single family has been identified with a mutation in the gene for ubiquitin C-terminal hydrolase L1 (UCH-L1) (50). No pathological information is available from this family but mice with intronic...

Pathophysiology Of Parkinson Disease

Investigators have long considered the progressive destruction of nigrostriatal dopaminergic neurons with consequent striatal dopamine deficiency as the pathological hallmark of PD. The presence of Lewy bodies in surviving dopaminergic neurons in the substantia nigra is also considered central to the pathologic confirmation of PD. In recent years it has become evident, however, that neither of these dogmas is absolutely true. While nigrostriatal dopaminergic cellular loss is certainly a central feature of the disease process, the damage is not confined to this pathway and neuronal loss in other locations within the central nervous system has clearly been identified. Moreover, damage in PD is not even confined to the central nervous system. Neuronal loss and even dopamine deficiency are documented within the enteric nervous system of the gastrointestinal tract (Singaram et al. 1995). Peripheral cardiac sympathetic de-nervation is also identified in the setting of PD (Goldstein 2003).

Genetics Of Parkinson Disease

Modern molecular genetic techniques have helped investigators identify a growing number of mutations that produce a phenotypic picture of PD. It is also quite clear, however, that the vast majority of individuals with PD does not possess one of these mutations and that additional factors, perhaps susceptibility genes, remain to be discovered. A detailed discussion of the genetic aspects of PD lies beyond the scope of this chapter, but excellent reviews of the subject have been published (Warner and Schapira. TABLE 2 Genetic Factors in Parkinson Disease TABLE 2 Genetic Factors in Parkinson Disease

Apraxia In Other Atypical Parkinsonian Disorders

Limb apraxic deficits in PSP seem to correlate with low MMSE, whereas in PD they appear to correlate with neuropsychological tests reflecting frontal lobe dysfunction and visuospatial cognitive deficits (13). Since focal lesions restricted to the basal ganglia only rarely cause apraxia and patients with MSA, which is characterized by severe basal ganglion and slight cortical involvement, fail to exhibit praxic deficits, we suggested that apraxia in PSP and PD reflect combined corticostriatal dysfunction (13). Cortical degeneration is now recognized to be common in PSP and identified mainly in the cingulate, superior, and medial frontal gyri (72,74). However, in PSP patients with limb apraxia cortical pathology may predominate in motor cortices or coexist with Alzheimer's disease pathology (74). In PD patients, impairment of neuropsychological tests reflecting frontal lobe function correlated with reduced fluorodopa uptake in caudate nucleus (75), and proton magnetic resonance...

The Pharmacological Treatment Of Parkinson Disease And Its Complications

In the complicated stage of PD, the patients usually exhibit abnormal involuntary movements (dyskinesia). Dyskinesias appear in three temporal patterns in relation to the intake of antiparkinsonian medications. On-phase dyskinesias manifest themselves when plasma (and brain) levels of L-dopa and DA are highest, and they represent the most common pattern. Dyskinesias can however appear also at low L-dopa DA levels (off phase dyskinesia), and when L-dopa DA levels are rising and falling, that is at the beginning and the end of the L-dopa action cycle (biphasic dyskinesia) (Marsden et al. 1981 Luquin et al. 1992 Nutt 1992 Quinn 1998). While large individual variability occurs in the phenomenology of dyskinesia at any point during the dopaminergic drug cycle, certain types of dyskinetic movements are more commonly seen during specific phases. On-phase dyskinesias are typically characterized by choreiform and choreo-dystonic movements that appear spontaneously but are provoked or...

Hemiplegic Parkinsons Disease

Corticobasal Degeneration

Early neurologists considered Parkinson's disease to be a bilateral condition, but often commented on the mild asymmetry of tremor, especially in the early years of disease. Within the context of this asymmetric but bilateral archetype, they distinguished another form of Parkinson's disease that was highly asymmetric with prominent disability in the involved upper extremity beyond that expected with bradykinesia alone (3). Collectively termed hemiplegic Parkinson's disease, these cases form a large series in the French neurological literature of the late 19th century and include cases of abrupt strokelike onset as well as slowly progressive disability (9) (Fig. 3). They are discussed in the section on corticobasal degeneration, because they clinically fit best into this designation among the group of atypical parkinsonian disorders. Because infectious disease (abscess and hemorrhagic strokes especially from military tuberculosis) were frequent disorders in the 19th century, some of...

Detection of boundaries of subthalamic nucleus by multiplecell spike density analysis in deep brain stimulation for

When microelectrode recording of single cell activity is employed for targeting the subthalamic nucleus (STN), multiple sampling of single cells is needed to determine whether the electrode has passed through the ventral boundaries of the STN. In contrast, stepwise recording of multiple cell activities by a semimicroelectrode reveals robust changes in such activities at the dorsal and ventral boundaries. We attempted to quantify changes in multiple cell activities by computing multiple-cell spike density (MSD). We analyzed MSD in 60 sides of 30 patients with Parkinson's disease. Neural noise level was defined as the lowest cut-off level at which neural noise is separated from larger amplitude spikes. MSD was analyzed at cut-off levels ranging from 1.2 to 2.0-fold the neural noise level in the white matter in each trajectory. Both the dorsal and ventral boundaries were clearly identified by an increase and a decrease (p < 0.0001) in MSD, respectively, in all the 60 sides. The cut-off...

Postanoxic Parkinsonism

Parkinsonism can rarely result from hypoxic ischemic injury. Different movement disorders including chorea, tics, athetosis, dystonia, and myoclonus have been reported. Patients can develop parkinsonism with or without dystonia weeks to months after the ischemic event (74). MRI findings include T1 hyper intensities in the basal ganglia bilaterally, indicative of ischemia or gliosis. In the case described by Li et al. (74), the clinical findings included mainly an akinetic rigid syndrome with hypomimia, limitation of down gaze, dysarthria, rigidity, postural tremor, slow rapid alternating movements, shuffling gait, start hesitation, and freezing of gait occurring 3 wk after an anoxic injury owing to cardiac arrest. There was no improvement with dopaminergic drugs. The autopsy examination showed multiple old infarcts with the presence of macrophages indicative of old hemorrhagic infarct in the basal ganglia.

Elegans Parkinson Disease Models Generated By Transgenic Manipulations

Elegans Twitching

Researchers have also applied transgenic approaches to C. elegans (Mello and Fire 1995). We have produced a trans-genic Parkinson disease model in C. elegans using overexpression of a-synuclein (Lakso et al. 2003). The product of this gene is found in Lewy bodies, the pathological hallmark of Parkinson disease (Spillantini et al. 1997). Mutations in this gene lead to familial forms of Parkinson disease (Poly-meropoulus et al. 1997). Some of the biochemical features of Parkinson disease were recapitulated in our model. For example, loss of dopaminergic neurons and processes was observed when a-synuclein was overexpressed under control of a dopaminergic neuron-specific promoter. Cellular inclusions consisting of a-synuclein protein were also observed although these events were rare. With regard to movement deficits, a thrashing assay was used. We observed that transgenic C. elegans overexpressing a-synuclein under a pan-neuronal promoter had thrashing values 50 less than transgenic...

Elegans Parkinson Disease Models Generated By Genetic Mutations

Parkinson disease models based on neurochemical criteria would likely be more useful. A phenotypic class of C. elegans that is catecholamine-defective(cat) was described in 1975 (Sulston et al. 1975). At least six separate genetic loci were identified using formaldehyde-induced fluorescence techniques. Later genetic mapping and cloning identified many of these genes as involved in the synthesis TABLE 2 Summary of C. elegans Parkinson Disease Models 2001). In dop-1 mutants, the habituation was enhanced, implicating this dopamine receptor in a type of behavioral plasticity, but also suggesting that this form of behavior could be an early indicator of lost dopamine signaling. In this context, learning and memory deficits are known to precede movement deficits in some Parkinson disease animal models.

Utility of 6Hydroxydopamine Lesioned Rats in the Preclinical Screening of Novel Treatments for Parkinson Disease

Parkinson disease (PD) is one of the most common neurodegenerative disorders, affecting about 1 of people over sixty years of age (for review see Bezard et al. 2001 Dauer and Przedborski 2003 Fahn 2003). The disease got its name from the English neurologist James Parkinson, who first described it in 1817 as a shaking palsy. The characteristic motor symptoms of PD consist of resting tremor, rigidity, hypo- and bradykinesia, and postural abnormalities (Gelb et al. 1999). These symptoms are caused by the depletion of dopamine (DA) in the target structures of nigral DA neurons, whose progressive degeneration represents the pathological hallmark of PD (Dauer and Przedborski 2003 Fahn 2003). Positron emission tomography (PET) studies in human patients have shown that the severity of Parkinson-ian motor symptoms is inversely related to the levels of 18F-fluorodopa (FD) uptake in the motor part of the striatum, that is, the putamen (Morrish et al. 1996 Brooks 2003). (Ito et al. 2002 Brooks...

Vascular Parkinsonism

VP, also known as arteriosclerotic parkinsonism, multi-infarct parkinsonism, and lower body parkinsonism, can result from lacunar infarctions, leukoaraiosis, and Binswanger's disease. In 1929, Critchley (2) described arteriosclerotic parkinsonism characterized by rigidity, pseudobulbar affect, dementia, incontinence, and short stepped gait in an elderly hypertensive individual with multiple ischemic insults in the basal ganglia. Zijlman et al. (3) in their report of clinico-pathological findings of VP showed the variability of clinical presentation of VP both clinically and pathologically. Based on the clinical evolution of symptoms in 17 patients in this clinico-pathological study, the following criteria for VP were proposed parkinsonism in the presence of cerebrovascular disease, a relationship between the above two features, and (a) acute or delayed progressive onset with infarcts in or near areas that can increase basal ganglia output, or decrease the thalamocortical drive...

Druginduced Parkinsonism And Oculogyric Crisis

Drug intoxications, especially with phenothiazines such as the butyrophenones, may produce a parkinsonian picture with slowing of saccades and an akinetic mutism picture. A distinct syndrome is oculogyric crisis, which was once a common feature of postencephalitic parkinsonism, but is now a side effect of drugs, especially neuroleptic agents (87). Oculogyric crises may also rarely be a feature of Wilson's disease (88), and disorders of amino acid metabolism (aromatic L-amino acid decarboxylase deficiency) (89).

Other Genetic Diseases Occasionally Presenting With Atypical Parkinsonism

Huntington's disease (HD) is an autosomal-dominantly inherited disorder, usually characterized by a hyperkinetic movement disorder, personality changes, and dementia. It is caused by the pathologic expansion of a CAG-trinucleotide repeat sequence in the gene for Huntingtin on chromosome 4 (94). The fact that particularly cases of early onset frequently present with dystonia and parkin-sonism, rather than with chorea, has long been recognized (95). In addition, the widespread use of molecular diagnosis for HD has shown that the phenotypic spectrum may even include late-onset levodopa-responsive parkinsonism (96) and atypical parkinsonian syndromes (97). Like HD, the spinocerebellar ataxias (SCAs) are caused by expansions of CAG repeat sequences. The core syndrome is usually that of a progressive cerebellar ataxia with or without additional neurologic features. Particularly in SCA1, 2, and 3, extrapyramidal symptoms are relatively common, and have been described in 10-50 of patients...

Modeling Cognitive Deficits Of Parkinsonism With Chronic Administration Of Mptp

Late Cognitive Deficits Parkinsons

Our initial idea was to produce cognitive deficits in monkeys pretrained to perform a variety of cognitive tasks by administering the dopaminergic neurotoxin MPTP in doses too low to induce gross parkinsonian motor deficits. Since the clinical literature indicated that cognitive deficits are present at the earliest stages of PD, our goal was try to model this early stage of PD in nonhuman primates. Over several years we developed and refined the chronic-low-dose MPTP administration protocol to produce cognitive deficits in monkeys with minimal or no motor impairments. With continued MPTP exposure, animals develop parkinsonian motor deficits superimposed on earlier appearing cognitive deficits. In the chronic-low-dose MPTP model of early parkinsonism, animals develop cognitive deficits analogous to those described in early PD patients 25-28 , including deficits in attention, attention set shifting, cognitive flexibility, planning, and problem solving, but not in working or reference...

Rasagiline Parkinsons Disease [7987

Rasagiline is a second-generation, irreversible monoamine oxidase type B (MAO-B) inhibitor that has been launched for the treatment of Parkinson's disease (PD). Unlike its predecessor selegiline, it is not metabolized to amphetamine derivatives and is, therefore, devoid of the sympathomimetic activity responsible for adverse side effects. Rasagiline is, however, similar to selegiline in the retention of the propargylamine moiety this essential pharmacophore binds covalently to selectively form an irreversible bond with the flavin adenine dinucleotide portion of the MAO-B enzyme. SAR dictates that a distance of no more than two carbon units between the aromatic ring and the amine is essential for conferring MAO-B specificity (IC50 14 nM vs. 700 nM for MAO-A). The inhibition of MAO-B prevents the degradation of dopamine, thereby, prolonging the action of dopamine to reduce the effects of dopaminergic neuronal deficit. Rasagiline has been approved for both initial monotherapy in patients...

Visuospatial Disorders In Parkinson Disease

Visuospatial abnormalities have often been reported in PD patients. Early in 1964, Proctor et al. (105) demonstrated that PD patients have difficulty in determining when a rod is vertical if they are in a darkened room. Later, this abnormality was confirmed both in patients seated in a chair that is tilted either to the right or to the left (13), and in patients who are upright (106). Subsequently, as we have already documented, a number of authors reported that PD is associated with disproportionate impairments in visuospatial abilities. However, for a long time, consensus on the specificity and significance of experimental data was lacking. Part of the debate stemmed from methodological inadequacies of early studies that did not account for factors such as motor speed, dexterity, and presence or absence of pharmacological treatment. On this basis, it was suggested (107) that impaired visuospatial ability in PD patients may be owing to generic increase in reaction time or other...

Parkinsonism Without Prominent Rest Tremor

Early neurologists recognized resting tremor as the most distinctive feature of typical Parkinson's disease, and placed patients who had unusual, intermittent tremor patterns or no tremor into the clinical category termed Parkinson's disease without tremor (3,4). Some of these cases actually had tremor, but the movements were mild in severity or intermittent and primarily induced with emotion or action (3). It is possible that myoclonus, a feature frequently seen in corticobasal degeneration, and mild action tremor that can be seen in multiple system atrophy would have been categorized as one of these intermittent tremors. Myoclonus was appreciated in the 19th century, especially by Germanic and Austrian researchers (6,7), but not specifically designated as an aspect of atypical Parkinson's disease. Charcot studied tremor extensively and drew attention to its typical features in Parkinson's disease. He conducted his tremor examination with patients at rest and during activity. In...

Elegans Parkinson Disease Models Generated By Chemical Treatments

Investigators have applied chemical neurotoxin treatments to C. elegans as a rapid and facile means to model Parkinson disease. Among neurotoxins specifically targeting dopaminergic neurons, we have used 6-hydroxydopamine (6-OHDA) (Nass et al. 2002). A key to visualizing dopamin-ergic neurons in this study was using GFP controlled by the C. elegans dopamine transporter (dat-1) (Nass et al. 2001). Transgenic injection of this construct permits identification of all eight hermaphrodite neurons under fluorescent microscopy in whole animals. After 6-OHDA treatment, death of CEP neurons could be seen as early as thirty minutes after the injection. Membrane blebbing could be seen within two hours. Ultrastructural studies using transmission electron microscopy confirmed overt pathology in CEP neurons and suggested an apoptotic pattern of cell death due to presence of chromatin condensation. Cell perturbations required the C. elegans dopamine transporter, but not a cell death pathway mediated...

Alzheimer and Parkinson Diseases

Inflammatory Tangle

Alzheimer and Parkinson diseases are degenerative disorders of the brain associated with neurotransmitter deficiencies. Parkinson30 disease (PD), also called paralysis agitans or parkinson-ism, is a progressive loss of motor function beginning in a person's 50s or 60s. It is due to degeneration of dopamine-releasing neurons in a portion of the brain called the substantia nigra. A gene has recently been identified for a hereditary form of PD, but most cases are nonhereditary and of little-known cause some authorities suspect environmental neurotoxins. Dopamine (DA) is an inhibitory neurotransmitter that normally prevents excessive activity in motor centers of the brain called the basal nuclei. Degeneration of the dopamine-releasing neurons leads to an excessive ratio of ACh to DA, leading to hyperactivity of the basal nuclei. As a result, a person with PD suffers involuntary muscle contractions. These take such forms as shaking of the hands (tremor) and compulsive pill-rolling motions...

Structural Lesions Causing Parkinsonism

A variety of structural lesions can cause parkinsonism. Siderowf et al. (93) argue that the first described case of PSP in a patient with progressive opthalmoparesis and postural instability, and structural lesion with a tumor in the right cerebral peduncle is not idiopathic PSP. Brainstem astrocytoma was reported to be the cause of unilateral parkinsonian symptoms the symptoms resolved after resection of the tumor (94). A frontal meningioma can sometimes present with rest tremor without other signs of parkinsonism (95). Dopa-responsive parkinsonism has been reported resulting from a right temporal lobe hemorrhage (96). Intrinsic brainstem tumors can cause parkinsonism. Posterior fossa tumors present with pyramidal tract signs, cerebellar signs, and hydrocephalus in addition to parkinsonism. The parkinsonian symptoms predominantly are seen contralateral to the lesion. In some cases ipsilateral symptoms have also been reported. The parkinsonism associated with mass lesions of the...

Elegans Parkinson Disease Models

Beyond genetics, the transparency of C. elegans has long been recognized as a powerful tool to study development. Currently, the use of GFP to identify neuronal populations provides a means to visualize cell death events in a living model. Moreover, neuropathology can be visualized in the model using a large range of microscopy and immunohisto-chemical techniques (Crittenden and Kimble 1999 Miller and Shakes 1995). These events can be studied over time, which provides the next advantage the short life span of C. elegans. Parkinson disease, for the most part, is an age-associated disorder. The approximate three-week life span affords investigators the opportunity to study cellular events over the life of the animal model and the possibility to conduct simple life span measurements. Practical considerations, such as the ability to freeze worm stocks, and the ability to grow at room temperature also make C. elegans an attractive model. From a pharmacologic perspective, C. elegans is...

Parkinsonism With Atypical Postures

Charcot studied muscle tone extensively and established that most Parkinson's disease subjects showed a flexed posture with the shoulders hunched forward, neck bent down toward the chest, and the arms held in partial flexion at rest. In contrast, he found a small number of parkinsonian patients Fig. 1. Tremor recording machine used by Charcot to separate cases of typical rest tremor from those with postural tremor and action-induced tremor. Early studies focused on the differentiation by tremor type of multiple sclerosis and Parkinson's disease, but this apparatus was later used to study the various formes frustes of Parkinson's disease as well. In the insert, tremor recordings are shown for resting posture (AB) and action (BC) in patients with different tremor patterns. From Dictionnaire Encyclop dique des Sciences M dicales, 1883. Fig. 1. Tremor recording machine used by Charcot to separate cases of typical rest tremor from those with postural tremor and action-induced tremor. Early...

Epidemiology Of Parkinson Disease

Parkinson disease is the second most common neu-rodegenerative disorder, trailing only Alzheimer disease. In the general population, the prevalence of PD is approximately 100 in 100,000. However, PD is an age-related illness and in individuals age sixty-five or older its prevalence mushrooms to 1-2 . The average age of symptom onset is sixty to sixty-five, but approximately 10 of PD patients develop symptoms before age forty. Investigators have never identified a uniform etiology for PD and it has become increasingly clear in recent years that there is probably no single cause and that PD is, in fact, not a disease in the strict sense, but rather a syndrome with multiple TABLE 1 Possible Environmental Factors in Parkinson Disease

The Rotenone Model Of Parkinson Disease

To model the systemic defect in complex I reported in PD, researchers have used rotenone exposure. Rotenone is a commonly used pesticide and potent, specific inhibitor of mitochondrial complex I. Although MPP+ is a mitochon-drial toxin, it is not well suited to mimic the systemic mito-chondrial impairment that occurs in PD. MPP+ is a substrate for the dopamine transporter and depends on expression of the dopamine transporter to gain access to cells (Javitch and Snyder 1984). Thus, MPP+ inhibits complex I activity solely in dopaminergic neurons. Rotenone, on the other hand, because of its lipophilic nature, crosses biological membranes easily and independent of transporters. As a result, systemic rotenone exposure inhibits complex I uniformly throughout brain (Betarbet et al. 2000). This model system addresses whether the nigrostriatal dopaminergic pathway is intrinsically sensitive to complex I impairment. Behavioral Symptoms of Parkinson Disease III. The Rotenone Model of Parkinson...

Infectious Causes Of Parkinsonism

Secondary parkinsonism has been reported by various authors as case reports, but Mattos et al. (59) have reported movement disorders in 28 HIV patients of whom 14 patients had parkinsonism. The mean age at onset of parkinsonism was 37.2 yr (range 25-63). They report mean Hoehn and Yahr scale of 2.5 (range of 1-5). The clinical features included tremor, and rapid progression of parkinsonian symptoms with time of onset to death being five mo in eight patients. Five patients were levodopa responsive. Imaging study with CT scans showed hydrocephalus ex-vacuo, and one patient had toxo-plasmosis involving the basal ganglia. One patient with T1 enhancement on the MRI of the brain had ipsilateral ophthalmoplegia and contralateral parkinsonism. Only two of the patients with parkinsonism had other parkinsonian risk factors such as metaclopramide exposure and neurotoxoplasmosis (59). Maggi et al. (60) described parkinsonism in a patient with AIDS and toxoplasmosis with abulia, VII cranial...

Parkinsonism Owing To Toxin Exposure

Several studies have explored the role of various environmental causes of parkinsonism, especially exposure to industrial toxins, organic solvents, pesticides, and other putative toxins (35,36). Population studies have shown a link between risk of PD, and chronic (more than 20 yr) exposure to manganese, lead-copper combinations, and iron-copper (37). Mercury exposure has also been linked to PD, but no firm evidence exists for mercury-induced parkinsonism. In the case-control study from Singapore, scalp hair mercury level has been shown to be a poor predictor of risk of PD (38). Exposure to (MPTP) has been used as an experimental model of PD since the discovery in 1982 that this meperidine analog can cause parkinsonism in humans and certain animal species. MPTP after undergoing biotransformation to 1-methyl-4-phenylpyridium ion (MPP+) via monoamine-oxidase B, is taken up to the dopaminergic terminal by dopamine transporter where it inhibits complex I of the mitochondrial respiratory...

Pathological Features Of Parkinson Disease

The cardinal feature of PD is relatively selective neurodegeneration of the nigrostriatal dopaminergic pathway, a neuronal circuit that controls motor activity. The symptoms of PD, including tremor, rigidity, and bradykinesia, are believed to result from depletion of striatal dopamine and the resultant changes in motor circuitry (Wooten 1997). For this reason, dopamine replacement therapy has been the gold standard for treating PD symptoms. Investigators have hypothesized that neurodegeneration of the nigrostriatal pathway begins in dopaminergic terminals in the striatum and progressively affects nigral cell bodies. Roughly 80 of dopaminegric nigral neurons must be lost before the onset of symptoms. Intrinsic neurons of the striatum and other basal ganglia nuclei are markedly less affected in PD. II. Pathological Features of Parkinson Disease

Hemiparkinsonismhemiatrophy

Hemiparkinsonism-hemiatrophy (HPHA) syndrome was first described by Klawans in 1981 (87), who described four individuals with known hemiatrophy with narrow extremities on one side who developed delayed-onset hemiparkinsonism between ages 31 and 40 with tremor on the same side as the hemiatrophy along with rigidity, akinesia, and dystonia, but no evidence of hypomimia, or abnormal posture or lack of postural reflexes. Their symptoms remained unilateral between 5 and 35 yr after onset of illness. They did not respond well to levodopa. HPHA can be differentiated from idio-pathic PD by the clinical features of hemiatrophy, asymmetric parkinsonism more prominent on the side of hemiatrophy, dystonia, early age at onset, history of birth injury, and slow progression of the disease. Mean age of onset of parkinsonism in HPHA is 43.7 yr (range 31-61), and mean duration of symptoms was 9.4 yr (range 1-35 yr). The first symptom in majority of cases is tremor, followed by bradykinesia and...

Drosophila Models of Parkinson Disease

Our knowledge of the molecular mechanisms of Parkinson disease (PD) has been dramatically advanced by the recent identification of genes underlying relatively rare heritable forms of this disorder (Hardy et al., 2003). These breakthroughs may provide a window into the mechanisms underlying the more common sporadic form of PD. However, our current understanding of the functions of these genes and the mechanisms by which their mutational alteration results in neuronal death is limited. One approach to this problem that has great potential is classical genetic analysis in the fruit fly Drosophila melanogaster to identify the genetic pathways leading to pathology in fly models of this disease. This review will describe the features that make Drosophila useful in studies of the genes implicated in PD and how these studies have begun to contribute to our understanding of the pathogenesis of this disorder.

The Paraquat Model Of Parkinson Disease

Systemic paraquat exposure reproduced some characteristics of the selective dopaminergic degeneration observed in PD. Mice exposed to paraquat showed selective degeneration of dopaminergic neurons of the substantia nigra (Brooks et al. 1999 McCormack et al. 2002). GABAergic neurons of the substantia nigra pars compacta were spared and no evidence appeared of degenerating neurons in the hippocampus (McCormack et al. 2002). Systemic paraquat exposure, however, did not replicate the striatal dopamine depletion that is characteristic of PD. Perhaps, there is a compensatory increase in tyrosine hydroxylase activity in surviving dopaminergic neurons to maintain striatal dopamine levels (McCormack et al. 2002). In rats exposed to paraquat, however, there was irreparable striatal dopa-mine depletion (Liou et al. 1996). Additionally, paraquat was toxic to dopaminergic neurons in organotypic midbrain cultures. However, the selectivity of the effects of paraquat on dopaminergic cells was not...

Parkinson Disease And Motor Response Complications

Parkinson Disease and Levodopa Therapy PD is a neurodegenerative disorder of unknown etiology that currently afflicts over one million Americans. The pathological hallmark of PD is a selective loss of dopamin-ergic neurons in the substantia nigra pars compacta in the midbrain that projects to the corpus striatum (Greenfield and Bonsaquet 1953). When the loss of dopamine (DA) exceeds 50-80 , Parkinsonian symptoms become clinically evident (Ehringer and Hornykiewcz 1960 Hornykiewcz 1963). The cardinal features of PD include resting tremor, rigidity, bradykinesia, and impaired postural reflexes (Parkinson 1817 Lang and Lonzano 1998). Since Cotzias demonstrated the dramatic therapeutic effects of the dopamine precursor levodopa on the motor symptoms of PD patients (Cotzias et al. 1967), the prevailing therapeutic strategy has been to restore striatal dopamin-ergic transmission (Lang and Lonzano 1998). Initially, pharmacologic agents such as levodopa, the metabolic precursor of DA, or a...

Metabolic Causes Of Parkinsonism

Important metabolic causes of parkinsonism include hypothyroidism and parathyroid dysfunction. Patients with hyperparathyroidism have clinical presentation identical to that of idiopathic PD, but the syndrome is levodopa resistant. The symptoms, however, may be relieved after resolution of the parathyroid dysfunction by surgical removal of the parathyroid adenoma. Hypoparathyroidism may also cause levodopa unresponsive parkinsonism (69,70). Bilateral striopallidodentate calcinosis, also known as Fahr's disease, is a rare disorder with calcium deposition in the subcortical nucleii and white matter bilaterally. Parkinsonism is reported in 57 of patients with this disorder other movement disorders seen in Fahr's disease include chorea, tremor, dystonia, athetosis, and orofacial dyskinesias (71). Additional neurological manifestations include cognitive impairment, cerebellar signs, speech disorder, gait disorder, pyramidal signs, sensory symptoms, and psychiatric features (72). Patients...

Alsparkinsonism Dementia Complex Of Guam

A high incidence of neurodegenerative disease is found within the Chamorro population of the Western Pacific island of Guam, and includes parkinsonism, dementia, and amyotrophic lateral sclerosis (ALS), each of which may occur in isolation but are more commonly combined (121). The cause is unknown but a toxic or viral etiology has been postulated (122-124). The histopathology is dominated by the presence of numerous NFTs (125,126), with similar immunohistochemical, biochemical, and ultrastructural features as those seen in AD (127,128), but usually in the absence of SP (Fig. 6A,B). The anatomical distribution of NFTs is different from AD (129) and more similar to that seen in PSP and postencephalitic parkinsonism (PEP) (130,131). Chronic degenerative changes including neuronal loss and gliosis are found in regions where NFTs are numerous, including the frontotem-poral neocortex, hippocampus, entorhinal cortex, nucleus basalis, basal ganglia, thalamus, subthalamus, substantia nigra,...

Clinical Examination Of Eye Movements In Parkinsonism

The systematic examination of eye movements is summarized in Table 1. The most useful part of the examination concerns saccades, which are the rapid eye movements by which we voluntarily move our line of sight (direction of gaze). Saccades are perhaps the best understood of all movements both in terms of their dynamic properties and neurobiology (1-3). It is important to differentiate between limited range of movement, especially upward, and speed of saccades, especially vertically. Normal elderly subjects show limited upgaze (4), and this may be because of changes in the connective tissues of the orbit (5). Nonetheless, some normal elderly subjects make vertical saccades that have normal velocities, within their restricted range of motion (6). Range of movement is conventionally elicited as the patient attempts to follow the examiner's moving finger, but this does not test saccades. It is important to ask the patient to shift gaze on command between two stationary visual targets,...

Rotenone Rat and Other Neurotoxin Models of Parkinson Disease

Parkinson disease (PD) is a progressive neurodegenerative disease marked by motor and non-motor abnormalities. The hallmark pathological features of PD are selective nigrostriatal dopaminergic degeneration and formation of filamentous, cytoplasmic inclusions called Lewy bodies, containing a-synuclein and ubiquitin. Brains of PD patients show evidence of extensive oxidative damage and microglial activation. Additionally, PD patients are characterized by systemic mitochondrial dysfunction, marked by inhibition of complex I of the mitochondrial electron transport chain. The pathogenesis of idiopathic PD is believed to involve an interaction between genetic and environmental factors. Specifically, PD has been associated with pesticide exposure and rural living. Two recently developed animal models of PD investigate the involvement of environmental exposures in PD pathogenesis. In the rotenone model of PD, rats are exposed, chronically and systemically, to low doses of rotenone, a commonly...

Parkinson Disease

James Parkinson first described Parkinson disease (PD), a neurodegenerative disorder with an incidence range from 4.9 to 26 per 100,000 and prevalence of approximately 200 per 100,000, in 1817 in his monograph Essay on the Shaking Palsy. Parkinson termed the disease paralysis agitans and reported resting tremor, festinant gait, flexed posture, dysarthria, dysphagia, insomnia, and constipation as the hallmarks of the condition. Charcot subsequently used the term Parkinson's disease, and differentiated the resting tremor of PD from the cerebellar outflow action tremor seen in multiple sclerosis. He also noted that tremor was not always present in all PD cases, and that cognitive decline may also be a part of the disease. In 1893 researchers discovered that the substantia nigra was abnormal in those afflicted with PD. Subsequent examinations of the brains of patients dying with idiopathic PD demonstrated depigmentation of the substantia nigra in the midbrain, associated with a loss of...

Parkinsons disease

A disorder of the extrapyramidal motor system of unknown aetiology. Onset is gradual, and usually occurs after the age of 50. Pathological changes include degeneration of cells and loss of pigmented neurones in the substantia nigra, in excess of the rate normally associated with ageing.These cells synapse with dopamine receptors in the striatum (Mason et al 1996). Biochemical abnormalities in brain neurotransmitters, and in particular a deficiency of dopamine in the striatum and substantia nigra, have been demonstrated. Balance and movement are particularly affected by these changes. Parkinson's disease has also occurred following insults to the brain such as encephalitis lethargica, trauma, certain chemicals, major psychotropic drugs, cerebrovascular disease, or hypoxia. Parkinsonian features may occur in other degenerative CNS diseases that may exhibit additional signs such as autonomic failure (eg multiple system atrophy). introduction of levodopa, which increases the dopamine...

Parkinsonism

Major signs are resting tremor, rigidity, akinesia, and postural instability (2). Advanced PD rarely presents a diagnostic problem, but careful medical history and clinical examination is necessary at an early stage of a parkinsonian syndrome and in very old patients, especially because of other superimposed neurological or non-neurological disturbances (vascular lesions, musculoskeletal disease, vision and auditory problems). Micrographia and slowness of handwriting (the size of the handwriting progressively decreases after a few words or sentences in patients with PD there is a fast micrographia with small letters from the beginning in PSP patients). From Current Clinical Neurology Atypical Parkinsonian Disorders Edited by I. Litvan Humana Press Inc., Totowa, NJ In all cases, the examiner has to obtain a complete drug history as drug-induced parkinsonism and PD can present with the same clinical signs.

Series Editors Introduction

Since the original classic description of Parkinson's disease, there have been swings in concept from a unitary disease with characteristic clinical features and unique neuropathologic changes to that of a more variable disorder with multiple etiologies owing to a spectrum of pathological processes. Originally, the terms paralysis agitans and Parkinson's disease first used in the 19th century implied a unitary disease. The concept of parkinsonism as a special disease entity was supported by the stereotyped features of akinesia, rigidity, tremor, and postural instability. The appearance of postencephalitic parkinsonism and later the recognition of arteriosclerotic parkinsonism led to the realization that there must be multiple forms of the disease. Idiopathic Parkinson's disease finally became anchored by identification of the Lewy body, which provided the necessary objective marker for what, at least temporarily, quite remarkably came to be called Lewy body disease. However, the later...

Classification and Clinical Features of Movement Disorders

The sensorimotor system is the primary means of interaction with the world. Incoming (sensory) information is processed in the nervous system, and in animals it may be measured by behavioral (usually motor) responses. Central to this merging of sensory and motor function are the structures of the basal ganglia the substantia nigra, the caudate, putamen, globus pallidus, and subthalamic nucleus. Disturbances in the basal ganglia therefore lead to altered amplitude, rate, or content of movement, and may produce symptoms classified as a movement disorder. This chapter will review the functional architecture of the basal ganglia from a phylogenetic standpoint, and briefly review neuronal loops involved in cognitive, affective, and motor behaviors. In addition, this chapter will cover hypokinetic and hyper-kinetic movement disorders with emphasis on etiology, historical and physical findings, pathogenesis, and treatment. Parkinson disease is the prototypical movement disorder associated...

Clinical Diagnosis Of Movement Disorders

Investigators gathering historical information from a clinical evaluation of movement disorders should gather data pertaining to age of onset, symptom progression, type of involuntary movement, aggravating factors, and relieving factors (e.g., anxiety, stress, sleep, alcohol, food, and medications). Almost all involuntary movements, except for segmental myoclonus, tics, and hemifacial spasm, disappear during sleep. In addition past medical history, recent travel history, family history, toxins chemical exposure, and information regarding medications are important. Dopamine receptor-blocking drugs, such as traditional antipsychotic and antiemetic medications, are associated with Parkinsonism and tardive dyskinesia other agents such as cortico-steroids and medications for obstructive pulmonary disease are known to produce tremor. Neurological examination should include assessment of language, memory, and other higher cortical functions. Frontal release signs such as Myerson's sign are...

Differential Diagnosis

If the patient lacks a family history for a choreic or psychiatric disorder, then the clinician should consider the following disorders senile chorea, tardive dyskinesia, central nervous system (CNS) vasculitis, subdural hematoma, Wilson disease, pantothenate kinase-associated neurodegeneration, Sydenham chorea, antiphospholipid antibody syndrome, Creutzfeldt-Jakob disease, and various toxic and metabolic disorders. The specific toxins causing chorea include oral contraceptives, levodopa, CNS stimulants, neuroleptics, phenytoin, carbamazepine, ethosuximide, and other drugs. Metabolic-endocrine disorders associated with chorea include chorea gravidarum, thyrotoxicosis, hypoparathyroidism, hypernatremia, Addison disease, and chronic hepatocerebral degeneration, among others (Stacy and Jankovic 1992b).

Genetics of Dystonia

One type of inherited dystonia that deserves special emphasis is dopa-responsive dystonia (DRD), formerly designated as DYT5. It is an autosomal dominant, childhood-onset dystonia that is due to mutations in the gene for GTP cyclohydrolase I. This disorder is more common in girls (2.5 1), and is frequently associated with Parkinsonian features therefore, it may be difficult to differentiate this condition from juvenile PD. Most patients report a dramatic improvement with levodopa. Maximum benefit occurs within several days of levodopa therapy, and when combined with a dopa-decarboxylase inhibitor (carbidopa), patients may be maintained on as little as 50 mg day (Nygaard et al. 1991).

Clinical Features of Wilson Disease

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism with usual onset in children and young adolescents. The characteristic features are facial and generalized dystonia, rigidity, postural instability, dysarthria, drooling, sardonic facial grin, seizures, cerebel-lar incoordination, tremor, behavioral changes, deterioration in school performance, and evidence of hepatic dysfunction. An adult patient may present with Parkinsonian features, choreoathetosis, and a violent postural (wing-beating) tremor. The clinical hallmark of the disorder is a brownish-yellow ring at the corneal rim (Kayser-Fleischer ring), which is due to copper deposits in the cornea (Jankovic and Stacy 1998).

Corticobasal Degeneration

The clinical and pathological hallmarks of corticobasal degeneration were delineated in 1968 by Rebeiz (23). Asymmetric parkinsonism in the context of a progressive dyspraxia, unilateral dystonia, and cortical sensory impairment are the major clinical findings found in association with corticodentatonigral degeneration with neuronal achromasia. In addition to the Dutil report cited earlier (see Fig. 3), a thesis by Bechet (24), dated 1892, documents a patient (case VIII) with possible corticobasal degeneration. The patient's hallmarks were progressive tremor and contracture of the right upper extremity. Gradually, the trunk and neck developed extreme rigidity as well. The remarkable posture of the right upper extremity dominated the atypical picture

Multiple System Atrophy

This diagnosis is particularly difficult to study historically, because the variety of symptoms and different phenotypes have been labeled with a wide vocabulary and nosology. In 1865, Sanders introduced the term dystaxia or pseudo-paralysis agitans to describe a patient with severe action tremor and gait impairment without sensory loss (29). Dejerine and Thomas described olivopontocerebellar atrophy in 1900 and emphasized varying mixtures of parkinsonian, cerebellar, and autonomic dysfunction (30). Critchley and Greenfield reviewed cases from the early 20th century, citing such names as Pierre Marie, Murri, Lhermitte, and Wilson, commenting on the changing terminology and noso-graphic confusion related to this disorder (31). In 1925, Ley reported the same type of presentation as Dejerine and Thomas in a 50-yr-old man, and at autopsy, he noted not only olivopontocerebellar lesions, but also atrophic substantia nigra (32,33). In 1960, Shy and Drager described two patients with...

Progressive Supranuclear Palsy

Vertical Supranuclear Gaze Palsy

In 1963, Steele, Richardson, and Olszewski presented a report at the American Neurological Association of a new syndrome typified by parkinsonism, marked vertical gaze paresis, dementia, and axial rigidity (10,11). Though they felt they were describing a new syndrome, they referred colleagues to similar cases from the recent past (12-14) (Fig. 4). H. Houston Merritt opened the discussion, commenting that he had not seen similar cases, that the involved areas all related to cell populations of similar phylogenetic age, and that dementia was of particular interest. F. McNaughton acclaimed I believe that the authors have described a clear-cut neurological syndrome and to judge from the pathological studies, it may, in fact, represent a new disease entity. D. Denny-Brown was less sure and ascribed the cases to variants of Jakob's spastic pseudosclerosis (10). Prior to these 20th-century descriptions, several cases of Parkinson's disease with extended posture can be identified with...

Alternatives and Complements to Animal Models

Research activities targeting a particular movement disorder, whether it is Tourette syndrome, blepharospasm or myoclonus, must begin and end with patients. Patients provide the material and motivation for scientific investigation. Skilled clinicians initially described the primary features, secondary manifestations, and pathological hallmarks of each type of movement disorder without access to powerful modern tools of science such as magnetic resonance imaging (MRI) and the polymerase chain reaction (PCR). Even in the twenty-first century, neurologists diagnose nearly all patients with movement disorders at the bedside. Parkinson disease, cervical dystonia, essential tremor, Friedreich ataxia, and Huntington disease can be easily diagnosed, in most instances, without computed tomography, electrophysiological studies, or genetic testing. For example, identifying an expansion of CAG trinucleotide repeats in the IT15 gene serves only to confirm a clinical diagnosis of Huntington...

Implications From Prevalence and Incidence Data

Despite rather limited data, there are no clear signs that there are widespread geographical differences in PSP and MSA, however there are almost no data from developing countries and one cannot exclude that in other populations or ethnic groups there may be higher rates. Atypical parkinsonism has been reported with greater frequency in the Caribbean (18) and among South Asians and African Caribbeans (19) in the United Kingdom, though these latter observations remain controversial. Little obvious differences exist across Europe, as has been noted for PD (17), or North America, yet more higher-quality studies are required especially to estimate incidence rates.

Risk Factors For Psp And

The epidemiology of PD has been greatly aided by two natural experiments that generated important hypotheses regarding its etiology. The first was the encephalitis lethargica epidemic, which suggested a role for an infective agent (20). The second was the strange occurrence of MPTP-induced parkinsonism (21), which suggested the role of a neurotoxic agent and led to studies examining the role of pesticides because of its similarity with paraquat (22). The relevance of these models for the etiology of PSP and or MSA is far more questionable. However, in the absence of any other clues, most researchers have simply used risk factors that have been suggested to be important for PD, e.g., smoking behavior, head injury, pesticides, well water, etc., and tested them out in PSP and MSA as essentially a hypothesis-generating exercise.

The Value of Animal Models

The field of movement disorders research is difficult to imagine without animal models. Neuroscience research in general, and motor systems science in particular, are critically dependent on experimentation with animals. The profound complexity of normal and abnormal neural networks cannot be reproduced in either the test tube or culture dish. Attempts to identify molecular, genetic, and neurophysio-logical defects in animal models of movement disorders have forced scientists to make more focused analyses of normal neural function and, as a result, significant advances have been made in motor systems physiology. For example, animal models of Parkinson disease and dystonia have contributed to our understanding of basal ganglia and cerebel-lar local area networks, respectively. Normal motor behavior is the final product of massive neural computation performed by tissues with precise three-dimensional organizations and connectivity patterns. Similar to an electronics technician searching...

Nonhuman Primate Models Of Motor Response Complications

MPTP and Parkinson Disease In 1982, several young drug addicts in California developed a severe Parkinson-like syndrome after injecting a potent synthetic drug containing (MPTP) (Langston et al. 1983 Jenner 2003). Exposure to MPTP produced bradykinesia and rigidity, almost identical to signs exhibited by patients with idio-pathic Parkinson disease (PD) (Ballard et al. 1985 Jenner 2003). Moreover, these symptoms showed optimal therapeutic response to dopamine and dopamine agonist. B. MPTP and Nonhuman Primate Model of Parkinson Disease The possibility of recreating a syndrome resembling the major characteristics of PD triggered researchers to develop an experimental animal model using systemic administration of MPTP. Previously, the commonly used animal model of PD was the 6-hydroxydopamine (6-OHDA) rat, which is an excellent model for testing and determining modes of action of new pharmacological compounds. However, the model lacks the behavioral features of idiopathic PD and the...

Pathogenesis Of Motor Response Complications In Nonhuman Primates

While the entity of nigral degeneration can definitely play a role in the onset of motor complications (Di Monte et al. 2000), it is not essential for inducing dyskinesias (Jenner 2000). Any dopaminergic agent can induce dyskinetic movements, including both D1 and D2 dopamine agonists (Jenner 2000). Their ability to induce involuntary movements is mostly attributed to their pharmacokinetic and pharmacodynamic properties long-acting dopamine agonists are less prone to induce complications than short-acting ones. While normal motor function depends on the continuous synthesis and release of dopamine by neurons projecting from the substantia nigra to the striatum, the pulsatile stimulation resulting from the standard anti-Parkinsonian therapy is deemed responsible for the pathogenesis of motor complications (Chase 1998). In the non-Parkinsonian brain, the nigrostriatal pathway is usually tonically active, leading to relatively constant dopaminergic stimulation of striatal dopamine...

Research Applications

Numerous investigators have done physiological and electrophysiological studies with MPTP-treated nonhuman primates while the animal was active. For example, MPTP-treated nonhuman primates have prolonged reaction times measured by EMG and prolonged time to reach and manipulate food rewards (Schultz et al. 1989). Furthermore, independence of pallidal neurons may diminish after MPTP-induced parkinsonism as demonstrated by increased synchrony of firing between pallidal neurons (Nini et al. 1995). Tonically active neurons in striatum also increase their synchrony with firing of pallidal neurons after MPTP in vervet monkeys (Raz et al. 2001). Dopamine replacement therapy normalizes firing rates in GPe and GPi in vervet monkeys trained to perform a button-pressing task and also reverses the abnormal MPTP-induced synchronization of pallidal neuronial firing (Heimer et al. 2002). Other studies found that responses to reversible lesions using focal injections of the GABA agonist muscimol into...

Concluding Remarks

Thanks to the efforts of many investigators, a wide repertoire of behavioral testing methods have now been devised and characterized to permit a preclinical screening of anti-Parkinsonian treatments in the rat. Our laboratory has contributed to the characterization and validation of the first testing method that specifically rates L-dopa-induced abnormal involuntary movements (dyskinesia) in the rat. Since new treatments for PD will be successful to the extent that they can alleviate akinesia without producing abnormal movements and postures, the availability of a dyskinesia model in the rat represents a considerable methodological and conceptual advance. As we have illustrated in this chapter, different behavioral tests evaluate different aspects of a rat's motor function, they show different relationships to the degree of brain DA depletion, and exhibit different sensitivities to the anti-akinetic effect of L-dopa and to the disrupting effect of L-dopa-induced dyskinesia. Thus, the...

Genetic Contributions In

In PSP, the age of onset for initial symptoms ranges from fifty-five to past eighty years, with a five to six year duration of disease before death 11,95,116 . PSP is clinically characterized by Parkinsonism and prominent vertical gaze palsy 43,127 . Patients can also exhibit deficits in visual attention, information processing, long-term memory, conceptualization, and social cognition 70,84,86,102,106 . PSP is one of a number of Parkinsonian disorders that manifest as dementias, movement disorders, or both and share neu-ropathology that includes ubiquitinated neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau proteins and ubiquitinated a-synuclein proteins (found in the form of Lewy bodies LBs ) 108 . These overlapping neurodegenerative diseases include Parkinson disease (PD), Parkinsonism-Dementia Complex of Guam (PDC-G) and Guamanian-ALS (ALS-G), frontotemporal dementia with Parkinsonism chromosome-17 type (FTDP), and progressive supranuclear palsy (PSP). Among...

Legend To Videotape

This video shows a 67-yr-old patient with a two-year history of probable DLB (MMSE 21), with no previous neurological, psychiatric or medical history. Parkinsonian features appeared within the first year of cognitive impairment. Medication comprised a cholinesterase inhibitor and low dose co-careldopa. Sequence 3 Assessment of parkinsonian features, including reduced blink rate, significant hypomimia, monotonous speech, bradyphrenia, limb bradykinesia and reduced arm swing when walking.

Clinical Presentations Of Huntington Disease

A type of late onset HD presents with significant features of Parkinson disease. The combination of both hyperkinesia and bradykinesia is different from the rigid type of juvenile onset of HD in that the Parkinsonian features may improve after treatment with L-dopa. The age of onset of these patients has varied from less than fifty to mid-to-late sixties, and CAG repeats reported in these patients have varied from forty-two to forty-six.81

Other Investigations

CSF-NFL and levodopa tests combined with discriminant analysis may contribute to the differential diagnosis of Parkinsonian syndromes (Holmberg et al., 2001). Whereas the CSF-NFL and levodopa tests predicted 79 and 85 correct diagnoses (PD or non-PD MSA and PSP ), respectively, the combined test predicted 90 correct diagnoses. The authors conclude that the CSF-NFL and levodopa tests

Clinical Diagnostic Criteria

Clinical diagnostic criteria for MSA were first proposed by Quinn in 1989 (11) and later slightly modified in 1994 (12). According to this schema, patients are classified as either striatonigral degeneration (SND) or olivopontocerebellar atrophy (OPCA) type MSA depending on the predominance of parkinsonism or cerebellar ataxia. There are three levels of diagnostic probability possible, probable, and definite. Patients with sporadic adult-onset poorly levodopa-responsive parkinsonism fulfill criteria for possible SND. The presence of other atypical features such as severe autonomic failure, cerebellar or pyramidal signs, or a pathological sphincter electromyogram (EMG) is required for a diagnosis of probable SND. Patients with sporadic late-onset predominant cerebellar ataxia with additional mild parkinsonism or pyramidal signs are considered possible OPCA-type MSA. This may result in confusion since some patients with possible OPCA may also qualify for probable SND provided...

Diffuse Lewy Body Disease

Dementia with Lewy bodies (DLB) is the second most common type of cognitive degeneration after Alzheimer's disease (AD) (169). Clinically, DLB is characterized by spontaneous parkinsonism and progressive dementia associated with fluctuating cognitive functions, and hallucination (169). Parkinsonism and dementia tend to co-occur. A history of Parkinsonism predating dementia by more than 1 yr might be better designated Parkinson's disease with dementia. Since publication of the clinical and pathological diagnosis criteria (169), several studies have tried to delineate the neuropsychological features that distinguish DLB disease from AD. A number of them have demonstrated that, compared with AD, visuospatial and visuoconstructive abilities are disproportionately impaired in patients with DLB disease (170-173). Compared with AD patients matched for age, sex, education, and Mini Mental State Examination (MMSE) score, DLB patients perform worse on the Raven Colored Progressive Matrices test...

Clinical Characteristics

The hallmark feature of ET is a kinetic tremor, and this probably results from an abnormality in the cerebellum or cerebellar-thalamic outflow pathways. In addition, recent work has demonstrated that, as in other neurodegenerative diseases (e.g., Parkinson disease PD , Alzhemier disease, and Huntington disease), involvement of the central nervous system may be diffuse, having the tendency to evolve over It is well known that some patients with ET develop a tremor at rest 9,33 . In one study 10 , investigators studied the prevalence and clinical correlates of this tremor in a sample of ET patients who were referred to a tertiary referral center. In that study 10 , 18.8 of the ET patients had a rest tremor (i.e., approximately one in five ET cases), which suggests that this type of tremor is not uncommon in ET patients who are seen at tertiary referral centers. When compared to the ET patients without rest tremor, those with rest tremor had a disease of longer duration and of greater...

Relevance Of C Elegans In Modeling Human Movement Disorders

A surprisingly limited number of worm models have been created that attempt to recapitulate features of human movement disorders, especially when one considers the number of mouse models. Even considering the number of Drosophila models, a paucity of invertebrate movement disorder models remains. Published models include an amy-otrophic lateral sclerosis model in Drosophila (Elia et al. 1999), a Parkinson disease model in Drosophila (Feany and Bender 2000), and several polyglutamine repeat diseases including Huntington in C. elegans (Faber et al. 1999) and in Drosophila (Jackson 1998). If viewed from the perspective of movement phenotypes, an Alzheimer disease model in C. elegans that overexpresses beta-amyloid peptide results in a dramatic progressive paralysis (Link 1995). A more recent study has described overexpression of torsin A that serves as a model of torsion dystonia (Caldwell et al. 2003). C. elegans, an in vivo system. These studies could include transgenic crosses with C....

Clinical Classification Of Dystonia

1998) to distinguish pure dystonic syndromes from those with dystonia plus other movement disorders, such as dopa-responsive dystonia, where Parkinsonism and spasticity may also be present. Current nomenclature refers to primary torsion dystonia when (1) dystonia is the only neurological feature (with the exception of tremor), (2) an exogenous or acquired cause cannot be historically identified (e.g., stroke, neuroleptic exposure), (3) there is no laboratory or imaging abnormality to suggest an acquired or degenerative etiology (e.g., Parkinson Disease, Wilson Disease), and (4) there is no dramatic response to levodopa,

Definition And Identification Of Key Neuropsychiatry Symptoms

The definition of psychotic symptoms (i.e., delusions, delusional misidentification, and hallucinations) requires particular consideration as these symptoms are very frequent in some parkinsonian disorders, particularly in patients with dementia. In addition, as they are phenomenologically different from psychotic symptoms occurring in patients with functional psychoses and cannot be reliably observed or inferred from behavior, a specific method is required to identify these symptoms in patients with cognitive impairments. According to Burns, delusions are defined as false, unshakable ideas or beliefs that are held with extraordinary conviction and subjective certainty (3). To minimize overlap with confabulation and delirium, they should be reiterated on at least two occasions more than 1 wk apart. Hallucinations are described as percepts in the absence of a stimulus, reported directly by either the patient or indirectly via an informant, and may occur in any modality. Typically,...

Behavioral Dysfunction

Classical antipsychotic drugs that potently block dopaminergic receptors can ameliorate psychotic symptoms but worsen parkinsonism, at times seriously enough to require levodopa (84). Better results in treating psychosis have been obtained with the atypical neuroleptics, possibly owing to their predominant antiserotoninergic rather than antidopaminergic activity. An extensive chart review revealed that 90 of DLB patients had partial to complete resolution of psychosis using long-term quetiapine, although in 27 motor worsening was noted at some point during treatment (85). A large, randomized blinded trial found that olanzapine (5 or 10 mg) reduces psychosis without exacerbating parkinsonism (86). Relatively small doses of clozapine have also been used successfully for the relief of paranoid delusions, psychosis, and agitation, albeit at the risk of agranulocytosis (84). Indeed, caution is generally warranted in using neuroleptics, since sedation, confusion, immobility, postural...

Tissue Specific Ablation

In several movement disorders, neurodegeneration of specific neuronal types is observed, such as the dopaminer-gic neurons in Parkinson disease and striatal neurons in Huntington disease. A model that mimics neurodegeneration without regard for the genetics of the disorder can also be achieved with the transgenic approach. A widely used method of genetic ablation of specific tissues relies on the diphtheria toxin A-chain gene (DTA). The toxin gene's expression is controlled by the tissue-specific promoter it is linked to (Breitman et al. 1987 Palmiter et al. 1987). When expressed, the toxin causes cell death. A variation on this technique has been developed that allows for inducibility of the toxin. The promoter of tTA selects for the tissue type and the tet-op promoter drives DTA expression (Lee et al 1998). Another conditional ablation method uses the human inter-leukin 2 receptor that is controlled by a desired promoter. Application of the recombinant immunotoxin anti-Tac(Fv)-PE40...

Dementia With Lewy Bodies

DLB has not been examined as extensively with PET and SPECT as other atypical parkinsonian disorders. Albin and colleagues have reported the 18FDG PET findings of six demented individuals with pathologically verified diffuse Lewy body disease (71), three of whom had had pure DLB and three combined DLB and Alzheimer's disease (DLB-AD) pathology. These patients showed hypome-tabolism in association cortices with relative sparing of subcortical structures and primary somatomotor cortex, a pattern reported previously in AD. The main difference in comparison to patients with AD was the more pronounced hypometabolism in the occipital association cortex and primary visual cortex, indicating the presence of diffuse cortical abnormalities in DLB and suggesting that FDG-PET may possibly be useful in discriminating DLB from AD antemortem (Fig. 4). A direct metabolic comparison of patients with PD and DLB has not been performed to date to our knowledge since occipital decreases in occipital...

Treatment Of Huntington Disease

Currently, only symptomatic therapy is available for HD.96 The major goals of symptomatic therapy are to control psychosis, treat depression and suicidal tendencies, and possibly control the severity of chorea and other motor manifestations. Dopaminergic and serotonergic receptor blockade with typical and atypical antipsychotics have been the major source symptomatic therapy for HD patients. Among the drugs that are commonly used are haloperidol, risperidol, quetiapine, olanzapine, and clozaril.97-100 Anti-dopaminergic agents appear to be ineffective in the treatment of chorea. However, long-term use of typical antipsychotics may also complicate the course of the disease by inducing either drug-induced Parkinson's disease and or tardive dyskinesias and tardive dystonia. Severe depression is treated with SSRIs and other antidepressants. 1. Biglan, K., and I. Shoulson. 2002. Huntington's disease. In Parkinson s Disease and Movement Disorders. 4th Ed. Ed. J. Jankovic, and E. Tolosa. pp....

Overview Of A Movement Disorders Rehabilitation Program

The rehabilitation team monitors medication effects and side effects. Educational inservices are given to assure correct identification of parkinsonian signs and side effects including tremor, freezing, wearing-off phenomena, dyskinesias, hallucinations, and orthostasis. Clinical responses are documented and tracked in relation to medication dosing. These observations are key for medication adjustment decisions.

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