Parkinson Disease Alternative Treatment

Parkinson Diseases Handbook By Lianna Marie

This is a guidebook including the 109 pages that reveals step-by-step instructions for treating Parkinsons disease. The book was completed for her 16-year experience in Parkinsons disease treatment. In this book, people will discover what they should know about Essential Tremor, and how Essential Tremor differs from Parkinson's disease. People will find out 12 essential differences between Essential Tremor and Parkinson's disease in this book. Moreover, the book also reveals what people should know about Early Onset Parkinson's, how they can control their anxiety and depression, and what they should know about stress. Part of the money from every purchase goes to Parkinson's Disease research, to help make a complete cure for this disease possible. Not only will you be getting all the information you need, but your purchase will help prevent others from having to go through the same thing. More here...

All About Parkinsons Disease Overview

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Author: Lianna Marie
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Review: Everything You Need To Know About Parkinson's Disease

Highly Recommended

All of the information that the author discovered has been compiled into a downloadable pdf so that purchasers of All About Parkinson's Disease can begin putting the methods it teaches to use as soon as possible.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

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Genes Causing Parkinsonism

Golbe and his colleagues first reported a large family with an autosomal dominant form of parkinsonism in 1990 (20). Beginning with patients living in New Jersey, United States. the ancestry of this family was traced to a single couple in the village of Contursi, in the Campania region near Salerno in the south of Italy. Members of this family had immigrated to the United States around the turn of the 20th century and more than 60 family members over five generations had been diagnosed with disease. The disease described in this family ranged from a relatively typical PD to a disorder more reminiscent of diffuse Lewy body disease. The mean age at onset is early (mean 45.6, SD 13-48) and patients often develop dementia (21). mutation, a G-to-A transition at nucleotide 209, resulted in an alanine to threonine (A53T) substitution in this protein (23). The same mutation segregated with a similar disease in an additional three Greek kindreds examined by the authors. Subsequently, two other...

Basal ganglia discharge abnormalities in Parkinsons disease T Wichmann12 and M R DeLong1

In the traditional model of the pathophysiology of parkinsonism, parkinso-nian motor signs are viewed as the result of changes in discharge rates in the basal ganglia. However, not all experimental findings can be explained by rate changes alone, and changes in discharge patterns in these nuclei are increasingly emphasized as pathophys-iologically important, including changes in burst discharges, in synchrony, and in oscillatory activity. This brief review highlights the pathophysiologic relevance of these rate and pattern changes in the pathophysiology of parkinsonism.

Charcot on the Fundamental Characteristics of Parkinsons Disease

In the next section of his lectures, Charcot gives an overview of Parkinson's disease with respect to its etiology and diagnostic features. He begins by proposing that the disease itself is a neurosis, absent of a true physiological and pathological basis. This conclusion Charcot based on the absence of clear neuropathological abnormalities seen in postmortem examination of patients who died with Parkinson's. He states, Paralysis agitans, separated from foreign elements, is, gentlemen, at present a neurosis, in this sense that it possesses no proper lesion.12- p. 134 Charcot next turned his attention to the age of onset and the potential causes of Parkinson's disease. The discussion of the pertinence and applicability of symptoms in the diagnosis of Parkinson's disease serves as the next topic of discussion. In this discourse, Dr. Char-cot refers to the tremors, postural instability, and bradyki-nesia. The symptoms of paralysis agitans are not all of the same value. The most striking...

Bad oscillations in Parkinsons disease P Brown

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronise their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronised oscillation in the beta band (13-30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and movement suppress this activity, with the timing and degree of suppression closely correlating with behavioural performance. Accordingly synchronisation in the beta band has been hypothesised to be essentially antikinetic in nature and patho-physiologically relevant to bradykinesia. count for the major therapeutic benefits of functional neurosurgery in Parkinson's disease (PD). The implication is that it is not the degree of collective excitation or inhibition brought to bear at different stages of the BG-cortical loop, but rather...

Genetic Variants Where Parkinsonism Is Part Of The Clinical Spectrum

There are other genetic variants where parkinsonism is part of the clinical spectrum but where detailed clinical evaluation may preclude PD as a diagnosis. Although it would be distracting to describe all diseases where parkinsonism may be a feature, we have chosen four to discuss briefly. Spinocerebellar ataxias (SCAs) represent a family of genetically heterogeneous, dominant, neurodegenerative disorders that are mainly characterized by progressive ataxia resulting from the degeneration of cerebellar and spinal systems. In SCA-1, -2, -3, -6, -7, and -17, causal mutations have been characterized as expanded CAG repeats, which are translated into poly glutamine tracts within the protein product. L-dopa-responsive parkinsonism with minimal cerebellar deficits has been described in several of the SCAs, particularly SCA2 and SCA3 (also known as Machado-Joseph disease) (80-85). In 2000, a Taiwanese family was described with SCA2 expansion ranging from 33 to 43 repeats (normal 17 to 31...

Charcot on Nonmotor Symptoms of Parkinsons Disease

There is also elaboration on the more subtle physical, emotional and psychiatric nuances of paralysis agitans. Paralysis agitans is not merely one of the saddest of diseases, in as much as it deprives the patients of the use of their limbs, and sooner or later reduces them to almost absolute inaction it is also a cruel affection, because of the unpleasant sensations which the sufferers experience. Usually, indeed, (the neuralgic cases which we have already described being excepted), they are not affected by acute pains, but by disagreeable sensations of a special order. They complain of cramps, or rather of a nearly permanent sensation of tension and traction in most of the muscles. There is also a feeling of utter prostration, of fatigue, which comes on especially after the fits of trembling in short, an indefinable uneasiness, which shows itself in a perpetual desire for change of posture. Seated, the patients every moment feel obliged to get up standing, after a few steps they...

Charcot on Treatment Alternatives for Parkinsons Disease

This is one of the first descriptions of a centrally acting anticholinergic medication used for the treatment of Parkinson's disease. Subsequent practitioners drew from Charcot's experience and treated patients for years with various preparations of other derivatives of hyoscyamine. While Charcot speculated extensively on the pathology and etiology of paralysis agitans, no significant contribution was made at this time.12- pp. 150 152 However, his work allowed future neuropathologists to distinguish Parkinson's disease from the multitude of other neurological disorders with which this disorder was confused. In a very real sense, then, the careful scientific documentation of Charcot set the stage for the determination of the precise pathological abnormality causing Parkinson's.

Parkinsons Disease After Charcot

Parkinson distinguished the rigidity of paralysis agitans from the spasticity associated with spinal cord damage, mentioning repeatedly his belief that the pathology of paralysis agitans resided in the medulla. In 1871, Dr. Meynert described damage to the corpus striatum and the lenticular nucleus.13 This may have been the first suggestion that the tremor of paralysis agitans as well as chorea might involve the basal ganglia. Drs. Murchison and Cayley described a case in 1871 of paralysis agitans.14 There was shrinkage of the cerebral hemispheres, thickening of the spinal cord and infiltration of the spinal cord with connective tissue and inflammatory cells probably related to typhus. In 1878, Dr. Dowse described a case of a patient who died at age 43.15 No gross lesions were found the central nervous system however, there was pigmented granular degeneration of nerve cells along the spinal cord and diffuse sclerosis in white matter tracts. Miliary degeneration...

Dopamine And Treatment Of Parkinsons Disease

Given this pathology, a logical approach to treating Parkinson's disease would be to try to restore the levels of dopamine in the CNS. It was well known that dopamine does not cross the blood-brain barrier because of its positive charge. However, zwitterionic amino acids had the advantage of broadly specific transport systems to carry them across this barrier into the brain. Based on this, a top candidate for increasing dopamine levels in the CNS would be its immediate precursor, L-dihydroxyphenylala-nine or L-dopa. Not only could L-dopa be transported across the blood-brain barrier, it also had the advantage of by-passing the rate limiting step in the synthesis of catecholamines, tyrosine hydroxylase. This, in turn, provided two advantages. First, it avoided the slowest step in the synthetic process. In addition, tyrosine hydroxylase had been shown to be present only in catecholamine-containing neurons in the CNS, the very neurons that were disappearing in Parkinson's disease....

Treatment Of Parkinsons Disease By Severity Of Symptoms

Before discussing levodopa therapy, it should be mentioned that the type of treatment depends in large part upon the severity of the disease facing the patient. The earliest FIGURE 5 Change in the different components (A) mental, (B) ADL, and (C) motor of the Unified Parkinson's Disease Rating Scale with coenzyme Q10. Abbreviation ADL, activities of daily living. Source From Ref. 26. FIGURE 5 Change in the different components (A) mental, (B) ADL, and (C) motor of the Unified Parkinson's Disease Rating Scale with coenzyme Q10. Abbreviation ADL, activities of daily living. Source From Ref. 26. stage of PD begins when the symptoms are first noticed and the diagnosis is made. The designation of early stage lasts until the symptoms begin to become troublesome to the patient, and intervention with symptomatic medications is needed. All symptomatic drugs can induce side effects, and if a patient is not troubled by mild symptoms socially or occupationally, the introduction of these drugs can...

Clinical Benefit from Levodopa Therapy

Levodopa remains today the most powerful drug available to treat PD. In fact, the absence of a robust response to high-dose levodopa essentially excludes the diagnosis of PD and suggests that there must be another explanation for the parkinsonian symptoms. In contrast, a marked and sustained response strongly supports the diagnosis of PD (55). Although numerous other treatment options are available in early PD when the disease is mild, virtually all patients will eventually require levodopa therapy as the disease worsens. However, as mentioned above, not all symptoms of PD are equally responsive to levodopa. Bradykinesia and rigidity generally show the most dramatic improvement with dopaminergic therapy. In fact, the presence of residual rigidity is a good means by which to determine if a patient would further improve by increasing the dose. Tremor has a more variable (and often incomplete) response to levodopa. A number of other symptoms, including postural instability, micrographia,...

Problems with Levodopa Therapy

As PD worsens or with long-term usage of levodopa, more serious and persistent complications, such as wearing off fluctuations and dyskinesias (abnormal involuntary movements) emerge these motor complications affect 75 of patients after six years of levodopa therapy (1). These problems markedly impair the quality of life and functional status of affected patients and prove challenging not only for the patient but also for the treating physician. Today, these motor complications, especially clinical fluctuations and dyskinesias, have limited the usefulness of levodopa. The initial paper by Cotzias et al. (52) describing the successful use of high dosage d, L-dopa in patients with PD did not mention motor complications. The adverse effects mentioned were predominantly anorexia, nausea, vomiting, faint-ness, and hematologic changes. Cotzias et al. (53) then substituted levodopa for d, L-dopa, which eliminated the hematologic adverse effects. This paper also presents the first report of...

Summary of Clinical Phases of Levodopa Therapy

One can usually discern four clinical phases of PD in relation to treatment with levodopa. When levodopa is first introduced, there is a long-duration response from each dose, with few motoric complications. This is the initial period of maximum benefit without adverse motor effects. The duration of this phase varies, but usually lasts two to three years. With continuing treatment, the duration of beneficial response gradually shortens in almost all patients (56), who then need to take levodopa more frequently during the day to minimize the duration of the off (relatively immobile) periods in addition, patients often develop dyskinesias at peak plasma levels of levodopa parallel to the timing of their doses. After approximately five years of levodopa therapy, 75 of patients have either developed troublesome response fluctuations (wearing-off and on-off phenomena) or troublesome dyskinesias (1). During the wearing-off, dose-failures, and on-off states (which can total 50 or more of the...

The nigrostriatal DA pathway and Parkinsons disease K Fuxe1 P Manger2 S Genedani3 and L Agnati3

The discovery of the nigrostriatal DA system in the rat was made possible by the highly specific and sensitive histochem-ical fluorescence method of Falck and Hillarp in combinations with electrolytic lesions in the substantia nigra and removal of major parts of the neostriatum. Recent work on DA neuron evolution shows that in the Bottlenose Dolphin the normal DA cell groups of the substantia nigra are very cell sparse, while there is a substantial expansion of the A9 medial and A10 lateral subdivisions forming an impressive ' ' ventral wing'' in the posterior substantia nigra. The nigrostriatal DA pathway mainly operates via Volume Transmission. Thus, DA diffuses along concentration gradients in the ECF to reach target cells with high affinity DA receptors. A novel feature of the DA receptor subtypes is their physical interaction in the plasma membrane of striatal neurons forming receptor mosaics (RM) with the existence of two types of RM. The ' ' functional decoding unit''...

The nature of dementia in Parkinsons disease

There have been numerous reports of the impairment of specific cognitive functions in patients with Parkinson's disease. Some of the impairments described are often only identifiable by specially designed methods of assessment, but some are revealed by tests of cognitive function that are in widespread use. Mortimer and his colleagues have reported a very high prevalence of cognitive impairment 93 per cent in a substantial group of patients with Parkinson's disease. (l) Examination of their data showed neither a clear distinction between impaired groups nor the presence of subtypes of Parkinson's disease in which cognitive impairment was a more frequent occurrence. Their findings led them to propose that cognitive impairment in Parkinson's disease lies on a continuum of severity, rather than arising as a feature of particular subgroups. The impairments identified include deficits in memory, language, visuospatial functioning, abstract reasoning, slowness in intellectual tasks, and...

Studies of dementia in Parkinsons disease

Cases of dementia in Parkinson's disease have been reported for over a hundred years. Frequently, the relationship between dementia and this disease in reported cases is impossible to discern. A number of cross-sectional or prevalence studies of dementia in Parkinson's disease have been carried out. The frequency of dementia reported ranges from zero to 81 per cent. In a review of 17 studies Brown and Marsden found that, overall, 35 per cent of subjects were regarded as demented. (14> However, if more stringent criteria for dementia were applied then the proportions demented fell to between 15 and 20 per cent. The authors regarded these figures to be more realistic, and this Follow-up studies have great advantages in studying the frequency of dementia in Parkinson's disease they allow the diagnosis of Parkinson's disease to be checked repeated assessment reduces errors in the recognition of dementia the pattern of evolution of dementia may be followed the underestimation of dementia...

Prediction of dementia in Parkinsons disease

There is a consensus from a number of studies as to which of those subjects with Parkinson's disease are most likely to suffer from dementia older people, patients with Parkinson's disease of longer duration, subjects who have a greater severity of motor symptoms and signs of Parkinson's disease, and those who show greater physical disability. M6 Some studies have shown that Parkinson's disease in men or of late onset is more likely to be associated with dementia. (,9) In parkinsonism, as distinct from Parkinson's disease, the likelihood of dementia is closely related to the pathological changes that underlie the symptoms of parkinsonism, which include diseases in which dementia is a leading feature, such as Alzheimer's disease. The explanation of an apparent association between the treatment of Parkinson's disease with levodopa and dementia is probably that successful treatment of the motor symptoms of Parkinson's disease prolongs life and thereby increases the risk of dementia.

Clinical aspects of Parkinsons disease with dementia

The recognition of cognitive impairment in patients with Parkinson's disease has major implications for their management. Although prospective studies of patients with Parkinson's disease show that the illness usually follows a course extending over many years, dementia brings with it important changes in the care a patient will require and in their life expectancy. These needs will progressively increase and will place an increasing burden upon the patient's immediate family and carers. The timing of wills and other legal procedures may be affected. The most important step in the recognition of dementia in Parkinson's disease is to suspect its presence. There are many features of Parkinson's disease that tend to obscure the appearance of new clinical features of the disease. The typical blank facial expression seen in Parkinson's disease may obscure a decline in intellectual activity, slowness in movement may conceal intellectual slowness, and sadness may suggest that morbid...

Stages of sporadic PDassociated pathology in the brain

Sporadic PD cases but also cases with incidental LNs LBs because such lesions probably represent the first step along a disease continuum. And, in fact, spontaneous remission seems not to occur after formation of the initial lesions or after the threshold to clinical disease has been crossed (Braak et al., 2003a). A methodological limitation to this approach is that the progression of the pathological process was reconstructed postmor-tally using cross-sectional data. Thus, the conclusions drawn from these data are not definitive, although it can be argued that they rest upon admissible assumptions. Clearly, the discovery of suitable biological markers that can be measured longitudinally can help to refine or refute the proposed staging procedure (Rachakonda et al., 2004). A. All cases with sporadic Parkinson's disease (PD)- C. Predominantly clinically diagnosed cases of sporadic PD (PD stages 4-6) C. Predominantly clinically diagnosed cases of sporadic PD (PD stages 4-6) I. Cases...

Clinical demographics of sporadic Parkinsons disease

Sporadic PD is one of the most reliable and stable neurological diagnoses with 92 of the clinical features remaining unchanged for 5-10 years (Jankovic et al., 2000). While the incidence of sporadic PD significantly increases with age, the average age of onset for levodopa-responsive motor symptoms is around 60 years old. Fewer studies have assessed the average age at death for sporadic PD patients, but recent large-scale risk analysis using death and mortality as outcomes suggest that patients survive to 76 years of age on average (Wirdefeldt et al., 2005). These data show that, in the relatively homogeneous group of patients with dopa- Fig. 1. Stages identified for sporadic PD and average demographics compared with the stages identified in the Braak staging scheme for sporadic PD and the demographics of the cases fulfilling criteria for these pathological stages. Note the considerable overlap in demographics for the pathological stages suggesting that, potentially, only the cases in...

Pathways To Parkinsonism

Uncover the underlying disease pathways that result in the nigral degeneration, which ultimately leads to the clinical phenotype. In recent years the prevailing model has become synuclein-centric, associated with protein misfolding. Its two central tenets are the protein accumulation associated with a-synuclein mutations and the dysfunction of the UPS, which is associated with PARKIN mutants. However, preliminary data obtained from two of the recently identified genes, DJ-1 and PINK1, indicates that these genes are involved in protection against oxidative damage and mitochondrial dysfunction. DJ-1 and PINK1 may therefore promote neuronal, survival, and loss of their activity may also be a major molecular route in the development of PD in both familial and sporadic forms of disease.

LRRK2 Genetics and the Pathogenic Mechanisms of Parkinsonism

In 1997, Hasegawa and Kowa reported a family from the Sagamihara area of Japan with autosomal dominant inheritance of Parkinson's disease (PD)-like symptoms (1). In 2002, after excluding known loci (2), the same group reported linkage to the long arm of chromosome 12 and named the locus PARK8 (3). By 2004, two groups simultaneously published the identification of the gene responsible, LRRK2 (for leucine-rich repeat kinase 2), for the PARK8 locus in four additional families from different parts of the world (4,5). Within a year of that discovery, the LRRK2 gene was shown to be the most common genetic cause of PD to date (6). This short chronology says a great deal about the accelerating pace of discovery in the genetics of PD, which, as others have pointed out (7), was once considered the archetype of a nongenetic disease. But, as is discussed in this chapter, these discoveries have blurred the boundaries between PD and atypical parkinsonian disorders and raise interesting questions...

Genetic Disorders Implicated with Misregulation of Iron Metabolism and Parkinsonism

Cognitive decline and extrapyramidal dysfunctions including dystonia and parkinsonism 27 . The disrupted expression or function of proteins involved in iron metabolism increases the concentration of iron in the brain (Table 2). How these mutated genes operate and interact to induce abnormal brain iron metabolism, transport and accumulation in the central nervous system (CNS) and how iron in turn interacts with proteins involved in parkinsonism (for example, a-synuclein), causing them to aggregate into toxic inclusions is the focus of much current parkinsonism, Parkinsonism, Parkinsonism dystonia, spasticity, parkinsonism, and rigidity substantia nigra parkinsonism, parkinsonism

Nongenetic causes of Parkinsons disease A R Chade M Kasten and C M Tanner

Department of Clinical Research, Parkinson's Institute, Sunnyvale, CA, USA Summary. Study of the nongenetic causes of Parkinson's disease (PD) was encouraged by discovery of a cluster of parkinsonism produced by neurotoxic pyridine (MPTP) in the 1980s. Since that time, epidemiologic investigations have suggested risk factors, though their results do not establish causality. Pesticide exposure has been associated with increased risk in many studies. Other proposed risks include rural residence and certain occupations. Cigarette smoking, use of coffee caffeine, and non-steroidal anti-inflammatory drugs (NSAIDs) all appear to lower risk of PD, while dietary lipid and milk consumption, high caloric intake, and head trauma may increase risk. The cause of PD is likely multifactorial. Underlying genetic susceptibility and combinations of risk and protective factors likely all contribute. The combined research effort by epidemiologists, geneticists, and basic scientists will be needed to...

Evidence For A Genetic Component In Parkinsons Disease

In later studies, Tanner and colleagues (11) examined concordance rates in the NAS NRC World War II Veteran Twins Registry. Screening 19,842 white male twins identified 193 twin pairs with at least one individual affected with PD. Overall there was no statistically significant difference in concordance rates in MZ twins (15.5 ) compared to DZ twins (11.1 ). However, when considering 16 pairs where one twin had onset of symptoms prior to age 50, concordance rates were significantly different (100 MZ vs. 16.7 DZ). The authors of the study interpreted their results as supporting a genetic etiology for early, but not late-onset PD. However, Langston (12) pointed out that an additional five to 10 years of follow-up will be necessary to ensure that the low concordance rates are not due to the inadequate follow-up, a problem also plaguing earlier twin studies of PD (9). This idea was supported by the study of Piccini et al. (13) who performed PET scans on twins in a large longitudinal study....

Screens for Risk of Parkinsons Disease

Follow-up studies from the Parkinson Study Group with increased sample sizes and or more stringent definitions of PD (39) have strengthened their strongest initial findings on chromosomes 2q, 6q, and Xq (36). A meta-analysis of these linkages studies has not yet been performed mainly due to the difficulty of combining data from the different genetic markers that have been genotyped in different datasets.

Genomic Modifiers Ageat Onset of Parkinsons Disease

The recent study of GSTO1 2 and AAO in PD and AD by our group demonstrated significant association for both disorders. The functions of GSTO1 are not well understood (49). The Ala140Asp and Thr217Asn variants of GSTO1 display reduced enzyme activity (50) and therefore might influence the susceptibility to oxidative stress. Recent data suggest that GSTO1 may be involved in the post-translational modification of the inflammatory cytokine Interleukin-1b (51) and contribute to inflammation, which is provocative given reports of the possible role of inflammation in PD (52). Recently, our group (53) found that only 39 174 families showed both positive linkage on chromosome 10 and positive association of GSTO1 with PD. In this set of families the average AAO difference between asparagine carriers and individuals homozygous for alanine at the GSTO1 rs4925 polymorphism is 7.9 4.78 years, much higher than 1.6 7.17 observed in the overall dataset. This data can be used to discuss various aspects...

Role of proteolytic processing and mitochondrial dysfunction in PD

Mutations in the parkin gene are thought to cause a loss of ligase function preventing the ubiquitination of its substrates. This supported the hypothesis of impaired ubiquitin-mediated protein degradation causing neurodegeneration in PD via accumulation of Parkin substrates. However, existing loss-of-function mouse models do not display any neuronal loss and do not exhibit an accumulation of any of the known Parkin substrates (Itier et al., 2003 Palacino et al., 2004 Goldberg et al., 2003). An interesting feature in parkin knockout mice was an effect on mitochon-drial respiratory capacity and indirect markers for oxidative stress (Palacino et al., 2004). Mitochondrial dysfunction is a common feature of PD (Beal, 2000). A specific and selective loss of mitochondrial complex I activity in the substantia nigra of PD patients reflects an important mechanism of mitochondrial pathology in PD (Shapira, 1999). Neuronal mitochondria function as integrators of diverse cellular stresses and...

Amyloid As A Common Theme In Neurodegenerative Parkinsonian Diseases

Parkinson's disease (PD) and Alzheimer's disease (AD) may be pathogenically linked by a single common mechanism the aggregation and deposition of mis-folded proteins (1-3). Indeed, as summarized in Table 1, nearly every major neurodegenerative disease is pathologically characterized by the insidious accumulation of insoluble filamentous aggregates of normally soluble proteins in the central nervous system (CNS) (3). Since these filamentous aggregates show the ultrastructural and tinctorial properties of amyloid (i.e., 10 nm wide fibrils with crossed-P-pleated sheet structures that stain with congo red, thioflavin-S, or other related dyes), these diseases are appropriately linked together as brain amyloidoses (4). An understanding that PD and other neurodegenerative parkinsonian diseases including cortical basal degeneration (CBD), progressive supranuclear palsy (PSP), and frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) are related brain amyloidoses may...

Tau Pathology In Parkinsonian Degeneration

Tau pathology defines several of the parkinsonian neurodegenerative diseases, including CBD, progressive supranuclear palsy (PSP), frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), amylotrophic lateral sclerosis parkinsonism-dementia complex of Guam (ALS PDC Guam) and dementia puglistica. Together, these diseases are referred to as tauopathies a designation that evokes the strong correlative evidence between tau pathology and neurodegeneration in these parkinsonian diseases.

Familial Parkinsonism Of

PARKINSON'S DISEASE PHENOTYPE In the Parkinson's disease phenotype of heredofamilial parkinsonism, some families have the exact genetic defect or an identified susceptibility locus on the chromosome (Table 14.1). Others have an as yet unknown genetic status. The pathogenesis of Parkinson's disease is largely unknown, but it is probably due to a combination of genetic and environmental factors.15 Genetics seem to play a prominent role, especially in patients with an early onset.516 Genetic linkages have been identified in families with Parkinson's disease or sporadic Parkinson's disease. Familial Parkinson's disease can be inherited as autosomal dominant or autosomal recessive trait. Patients with sporadic Parkinson's disease are most likely to carry an autosomal recessive gene, although it may be possible for Parkinson's disease that is autosomal dominant to have a sporadic presentation because of reduced penetrance or clinical expression.17

Frontal Temporal Dementia with Parkinsonism Linked to Chromosome

FTDP-17 is a heterogenous clinical pathologic entity that can now be defined by the presence of causative mutations in the tau gene (as described subsequently). As the name implies, the clinical picture is dominated by frontal-temporal dementia and parkinsonism. Different FTDP-17 syndromes have been described, and pheno-typic differences may reflect differences in regional distribution of tau pathology and degeneration in the brain (15).

Amylotrophic Lateral Sclerosis Parkinsonism Dementia Complex of Guam

Interestingly, in Guamanian ALS PDC patients, a-synuclein pathology is often present in multiple brain regions, including the substantia nigra and in the amygdala (47,48). Just as in AD and PD, the presence of multiple forms of brain amyloid in ALS PDC Guam (i.e., a-synuclein and tau filaments) suggests an

Therapy of Parkinsonism

Since there is no cure for parkinsonism, the aim of pharmacological therapy is to provide symptomatic relief. This is obtained through the use of drugs that either increase dopaminergic actions or diminish neuronal outflow from the striatum. These drugs include levodopa, which increases brain dopamine levels dopamine agonists, which directly stimulate dopamine receptors monoamine oxidase (MAO) inhibitors, which prevent dopamine metabolism and anticholinergic agents,

Levodopa and Carbidopa

Levodopa (L-DOPA), the most reliable and effective drug used in the treatment of parkinsonism, can be con sidered a form of replacement therapy. Levodopa is the biochemical precursor of dopamine (Fig. 31.2). It is used to elevate dopamine levels in the neostriatum of parkin-sonian patients. Dopamine itself does not cross the blood-brain barrier and therefore has no CNS effects. However, levodopa, as an amino acid, is transported into the brain by amino acid transport systems, where it

Other forms of familial PD

There are many families in which linkage analysis failed to show linkage to any one of the known loci that are associated with familial forms of PD. Such reports are increasing every year. According to our hands, we have analyzed 347 families for known PD-causing genes including non-Japanese families with either autosomal dominant or recessive inheritance. We found 116 families with parkin mutations, 8 families with PINK1 mutations, no DJ-1 mutation, 10 families with LRRK2 mutations, and 2 families with alpha-synuclein duplication. Overall mutation rate was 136 positive families out of 347 (39.2 ). In another word, approximately 60 of familial patients with PD did not have known mutations. Mutual relationship among the familial PD causing proteins is an interesting and important subject to study. Identifying new genes for familial PD would give us important information on this topic. Such information would also give us important clues to investigate pathogenesis of sporadic PD.

Other Types Of Familial Parkinsonism With Parkinsonplus Syndrome Phenotype

Spinocerebellar Ataxias with Levodopa-Responsive Parkinsonism protein (ataxin-2) on chromosome 12q has been reported in several patients of Chinese origin who have dopa-responsive familial parkinsonism.166-168 Members of a large ethnic Chinese family with SCA2 mutation and autosomal dominant inheritances have been described as having typical dopa-responsive asymmetric Parkinson's disease, parkinsonism-ataxia, or parkinsonism resembling progressive supranuclear palsy.166 Shan et al.167 also reported expanded CAG repeats in the SCA2 gene in two patients of Chinese origin who presented with dopa-responsive familial parkinsonism at the age of 50 yr. Both of these patients presented predominantly with 4 Hz resting tremor of the legs that responded to treatment with levodopa in one patient and to alcohol, primidone, or trihexiphenidyl in the other patient. Overt signs of cere-bellar dysfunction were absent, and there was mild slowing of the ocular saccades and gait hesitation suggestive of...

Introduction To Parkinlinked Parkinsons Disease

Parkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disorder. Patients often present with heterogeneous symptoms, reflecting the underlying complex nature of pathogenesis (1). Prevalent motor-related symptoms include bradykinesia, rigidity, resting tremor, and postural instability due in large part to the loss of pigmented, dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, additional brain regions that influence cognitive decline and other psychiatric conditions are affected both prior and subsequent to neurodegeneration in the midbrain, an important factor when considering pathogenic mechanisms in PD (2). In sporadic disease, lesions first occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Gradually, nuclear grays and cortical areas become affected as the disease process in the brain stem follows an ascending course. Lesions then appear in the...

Evidence For The Role Of Genes In Pd

Evidence for a familial contribution to PD dates back over 100 yr, when Leroux1-2 and Gowers3 both noted that 15 of PD patients reported an affected family member. In the intervening century, the view of the scientific community has fluctuated with regard to the importance of genetics in the etiology of PD. Several studies provided additional evidence for a genetic role in disease causation.4-7 In contrast, a few studies have strongly argued against a genetic role in PD. Most of the negative data have arisen from samples of monozygotic twins with low concordance rates for PD. The largest, a sample of World War II veteran twins, found greater concordance among twins with early-onset Single Gene Mutations Resulting in PD This genetic approach to the elucidation of disease genes has been successfully employed in the study of families with early onset, autosomal dominant Alzheimer disease. Studies performed by numerous laboratories using many different families led to the identification...

Parkinsons disease caused by mutations in the gene for Leucinerich repeat kinase 2 LRRK2 PARK8

To the pericentromeric region of chromosome 12. Affected in this family showed typical l-dopa responsive parkinsonism with onset in their fifties. Pathologically, nigral degeneration was found, but no Lewy bodies or other distinctive inclusions (Funayama et al., 2002). One particularly common mutation, Gly2019Ser, was detected on a founder hap-lotype across several European populations (Kachergus et al., 2005) and in up to 5 to 6 of several large cohorts of families with dominant parkinsonism (Di Fonzo et al., 2005 Nichols et al., 2005), and even in 1 to 2 of patients with sporadic late-onset disease (Gilks et al., 2005). Penetrance of this mutation is age-dependent, being about 20 with the age of 50 and rising to 80 at the age of 80. This reduced penetrance probably accounts for the finding of a negative family history in a significant proportion of cases. Second, clinical signs and symptoms resemble typical sporadic PD in most families. This is true also for age of onset, which is...

Complex I In Parkinsons Disease Evidence And Potential Mechanisms For Impairment

The previous sections establish that complex I is clearly capable of generating ROS under appropriate experimental circumstances, and that excessive ROS generation is most likely to be associated with some level of inhibition of complex I activity. This section of the chapter will describe the mitochondrial impairment that has been reported in PD patients, and will also consider possible mechanisms underlying the impairment. Finally, we will consider whether this level of impairment is consistent with mitochondrial dysfunction being a key pathogenic mechanism in the disease.

Evidence for Complex I Impairment in Parkinsons Disease

Over the last 15 years there have been a number of reports of diminished complex I activity in tissues obtained from patients with Parkinson's disease. Decreased complex I activity has been reported in substantia nigra and striatum of PD brains, and has also been described in skeletal muscle and platelets (78,79), and such deficits are apparent before the onset of treatment (80). Typically, the reported decrease of complex I activity from these studies is approximately 30 to 40 when corrected for citrate synthase activity. Moreover, the defect in complex I activity appears to be relatively selective, in that complexes II to IV are usually found to be unaffected (78). It is important to note that there are also studies that have failed to find a decrease in either activity of complex I (81,82), or in the binding of 3H dihydrorotenone to complex I from platelets (83). A mechanism for this deficit has not been established, so that it remains unclear whether there is a decrease in the...

Neuroimaging in Parkinsons disease W Lok Au J R Adams A Troiano and A J Stoessl

Pacific Parkinson's Research Centre, Vancouver, BC, Canada Summary. Structural imaging studies often reveal relatively limited findings in Parkinso-nian disorders, as the most profound changes are neurochemical and hence better revealed by functional studies such as PET or SPECT. However, newer magnetic resonance techniques such as spectroscopy, diffusion weighted imaging, diffusion tensor imaging and magnetization transfer have shown promise in differentiating between idiopathic Parkinson's and the atypical parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy. We review here recent advances in functional imaging as well as in structural studies of basal ganglia disorders. Functional studies may give insights into mechanisms underlying disease pathogenesis, as well as neurochemical alterations.

Prevalence Of Pain In Pd

Painful or unpleasant sensations in patients with PD are more common than one might expect, approximating 50 in most series.18-11 The true prevalence of pain in PD remains unknown but is suspected to be higher than in the general population because of the rigidity, dystonia, physical restraints, and motor complications that the disease imposes. In five recent surveys of painful sensations in patients with PD, summarized in Table 19.1, the prevalence of pain has been estimated at between 38 and 54 .1,8-11 The challenge for the clinician is to recognize when a patient's complaint of pain requires further evaluation and to categorize the painful symptoms of PD into a framework for diagnosis and treatment. One recent study classified painful sensations by etiology.11 In this survey, 43 of 95 patients with PD experienced pain. Muscle cramps occurred in 32 (74 ), dystonia-associated pain occurred in 12 (28 ), radicular or neuritic pain occurred in 6 (14 ), and joint pains occurred in 6 (14...

Genetic Data Supporting A Role For Ubiquitinproteasome System Involvement In Parkinsons Disease

A mutation in UCH-L1, I93M, has been found in one family with autosomal dominant PD (8). This mutation co-segregated with a Parkinsonian phenotype in this family, but the fact that it has not been encountered in multiple genetic studies around the world has cast doubt on its pathogenicity. Further genetic data regarding UCH-L1 provide another link to PD. A meta-analysis from multiple data sets from different populations has shown that a relatively common polymorphism, S18Y, is negatively associated with the chance of developing PD (9). It should be noted however that an even more recent meta-analysis, that included a large number of cases from Britain, did not detect a correlation between the presence of S18Y and PD (10). Therefore, at this point, there are no definitive genetic data linking UCH-L1 to PD. It is however likely that UCH-L1 mutations or polymorphisms, and in particular the S18Y variant, may play a role in the PD development within specific populations. UCH-L1 is an...

Specific Pain Syndromes In Pd

As a general approach, painful symptoms in PD should be considered in relation to the cardinal symptoms of tremor, rigidity, akinesia, dystonia, and akathisia that occur in PD. It is important to note whether antiparkinsonian medications induce, exacerbate, or relieve PDassociated pain. Most sensory symptoms are worse during off' motor fluctuations and are considered as nonmotor fluctuations. However, not all pain in the parkinsonian off' state represents a direct result of dopamine A careful appraisal of possible musculoskeletal or rheumatological pain mechanisms is important in patients with Parkinson's disease. Akathisia, while not painful, is intensely unpleasant and is a rare but distinctive symptom that occurs in PD. Primary parkinsonian pain, unrelated to a disturbance in motor function, is presumed to be of cen

Studies In Human Parkinsons Disease

Ubiquitin within LBs represents polyubiquitinated proteins (47), suggesting that, if there is dysfunction of the UPS in PD and related LB diseases, this should be at the level of the proteasome. A number of studies have directly assessed proteasomal activity in these disorders, using the method of cleavage of synthetic substrates by cell extracts from brain regions of patients and controls. McNaught and Jenner (48) measured enzymatic activities of the proteasome, and found a specific decrease of these activities in substantia nigra (SN) of PD patients compared to controls. This result has been confirmed by Tofaris et al. (29), who additionally found decreased proteasomal activity in the SN of DLBD patients. Other CNS regions showed normal activity in DLBD, except for frontal cortex, where activity was somewhat lower, without however reaching statistical significance. Furukawa et al. (49) also found normal proteasomal activity in extranigral regions of PD patients. In any case, it...

What are the requirements for the development of animal models of Parkinsons disease

Before discussing the advantages and the drawbacks of the various animal models of Parkinson's disease (PD), one has first to set the scene and try to identify the major characteristics of PD that should be reproduced in these models. If one asked patients suffering from PD what they would like to see in an animal model for testing neuroprotective strategies, they would almost certainly say that it should reproduce the clinical manifestations of the disease, thereby enabling putative neuroprotective treatments to be tested to see whether they alleviate the clinical manifestations of the disease and restrict its development. Thus, animal models of the disease should reproduce akinesia, rigidity and tremor. Whereas many models faithfully reproduce akinesia and rigidity, most do not exhibit a true parkinsonian rest tremor with a frequency of 4 to 5 Hz. True parkinsonian rest tremor is only seen in some species of monkey intoxicated by MPTP baboons and green monkeys being the ones most...

Animal models of Parkinsons disease based on the use of neurotoxins

Environmental toxins or reproduce the biochemical changes seen in the brain of patients post mortem. Yet, these two approaches are not mutually exclusive. In line with this, the vast majority of models are based on the finding that the activity of complex-1 in the mitochondria is decreased in PD. The toxin most commonly used to induce a complex-1 deficiency is MPTP, which induces a parkin-sonian syndrome in both humans and animals. Recently, we re-evaluated this model in C57Bl6 mice from both a behavioral and a biochemical standpoint (Rousselet et al., 2003). Using a chronic injection protocol and various cumulative doses of MPTP (60 mg, 420 mg, 540 mg), we showed that MPTP induced a dose-dependent loss of dopaminergic neurons in the substantia nigra. Furthermore, at the highest dosage, MPTP also partially destroyed dopaminergic neurons in the ventral tegmental area, thus reproducing the differential vulnerability of dopaminergic neurons in PD. Dopamine measurements made in the...

Drugs for Parkinsonism

Parkinsonism, better known as Parkinson's disease, is a chronic neurological disorder that affects balance and locomotion at the extrapyramidal motor tract. It is considered a syndrome because it has a combination of symptoms. Parkinsonism has three major features. These are rigidity, bradykinesia (slow movements), and tremors. Rigidity is the abnormal increase in muscle tone that causes the patient to make postural changes such a shuffling gate, the chest and head is thrust forward, and knees and hips are flexed. The patient walks without swinging his arms. These movements are slow (bradykinesia) and the patient exhibits involuntary tremors of the head and neck which may be more prevalent at rest and pill-rolling movements of the hands. Another characteristic symptoms is the masked facies (no facial expression) common in patients with Parkinson's disease. There are four types of drugs used to treat Parkinson's disease dopaminer-gics, dopamine agonists, MAO-B inhibitors, and...

Parkinsons disease

Dopamine agonists When levodopa responsiveness is lost dopamine agonists are used. Bromocriptine is a D2 agonist with mixed agonist and antagonist effects at D receptors. Lisuride and Pergolide are more potent and act mainly at D2 receptors. Apomorphine is an agonist at both D and D2 receptors given by continuous infusion or intermittent injection and is effective in shortening periods of prolonged immobility (freezing). Advances in drug treatment in recent years have reduced the need for stereotactic surgery (see page 370), but in patients with intractable tremor this is still of benefit. A stereotactic lesion is made in the globus pallidus or ventrolateral nucleus of the thalamus (contralateral to the tremor). Pallidotomy relieves contralateral dyskinesia. Human fetal and medullary transplantation experimental evidence shows that transplantation to the striatum of tissue capable of synthesising and releasing dopamine reverses the motor symptoms of Parkinson's disease. Despite much...

Mouse Models of Recessive Parkinsonism

Recessively inherited mutations in the PARKIN, DJ-1, and PINK1 genes have recently been linked to familial forms of parkinsonism, which are often clinically indistinguishable from Parkinson's disease (PD). Various mutant mice carrying a germline deletion in either the PARKIN or the DJ-1 gene have been developed to study the normal functions of these gene products, which may provide insights into the pathogenic mechanisms underlying the selective degeneration of dopaminergic neurons. This chapter will summarize recent studies of these loss-of-function mutant mice and discuss their implications to the pathogenesis of PD. The neuropathologic hallmarks of PD are progressive degeneration of dopa-minergic neurons and the presence of Lewy bodies (LBs) in the substantia nigra pars compacta (SNpc). The loss of the dopaminergic innervation to the striatum is thought to be the primary cause of resting tremor, rigidity, and bradykinesia, which are the cardinal clinical features of PD. The...

Increased Iron and Parkinsons Disease

The question of the temporal association between increased iron and neurodegeneration in PD is unclear. Earlier authors suggested that the increase in iron might be a late or secondary event in the disease process Dexter et al. 76 reported unchanged nigral iron levels in cases of so-called incidental Lewy body disease, representing an early preclinical state of PD. Their conclusion that increased iron only occurs in advanced stages of neurodegeneration was supported by unchanged SN iron concentrations in 'mild' PD cases, assessed semi-quantitatively as a mild nigral neuronal loss 54 . However, more recent work using transcranial ultrasound indicates that increased iron can be demonstrated in the SN in PD patients even prior to the onset of clinical symptoms 77 , suggesting that iron increase might occur earlier than previously thought. While both the sources and timing of increased iron in PD SN are still controversial, its presence appears to be involved in the two primary pathogenic...

Treatment of Parkinsons Disease with LDopa

Since its introduction in the late 1960s l-dopa or 'levodopa' (see Figure 1) has been generally accepted as the most effective treatment for the alleviation of the symptoms associated with PD. The effective chemical species required is dopamine, but being charged it cannot cross the membrane barrier dopa is uncharged and can cross into the cells where it is decarboxylated to yield therequired dopamine. However, not only is it unpleasant to take the large doses required, but it also gives rise to serious side effects (although these can be minimized by adding a blocker for decarboxylase and using the l-form of dopa exclusively). With reference to the cycle of events that may lead to the progression of PD (Figure 9), it can be shown that a continual increase in the dopamine content of the cells will result in ever increasing yield of the neurotoxin 6-OHDA. This has been confirmed by an examination of the urine of patients 86 . Thus, it is not surprising that levodopa treatment usually...

Kynurenines and Parkinsons disease

KYNA and Parkinson's disease The kynurenine pathway accounts for 80 of non-protein tryptophan metabolism. As it was discussed earlier, it includes an agonist (QUIN) and an antagonist (KYNA) at the NMDA receptors, which can behave as an excitotoxin and as a neuroprotectant agent in the central nervous system. It is well known that endogenous excitotoxins have been implicated in the degeneration of dopaminergic neurons in the substantia nigra pars compacta of patients with Parkinson's disease. Miranda et al. (1997) investigated whether an increased level of the endogenous KYNA can protect nigrostriatal dopamine neurons against QUIN-induced excitotoxin damage. They found that 1.5-fold increasing of the KYNA in the substantia nigra prevented the QUIN-induced reduction in striatal tyr-osine hydroxylase. However, 9 hours following the administration of nicotinylalanine (kynureninase and kynurenine hydroxylase inhibitor) with KYN (KYNA precursor) and probenecid (inhibitor of organic acid...

Detection of preclinical Parkinsons disease along the olfactory tract H W Berendse and M M Ponsen

The association of Parkinson's disease (PD) with an impaired sense of smell was first reported about thirty years ago. Since then, it has become quite firmly established that olfactory dysfunction is one of the first and most prevalent clinical manifestations of this disorder. Recent data from an ongoing prospective study indicate that otherwise unexplained hyposmia in first degree relatives of patients with sporadic PD is associated with an increased risk of developing clinical PD of at least 13 . In particular, a combination of impaired olfactory function and reduced striatal 123I b-CIT binding on a baseline SPECT scan appears to be a strong predictor of a subsequent diagnosis of PD. Pathological studies support these observations by demonstrating that the anterior olfactory structures may be one of the induction sites of PD pathology. Considering that there is a doubling rather than a loss of do-paminergic neurons in the olfactory bulb in PD patients, the pathophysiology...

Olfactory deficits in Parkinsons disease

Psychometric testing of olfactory function in PD patients has revealed that the prevalence of olfactory impairments is as high as 80-90 (Doty et al., 1988 Hawkes et al., 1997), thus at least equaling the prevalence of the characteristic resting tremor. The olfactory deficits are not restricted to any single functional modality but include impairments of odor detection, discrimination and identification. Moreover, deficits in olfactory function can be detected from the earliest clinical stage of disease onwards (Tissingh et al., 2001). Evidence is accumulating that olfactory testing can also be used to distinguish PD from several other disorders, such as progressive supranuclear palsy, vascular parkinsonism and essential tremor.

Loss Of Function Models Of Parkinsons Disease Functional Analysis of a Drosophila Parkin Ortholog

To explore the biological role of PARKIN, we and others generated a series of mutations in the Drosophila ortholog of PARKIN, including deletion, nonsense, and missense mutations. Flies lacking the PARKIN gene are semiviable and display reduced longevity, motor deficits, and male sterility (60,61). The motor deficit of PARKIN mutants is associated with a dramatic and widespread apoptotic degeneration of muscle tissue, and the male-sterility derives from a late defect in spermatid formation in the germline. Ultrastructural studies indicate that mitochondrial dysfunction is the earliest manifestation of muscle degeneration in PARKIN mutants, suggesting a role for PARKIN in mitochondrial integrity (60). This conclusion is further underscored by the finding that late spermatids in PARKIN mutants manifest dramatic structural alterations in the mitochondrial derivatives known as Nebenkern that are responsible for the energy production required for sperm motility (62). While humans and mice...

Olfactory deficits as a risk factor for Parkinsons disease

Patients with an established clinical diagnosis of PD often recall a loss or reduction of the sense of smell that started years before the onset of motor signs. Reports of olfactory dysfunction in asymptomatic first degree relatives of patients with a familial form of parkinsonism or sporadic PD further strengthened the idea that olfactory impairments might be a preclinical or prodromal sign of PD (Markopoulou et al., 1997). Some six years ago, we designed a prospective study, involving a cohort of first-degree relatives of PD patients, to determine whether olfactory impairments are indeed a sign of incipient PD. After exclusion of individuals with (suspected) parkinsonism, memory dysfunction or potential alternative causes of olfactory disturbances, the total number of relatives in the cohort was 361. At baseline, a combination of olfactory detection, identification and discrimination tasks was used to select groups of hyposmic (n 40) and nor-mosmic (n 38) individuals for...

Parkinsons disease pathology in anterior olfactory structures

Recent neuropathological studies in PD have provided compelling evidence in favor of a topographically predictable spreading of degenerative changes over the brain (Braak et al., 2003). Based on the distribution of alpha-synuclein containing Lewy bodies and Lewy neurites, six different pathological stages of PD have been proposed. The most striking observation is that Lewy body pathology in a number of extranigral brain areas, including the olfactory bulb and tract, appears to precede degeneration of nigros-triatal dopaminergic neurons. Although the presence of neuropathological changes typical of PD in the olfactory bulb and tract has been described previously (Pearce et al., 1995), these novel data suggest that the anterior olfactory system may actually be one of the induction sites of the neuropathological process in PD.

Prevalence Of Urinary Symptoms In Pd

There is a surprising dearth of information covering the prevalence of urinary symptoms in the parkinsonian population at large. levodopa era, who had been selected to undergo basal ganglia surgery. Eleven (38 ) had urological symptoms. Porter and Bors25 investigated a similar group of 62 patients being considered for basal ganglia surgery. Forty-four patients (71 ) had urinary symptoms, but the group was primarily male. These figures have a selection bias. It is likely that older and feeble individuals were excluded. Sakakibara et al.29 studied 115 PD patients (52 men and 63 women) and compared them to controls. All urinary symptoms were significantly higher in PD. Urgency (42 women, 54 men) daytime frequency (28 women, 16 men) nighttime frequency (53 women, 63 men) urge incontinence (25 women, 28 men) retardation in initiating urination (44 men) prolonga Lemack et al.17 selected 80 men and 39 women with mild to moderate PD (Hoehn and Yahr lower than stage 3) and performed a...

Treatment With Levodopa

Levodopa was first synthesized almost 100 years ago. It took almost half a century until Arvid Carlson discovered that this compound could reverse the reserpine-induced motor symptoms similar to the ones in idiopathic PD in rats. The next step was the successful administration of levodopa in PD patients, which was initially performed by various clinicians in the late 1950s and early 1960s. There is no doubt that levodopa is the most efficacious and best tolerated antiparkinsonian compound, as recently demonstrated by the ELLDOPA trial (14,15). A drawback of this drug was the short half-life in plasma from the beginning of levodopa administration in PD. The additional administration of an aromatic amino acid decarboxylase inhibitor (DDI) markedly reduced the peripheral levodopa degradation and thus improved the efficacy of levodopa on motor symptoms in PD patients (16). Two different DDIs are available, benserazide is administered with levodopa on a 1 4 basis and carbidopa on a 1 10...

Pathogenesis Of Voiding Dysfunction In Pd

Based on a series of experiments and subsequent experience with basal ganglia surgery, it is currently believed that the basal ganglia exert an inhibitory effect on the ponto-mesencephalic micturition center. Lesions of basal ganglia, as in PD, would result in partial or total disconnection of the micturition reflex from voluntary control. The result would be unhibited detrusor contractions elicited at low volume threshold (detrusor hyperreflexia).5 In PD, the presence of detrusor hyperreflexia with vesi- It is interesting to note that stimulation of the red nucleus, the subthalamic nucleus, and the substantia nigra was more inhibitory than that of the thalamus. This may suggest that current deep brain stimulation procedures may be more effective in improving voiding dysfunction if STN rather than the thalamus is the target. Stereotaxic thalamotomy in parkinsonian patients, on the other hand, demonstrated an increase in detrusor activity.22,25 The understanding of the pathophysiology...

Neurological Disorders and Neurodegenerative Diseases Parkinsons disease

Postmortem analyses of Parkinson's disease (PD)-diseased human substantia nigra have revealed a dramatic reduction in both NGF and BDNF mRNA and protein, raising the possibility that there may be a link between reduced levels of neurotrophins and Parkinson's disease. Recently, it has been reported that, in a Japanese population, homozygosity for a polymorphism of the BDNF gene occurs more frequently in patients with PD than in unaffected controls and, in addition, two single nucleotide polymorphisms at position C270T of the BDNF gene have been identified in patients with familial Parkinson, suggesting that BDNF may play a role in the development of Parkinson's disease.

Levodopainduced Elevation Of Homocysteine

The occurrence of increased hazard ratios for both ischemic heart and cerebrovascular disease is known in levodopa DDI-treated parkinsonian patients (33). Long-term levodopa intake supports homocysteine elevation, which has an atherosclerosis-promoting effect. The conversion of levodopa to 3-OMD via the COMT requires Mg2+ as a cofactor and S-adenosylmethionine as a methyl donor (34). Thus O-methylation of levodopa to 3-OMD is associated with the conversion of S-adenosylmethionine to S-adenosylhomocysteine and subsequently homocysteine, which additionally has NMDA agonistic properties (34). Accordingly elevated homocysteine levels appeared in treated PD patients compared to matched controls and significantly correlated to daily levodopa dosage (35-39). Trials on larger cohorts confirmed these previous results (38,40). L-Dopa treated parkinso-nian subjects showed augmented plasma concentrations of homocysteine (41,42). The demonstrated relationship between homocysteine and 3-OMD plasma...

Cardiovascular aspects of Parkinson disease D S Goldstein

This chapter provides an update about cardiovascular aspects of Parkinson disease (PD), with the following topics (1) Orthostatic hypotension (OH) as an early finding in PD (2) neurocirculatory abnormalities in PD + OH independent of levodopa treatment (3) cardiac and extracardiac noradrenergic denervation in PD + OH (4) progressive loss of cardiac sympathetic innervation in PD without OH.

As an early finding in PD

In PD, OH can pose a major management problem. Studies have varied widely in reported frequencies of OH in PD. In 5 large studies involving more than 80 patients each, the frequency of OH ranged from 30 to 58 (Briebach et al., 1990 Magalhaes et al., 1995 Senard et al., 1997 Allcock et al., 2004 Korchounov et al., 2004). A substantial minority of PD patients therefore have OH. an early finding in PD and even precede the movement disorder is therefore by no means new. Of 3 post-mortem case reports about PD + OH patients, where the timing of onset of OH with respect to the movement disorder was reported, in all 3 OH had developed first (Vanderhaeghen et al., 1970 Schober et al., 1975 Kaufmann et al., 2004). Carrying out an analysis of the frequency of OH as an early finding in PD + OH would require evidence that the patients did not have multiple system atrophy (MSA), which is almost always associated with OH. Diagnosing MSA differentially from PD + OH can be very difficult clinically....

Neurocirculatory abnormalities in PD OH independent of Levodopa treatment

Levodopa is a precursor of dopamine and therefore of norepinephrine (NE), the sympathetic neurotransmitter. In the treatment of PD, levodopa is usually combined with an inhibitor of L-aromatic-acid-decarboxylase that does not penetrate the blood-brain barrier. The combined treatment augments delivery of levodopa to the brain and mitigates nausea and vomiting thought to result from occupation of dopamine receptors outside the blood-brain barrier. Such treatment attenuates but does not prevent catechol-amine synthesis from levodopa outside the brain. Neurocirculatory abnormalities underlying OH might therefore might reflect levo-dopa treatment. To test this hypothesis, we carried out tests of reflexive cardiovagal gain (decrease in interbeat interval per unit decrease in systolic pressure during the Valsalva maneuver orthostatic increase in heart rate per unit decrease in pressure) and reflexive sympatho-neural function (decrease in pressure during the Valsalva maneuver orthostatic...

Progressive loss of cardiac sympathetic innervation in PD without OH

About half of the patients with PD without OH have been found to have a loss of 6- 18F fluorodopamine-derived radioactivity diffusely in the left ventricular myocardium, and a bit less than half had loss localized to the lateral or inferior walls, with relative preservation in the septum or anterior wall (Goldstein et al., 2002). Only a very small minority have had entirely normal cardiac 6- 18F fluorodopamine-derived radioactivity. Thus, virtually all patients with PD have evidence for at least some loss of cardiac sympathetic innervation. In PD without OH, cardiac noradrenergic denervation therefore seems to progress over years. If so, then cardiac sympathetic neuro-imaging might provide a biomarker for detection of early PD and for testing the efficacy of potential neuroprotective treatments. D. S. Goldstein Noradrenergic denervation in Parkinson disease

Mptpinduced Parkinsonism In Animals

Shortly after MPTP was found to provoke a parkinsonian syndrome in humans, researchers were prompted to test MPTP toxicity in a variety of animal species including monkeys, dogs, cats, and rodents (21,22). These investigations showed that most of the vertebrates and invertebrates tested were sensitive to the neurotoxic effects of MPTP (21,22), but with marked differences among species. Among mammals, monkeys, for example, were by far the most sensitive to MPTP whereas rats and guinea pigs were resistant and mice were of intermediate susceptibility.

Parkinsons Disease and Other Neurodegenerative Disorders

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, resulting in bradykinesia and a resting tremor. This disorder is reported to have a higher prevalence of sleep apnea ranging from 20 to 43 of the patients (41,42). The high prevalence of sleep apnea in this population occurs despite their lower average BMI that makes oxygen desaturation less prominent. Hogl (43) found snoring to be associated with daytime sleepiness. Yet, several investigators did not demonstrate a relationship of daytime sleepiness to AHI and the impact on the cardiovascular system is unknown (41).

Mitochondria And Parkinsons Disease

Systemic complex I inhibition is one of the key biochemical features of PD that has been virtually ignored, especially in terms of developing an animal model. We proposed that if systemic complex I inhibition has a central role in PD pathogenesis then systemic low levels of chronic complex I inhibition would induce selective degeneration of the nigrostriatal pathway. Indeed, continuous low levels of rotenone exposure in rats resulted in selective degeneration of the nigrostriatal pathway. However, before we discuss the rotenone model of PD it would be helpful to describe briefly the role of mitochondria, oxidative phosphorylation, and complex I inhibition.

Surgical Options for Treatment of PD

There are several surgical options for treatment of PD. Ablative surgical procedures or DBS targeting the thalamus, globus pallidus or the sub-thalamic nucleus are currently available. Transplantation surgery for PD remains inves-tigational. Thalamotomy is typically reserved for patients with isolated tremor, as this procedure has less impact on the rigidity and dyskinesias seen with PD 4 . Pallidotomy and sub-thalamotomy serve to decrease the tremor, rigidity and dyskinesias seen with PD. The target for pallidotomy is the postero-ventro-lateral portion of the globus pallidus. Unilateral pallidotomy mostly improves contralateral tremor and dyskinesia 8 . These results are sustained in 4-year follow-up studies 9 . These results are only seen in patients who are levodopa responders. As with all surgical interventions, there are risks. Surgical side effects include hemorrhage, infarct, aphonia, cognitive and gait disturbances. The side effects are increased for bilateral pallidotomies....

Importance Of Depression In Pd

Depression is the most common psychiatric complication affecting persons with Parkinson's disease (PD). Depressive symptoms may affect as many as half of all PD patients at some point in their illness, and, in many cases, depressive symptoms actually predate motor signs and symptoms. Aggressive surveillance for and treatment of depression is critical, since untreated depression produces a great deal of human suffering, and depression is usually treatable. In PD patients, depression may have even more impact on functional status than in other patients with depression. However, there is still uncertainty about many aspects of depression in PD despite an increasing amount of research devoted to this topic. In particular, issues revolving around differentiating depression from PD symptoms, the role of cognitive impairment from PD on mood symptoms, and unique treatment concerns in this population can be challenging for the clinician. This chapter provides an update on what is known about...

Prevalence Of Depression In Pd

The question of how frequently depression occurs in persons with PD is a striking example of how even ostensibly simple questions can be hard to answer when it comes to understanding depression in PD. Reported rates of depression have varied enormously from study to study. An overall depression rate of 43 is one of the most commonly cited figures.1 However, this figure includes persons with major depressive disorder and minor depression or dysthymia. Another confounding factor with this estimate is the population being studied. Studies that have reported high rates generally used specialty populations, in contrast to the lower rates generally seen in community-based samples. As part of a wider prevalence study of PD, Tandberg et al.2 carefully assessed depressive symptoms in PD patients. They found that 7.7 of community dwelling patients met DSM-III criteria3 for major depressive disorder (MDD). Additionally, they used the Montgomery-Asberg depression rating scale (MADRS)4 to obtain...

Risk Factors For Depression In Pd

Many attempts have been made to identify risk factors for developing depression in PD. However, these efforts have generally failed to consider factors known to predispose persons to depression in general. Leentjens et al. first considered general risk factors for depression (age, sex, prior history of depression, family history of depression, somatic comorbidity) in a PD population and found that these five risks factors predicted 75 of depression in their sample using a multivariate model.11 When disease-specific markers were then included in the model, only right-sided onset of PD improved the model. Thus, established risk factors for depression in general may also be markers of depression in PD. There is some evidence to suggest that depression in PD is more common in younger patients,12 females,1314 and in persons with more bradykinesia and rigidity (as opposed to tremor-dominance).1517 Several authors have suggested that there is a bimodal distribution to the onset of depression...

Role of cytokines in inflammatory process in Parkinsons disease M Sawada1 K Imamura2 and T Nagatsu13

We investigated whether the cyto-kines produced in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson's disease (PD) are neuropro-tective or neurotoxic. In autopsy brains of PD, the number of MHC class II (CR3 43)-positive activated microglia, which were also ICAM-1 (CD 54)-, LFA-1 (CD 11a)-, TNF-alpha-, and IL-6-positive, increased in the SN and putamen during progress of PD. At the early stage activated microglia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-posi-tive neurons in the SN. The activated micro-glia in PD were observed not only in the nigro-striatal region, but also in various brain regions such as the hippocampus and cerebral cortex. We examined the distribution of activated microglia and the expression of cytokines and neurotrophins in the hippocampus of PD and Lewy body disease (LBD). The levels of IL-6 and TNF-alpha mRNAs increased both in PD...

Are produced from activated microglia in the putamen in PD

Band, and MHC-II (CR3 43) protein as 34-and 28-kDa bands in homogenates of the putamen and peripheral blood mononuclear cells from PD patients, in agreement with our previous results by ELISA (Mogi and Nagatsu, 2000 Nagatsu et al., 1999). We then showed by immunohistochemistry that almost all activated microglia in the putamen from PD brains are positive for both ICAM-1 and LFA-1. We further proved by double immunofluorostaining the coexistence of TNF-alpha and IL-6 with MHC class II (CR3 43) in ICAM-1- and LFA-1-positive activated microglia in the putamen from PD patients. These results confirm that TNF-alpha and IL-6 are produced by activated microglia in the putamen in PD (Imamura et al., 2003).

In various regions of the brain in PD

The presence of activated microglia and the absence of reactive astrocytosis in the sub-stantia nigra of patients with PD suggest microglial involvement in the pathological process of dopamine neurons (McGeer et al., 1988 McGeer and McGeer, 1995 Mirza et al., 2000). We (Imamura et al., 2003) showed MHC class II (CR3 43)-positive activated microglia to be widely distributed not only in the substantia nigra and putamen, but also in various brain regions of PD patients, frequently in association with alpha-synuclein-positive Lewy neurites and monoaminergic neurons. In normal brains, many Ki-M1p-positive resting microglia, but only few MHC class II (CR3 43)-positive activated microglia were seen in the substantia nigra and putamen. In PD brains, however, MHC class II (CR3 43)-positive ramified microglia were seen in those regions. PD patients were shown to have a significantly higher number of MHC class II (CR3 43)-positive microglia compared with normal controls. The cell count of MHC...

The toxic change of reactive microglia suggests two step activation of microglia in PD

Based on these in vitro results suggesting the presence of neuroprotective or neurotoxic subsets of activated microglia, we propose a hypothesis of two-step activation of micro-glia in the brain in PD in vivo, as schematically shown in Fig. 2. Ramified resting microglia in the normal brain support neurons for control of neuronal activity, development, and homeostasis in the brain. The observation on activated microglia associated with intensely tyrosine hydroxylase (TH)-positive neurites in the striatum in the early stage of PD and with other non-degenerated neurons and neurites in various brain regions suggest that microglia activated by the first stimuli may act for neuroprotection by producing neurotrophins, neurotrophic cyto-kines, and antioxidant at the first step. The activated microglia at this first step may be neuroprotective. As described above, Sawada with coworkers found that microglia in a cell culture experiment are converted from the neuroprotective to neurotoxic forms...

Deep brain stimulation for the treatment of Parkinsons disease C Hamani J Neimat and A M Lozano

Approximately 30,000 patients have been treated throughout the world with deep brain stimulation for Parkinson's disease and other conditions. With accumulating experience, there has been an appreciation of the important benefits of this procedure, including the alleviation of disability and improvement in the quality of life. We have also become aware of some limitations of DBS surgery. Among the important issues that remain to be resolved are the timing of surgery, whether early or late in the course of the disease, and the best target for the individual patient, including a reassessment of the relative merits of globus pallidus versus subthalamic nucleus surgery. A better understanding of the symptoms that are resistant to both levodopa therapy and DBS surgery is also required. The introduction of deep brain stimulation (DBS) as a therapeutic alternative for the treatment of advanced Parkinson's disease (PD) has revolutionized the clinical management of this condition. In...

Deep brain stimulation in Parkinsons disease patients biochemical evidence

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen - PUT - and GPi) and in a thalamic relay nucleus, the antero-ventral thalamus (VA). It has been recently shown that subthalamic nucleus (STN) deep brain stimulation (DBS) increases cGMP in the internal pallidus (GPi) while it induces a motor improvement similar to l-dopa treatment, in Parkinson's disease (PD) patients (Stefani et al., 2005). In the central nervous system, extracellular cGMP levels are considered as a marker of excitatory activity, being enhanced either by increased glutamatergic or by reduced GABA transmission (Fedele and Raiteri, 1999 Pepicelli et al., 2004). Paradoxically therefore, the recent report (Stefani et al., 2005) suggests that STN-DBS...

Neuropsychological Characteristics Of Dementia In Pd

In the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV),47 dementia is defined as the development of multiple cognitive deficits that affect memory and that result in aphasia, apraxia, agnosia, or executive dysfunction. Impairment must result in occupational or social dysfunction, must represent a decline from a previous level of ability, and must exist separate from delirium. Given that the bedside evaluation, the MiniMental State Examination,48 and other common screening measures may not be sensitive to the presence of dementia in PD, an in-depth cognitive evaluation is often essential. In many cases, neuropsychological evaluation can assist in determining whether cognitive impairment or dementia

Neurochemistry Of Dementia In Pd

Surprisingly, the neurochemical modifications that attend cognitive decline in PD have received limited direct exploration. Necropsy description of degeneration within select populations of neurons has provided the impetus to examine specific transmitter systems. While degeneration of dopaminergic neurons in the substantia nigra compacta (SNc) is the pathologic hallmark of PD, depletion within the lateral compartment, projecting to the putamen, accounts for characteristic motor dysfunction. Degeneration within the medial SNc, with projections primarily to the caudate nucleus, correlates with cognitive disturbance measured by a global scale.144 In addition, diminished binding to the D1 subtype of dopamine receptor in the caudate nucleus also correlates with the magnitude of cognitive dysfunction.145 Cholinergic dysfunction, prominently involved in AD, is also observed in PDD. This is indicated by the finding that the affinity with which 3H quinuclidinylbenzilate (QNB) binds to...

Clinical Staging Of Gait Disorders In Pd

Gait Disorder

In accordance with progression of nigro-striato-pallidal dysfunction, gait disorders in PD can be staged as follows When stride-to-stride variation was compared during inter-episodic intervals (i.e., during regular walking, between two FOG episodes) among PD patients with FOG and those with no FOG in the off state, patients with FOG had significantly larger stride-to-stride variability.23,24 This observation and the report by Nieuwboer et al.25 about changes in stride length and cadence in the few steps prior to freezing episodes suggest primary disrhyth-mic locomotion in PD patients with FOG that may worsen until freezing appears. In other words, FOG might be the extreme form of a general continuous disrhythmicity.13 In the early stages of PD, a FOG episode usually lasts a second or two, occurring mainly in the form of turn or start hesitation and causing only minor disturbances in general function or quality of life, with tricks being needed only rarely to overcome the block. In a...

Animal models of Parkinsons disease based on a genetic etiology

Have therefore tried to develop transgenic mice over-expressing the wild-type a-synuclein or mutated forms of a-synuclein. Most of these models show a-synuclein-positive inclusions but no loss of dopaminergic neurons, whatever the age at which the animals are analyzed. Thus, this model may be extremely useful to analyze the early phase of a-synuclein fibrillation and accumulation but will not allow the testing of strategies to prevent the death of dopaminergic neurons. In order to avoid such limitations, Kirik and co-workers used a gene transfer methodology to overexpress a-synuclein in rats (Kink et al., 2002). They showed that, using a strong promoter (prion promoter), a-synuclein overexpression induced both a death of dopami-nergic neurons in the substantia nigra and an accumulation of intraneuronal a-synuclein. As far as PARK-2 is concerned, parkin knockout animals have also been developed by several groups of investigators. Yet, again, no loss of dopaminergic neurons has been...

Essay on the Shaking Palsy

Parkinson's Essay on the Shaking Palsy (1817) is often thought to represent his greatest contribution to medi-cine.26 27 The study is based on six cases, some never actually examined by Parkinson but observed on the streets. The five chapters of this 66-page octavo volume include I. Definition History Illustrative Cases, II. Pathognomic symptoms examined Tremor Coactus Scelotyrbe Festinians, III. Shaking Palsy distinguished from other disease with which it may be confounded, IV. Proximate cause Remote causes Illustrative cases, V. Considerations respecting the means of cure. Apologizing for mere conjecture regarding the etiology of the shaking palsy, Parkinson states his duty to submit his opinions to the examination of others, even in their present state of immaturity and imperfection and mission to inspire research on this disease.26 Parkinson recognized the long duration and slowly progressive nature of the disease. His first chapter commences with an often-quoted definition of...

Parkinsons disease premotor clinicopathological correlations E Ch Wolters1 and H Braak2

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo- akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson's disease (PD). Progressive loss of nigral neurons with Lewy bodies is considered an essential neuro-pathological feature. Recent studies, however, indicate that nigral degeneration is only a part of this synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, autonomic dysfunction, pain, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms suggests multiple causes and or pathogeneses within the present diagnostic disease entity. In this article, a recently proposed staging of PD-related brain pathology will be correlated with the various clinical expressions. It will be argued that the specific topographical sequence of the pathology, depending on the extent and progression of the...

Receptorreceptor interactions and development of A2A antagonists for treatment of PD

The A2A D2 heteromeric receptor complex is of particular interest in relation to Parkinson's disease (PD), since it is located in the striato-pallidal GABA pathway, being the first neuron in the indirect pathway mediating motor inhibition when activated, and offers new treatment strategies for PD, as A2A inhibits D2 receptor recognition and signalling in the heteromeric complex (Ferre et al., 1991 Fuxe et al., 1998). Based on this work, A2A antagonists were postulated to be potential antiparkinsonian drugs acting by enhancement of D2 signaling. Unspecific adenosine receptor antagonists, like caffeine and theophyllamine, were in fact already shown in 1974 to enhance the motor activat The major antiparkinsonian action of A2A antagonists appears to be the increase in the therapeutic ratio of l-dopa and D2 agonists allowing, for example, a lowering of the l-dopa dose with reduced development of dyskinesias (see Fuxe et al., 2001, 2003a Chase, 2004), which may be explained by the existence...

A new look at levodopa based on the Elldopa study

Levodopa has been the gold standard for Parkinson's disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these motor complications. This became more popular as the dopamine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they were much less likely to produce the unwanted motor complications, even though they had their own adverse effects. When it was recognized that dopamine, itself, might be a factor leading to the death of dopaminergic neurons through its contributing to the formation of oxyradicals, a new concern arose, namely that levodopa, through its conversion to brain dopamine, might add to the existing...

Genes and Oxidative Stress in Sporadic and Familial Parkinsonism cDNA Microarray Studies

In several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), prion disease and their models, oxidative stress (OS) mechanisms are thought to be involved, resulting in the generation of reactive oxygen species (ROS), as well as glutamate receptor abnormalities, ubiquitin-proteasome dysfunction, inflammatory and cytokine activation, dysfunction in neurotrophic factors, damage to mitochondria, cytoskeletal abnormalities, synaptic dysfunction and activation of apoptosis pathways (1-4). In many animal models, in vitro and cell culture models, studies showed association between OS and microglia mediation of neuronal damage such as in PD models with 6-hydroxydopamine, (MPTP), cerebral ischemia, methamphetamine or transgenic animals (5-9). The evidences that OS may be an important culprit in the manifestations of neurodegeneration are still under investigation, but should be taken seriously for possible drug...

Phenotype Of Parkinrelated Parkinsons Disease Clinical Features

The most typical features of Parkinson's disease caused by PARKIN mutations are early-onset typical parkinsonism with a slow clinical course, good or excellent response to low doses of levodopa, frequent treatment-induced dyskinesias and the absence of dementia (47,99). Other frequent signs, that occur in less than 50 of the cases, however, are foot dystonia, brisk reflexes, sleep benefit, and psychiatric or behavioral disorders (Table 1). Two studies (47,90) have compared the frequency of clinical signs in Parkinson's disease patients with and without PARKIN mutations, recruited according to the same clinical criteria. Although the range of ages at onset was similar in both groups of patients, the mean age at onset was significantly earlier in patients with mutations (31.4 11.9 vs. 38.1 11.2 p < 0.001), and dystonia, symmetry at onset and TABLE 1 Phenotype of PARKIN-Related Parkinson's disease Typical parkinsonism Levodopa induced dyskinesias No reduced olfaction Atypical or rare...

Defective Proprioception And Kinesthesia In Pd

Some empiric data support the role of basal ganglia in sensorimotor integration, and also reported are abnormalities in proprioception and kinesthesia in PD that would be predicted by the model to bias toward hypokinesis, bradykinesia, dyskinesias, or postural instability.37 3941 From the experiments described in the following paragraphs, a reasonably coherent picture emerges that prop-rioception has impaired discrimination value in PD and that, particularly in the off state, the system overestimates movements to be greater than they actually are. cits using a more subtle and quantitative test in which the metacarpophalangeal joint was passively placed in a flexion angle of 0.5 to 19.5 , and the subject estimated the angle relative to a visual representation of a 10 flexion.42 Both normal controls and on state PD patients underestimated the palmar angle (or equivalently overestimated the dorsal angle), particularly in the most flexed positions, but PD patients as a group were worse....

Antiparkinsonian Therapy And Hypersexuality

With the advent of antiparkinsonian therapy, reports of increased libido and sexual performance, hypersexual behavior (with or without concomitant hypomania), and rarely paraphilias have appeared in the literature.11-25 Comparisons cannot be made among studies, as different criteria were used to collect data. Due to the small size of the studies, the incidence of increased sexual drive in patients receiving treatment with antiparkinsonian therapy cannot be determined. The data does not provide a basis for identifying patients who might develop adverse sexual behavior in response to antiparkinsonian medications. Since the initial reports were conducted, medication regimens and dosages have changed. This also affects applicability of reports to current patient care. Not all early reviews found that levodopa increased sexual behavior.61 A review of 152 patients treated for parkinsonism between 11 1 68 and 7 31 69 did not find significant changes in patients' sexual interests. Increased...

Decreased Ferritin In Substantia Nigra Parkinson

Andrew R, Watson DG, Bet SA, Midgley JM, Wenlong H, Perry RK (1993) The determination of 6-hydro-xydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res 18 1175-1177 Berg D, Gerlach M, Youdim MBH, Double KL, Zecca L, Riederer P, Becker G (2001) Brain iron pathways and their relevance to Parkinson's disease. J Neurochem 79 225-236 Biemond P, Van Eijk H, Swaak A, Koster J (1984) Iron mobilisation from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes possible mechanism in inflammation diseases. J Clin Invest 73 1576-1579 Birgens HS (1991) The interaction of lactoferrin with Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P (1995) A quantitative analysis of iso-ferritins in selected regions of aged, parkinsonian and Alzheimer's diseased brains. J Neurochem 65 717-724 Davidson LA, Lonnerdal B (1989) Fe-saturation and proteolysis of human lactoferrin effect on brush-border receptor mediated uptake of Fe and...

Triggering endogenous neuroprotective mechanisms in Parkinsons disease studies with a cellular model

Glial cell line-derived neuro-trophic factor (GDNF) has been implicated in the protection of dopamine (DA) neurons from oxidative stress in animal models of Parkinson's disease (PD). We have now shown that GDNF can also protect against the effects of 6-hydroxydopamine (6-OHDA) in a dopaminergic cell line and in cultures of primary DA neurons prepared from rat sub-stantia nigra (SN). This appears to involve a rapid and transient increase in the phospho-rylation of several isoforms of extracellular signal-regulated kinase (ERK). Our evidence indicates that ERK activation also can be modulated by reactive oxygen species (ROS), including those generated by endogenous DA. Identification of the ways by which these pathways can be triggered should provide insights into the pathophysiology of PD, and may offer useful avenues for retarding the progression of the disorder. Bohn MC (1999) A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule...

Brain Iron in Parkinsons Disease

Increased regional total brain iron has been identified in a variety of neurodegenerative disorders such as PD, movement disorders associated with parkinsonism, Huntington's disease and the dementia syndromes, including AD 5,7,28 . The most striking feature of these changes is that increased brain iron is confined to those brain regions most affected by the degeneration characteristic of the particular disorder for example, in the movement disorders total iron levels are increased in the basal ganglia, while in AD the increased iron is associated with the pathological hallmarks of the disease in the vulnerable cortical regions 29,30 . Further, the number of regions affected also parallels the pattern of degeneration seen in each disease, so that in PD significantly increased iron levels are found only in the SN in the midbrain 5,7 , while multi-system atrophy and progressive supranuclear palsy are characterized by increased iron not only in the SN, but also in the degenerating caudate...

Is Levodopa Neurotoxic or Neuroprotective

One of the most controversial questions regarding the treatment of PD is whether levodopa is neurotoxic. The results of many in vitro studies have suggested that levodopa may be injurious to dopaminergic neurons (86,87). These findings have raised concerns that chronic levodopa exposure might hasten disease progression in PD patients. Accordingly, some physicians and patients have opted to defer the use of levodopa for as long as possible (28). Other physicians have continued to use levodopa as first-line therapy, arguing that in the absence of clinical evidence of toxicity (88-90), it is inappropriate to withhold the most potent symptomatic treatment for PDO. Until very recently, there was little clinical data to support or refute the possibility of levodopa toxicity. In 2002, however, two studies were published in which functional neuroimaging techniques had been used to compare patients initially treated with pramipexole versus levodopa comparison of the agonist pramipexole with...

Cardiac and extracardiac noradrenergic denervation in PD OH

More than 25 studies over the past several years have agreed remarkably on the finding that virtually all patients with PD have a loss of sympathetic innervation of the heart, as demonstrated by low myocardial concentrations of radioactivity after injection of the sympathoneural imaging agents, 123I-metaiodobenzylguanidine and 6- 18F fluorodopamine, neurochemical assessments during right heart catheterization (Goldstein et al., 2000), and post-mortem histopathol-ogy (Orimo et al., 2001, 2002 Amino et al., 2005). 6- F fluorodopamine can visualize sympathetic innervation in extracardiac organs and if so whether patients with PD + OH have neuroimaging evidence of extracardiac nor-adrenergic denervation (Tipre and Goldstein, 2005). To validate the method, healthy volunteers underwent 6- 18F fluorodopamine scanning of the head, thorax, and abdomen, with or without treatment with desipramine to block sympathoneural uptake of cate-cholamines. Desipramine treatment was associated with...

Sources Of Increased Iron In Parkinsons Disease

The question then arises as to the source of the increased iron. There are several possibilities and iron misregulation in the brain may have genetic (see Section 2.2) and nongenetic causes ( 52 and references cited therein). Firstly, local alterations in the BBB might result in an increased entry of peripheral iron for example, a change in the normal iron regulatory systems, such as a local increase in transferrin receptor number could result in an increase in SN iron. Results from studies investigating the density and distribution of the transferrin binding site in the midbrain in post-mortem PD suggested that transferrin receptor number, while increased in the caudate and putamen, are actually decreased on the perikarya of melanised neurons in the SN 53-55 . This agrees with results reported in the periphery where transferrin (and, in agreement with the ferritin results of Dexter et al. 56 ) levels were decreased in serum in PD 57 . Further, serum iron is reported to be either...

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