Is There A Cure for Parkinson Disease

The Parkinson's-Reversing Breakthrough

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

The ParkinsonsReversing Breakthrough Summary

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Classification Of Atypical Parkinsonian Disorders

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

Parkinsonism With Atypical Postures

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

Idiopathic Parkinsons Disease

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

Familial Parkinsons Disease

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

Alsparkinsonism Dementia Complex Of Guam

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

Postencephalitic Parkinsonism

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

Vascular Parkinsonism

Patients with cerebrovascular disease may develop features of parkinsonism (173-175) and a small but significant fraction of those with a clinical diagnosis of idiopathic PD will turn out to have vascular lesions demonstrated by neuroimaging or at autopsy (2,176). This vascular pseudoparkinsonism is most often seen in patients with cerebral arteriolosclerosis and multiple small lacunar infarcts affecting the basal ganglia or deep cerebral white matter (173-177) but has also been reported with isolated lesions of the substantia nigra (178,179).

Posttraumatic Parkinsonism

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

Other Genetic Diseases Occasionally Presenting With Atypical Parkinsonism

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

Epidemiology And Implications Of Neuropsychiatric Features In Parkinsonian Disorders

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

The Role Of Neuropsychiatric Assessment In Diagnosis Of Parkinsonian Disorders

During the last decade an increasing number of studies describing the neuropsychiatric characteristics of patients with neurodegenerative disorders have been published. Among the group of movement disorders, however, the majority of studies have focused on patients with PD, and only few studies with a low number of participants have explored the pattern of neuropsychiatry symptoms in atypical parkinsonian disorders, and thus the knowledge of the neuropsychiatric characteristics of these disorders is still limited. In addition, there are several other methodological caveats to consider when comparing different studies of the neuropsychiatric profile of patients with parkinsonism. First, patients can be selected from different sources. Clinical and demographic characteristics of patients attending a specialized movement disorder clinic may differ from patients referred to a neuropsychi-atric unit or residing in the community with regard to age, education, duration of disease, cognitive...

Apraxia In Other Atypical Parkinsonian Disorders

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

Visuospatial Disorders In Parkinson Disease

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

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

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

Clinical Examination Of Eye Movements In Parkinsonism

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

Note On Laboratory Methods For Studying Eye Movements In Parkinsonian Disorders

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

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

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

Druginduced Parkinsonism And Oculogyric Crisis

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

Followup of bilateral subthalamic deep brain stimulation for Parkinsons disease

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

Coactivation Of Striatal Neurons And Cognitive Problems Associated With Parkinsonian Syndromes

The previous subsection showed how, in parkinsonian syndromes, there is a general excess of striatal neural activity, driving both activation and suppression of behavior. In more detail, however, there is also evidence of a breakdown of the process by which one strategy of behavior or one focus of attention is selected to the exclusion of others. The mechanisms by which such selection normally occurs were discussed in Part I. It was apparent that one of the most sophisticated pieces of neural design in the basal ganglia is that needed to solve the credit assignment problem. In other words it is necessary to ensure that the patterns of activity relayed from the cortex, which the striato-nigral system detects as being motivationally favorable or unfavorable, can address each behavior-related cell assembly of the CTH network specifically, and exclusively, that is, without the extensive divergence which occurs in the cortex and some other neural networks. This highly specialized...

Clinical Diagnosis Of Familial Atypical Parkinsonian Disorders

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

Genetic Testing For Atypical Parkinsonian Disorders

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

The Role Of The Subthalamus In Production Of Parkinsonian Symptoms

In Section 3.4.2, evidence was reviewed that in parkinsonian syndromes, firing rate in STN neurons is markedly elevated, this being due mainly to loss of a direct dopaminergic inhibitory effect, rather than an indirect effect of striatal dopamine denervation. The importance of STN in production of parkinsonian symptoms is reinforced by the paper of Bergman et al. (1990), who showed in MPTP-treated monkeys, that an ibotenic acid lesion of STN reduced all major motor abnormalities in contralateral limbs (akinesia, tremor, and rigidity). Purposeful movements were regained and tremor was almost completely absent. The result was replicated in primates by Aziz et al. (1991). Subsequently, Wichmann et al. (1994b) found, in MPTP parkinsonian monkeys, that muscimol injections into STN, which blocked all activity there, also reduced akinesia, tremor, and rigidity, as well as producing contralateral dyskinesia. (Bicuculline injections into STN, which blocked the inhibitory input from GPe,...

Burst Firing In Components Of The Basal Ganglia And Parkinsonian Tremor

As mentioned above, tremor is one of the symptoms alleviated by STN lesions in parkinsonian monkeys (Bergman et al., 1990). Parkinsonian tremor in humans is also alleviated by pallidal lesions (Dogali et al., 1995) and by lesions of the motor thalamus (Tasker et al., 1983, 1997 Burchiel, 1995 Moriyama et al., 1999). Thus the explanation of parkinsonian tremor is likely to involve pathways through the motor thalamus, rather than through direct descending pathways to the brain stem. This conclusion is supported by the fact that lesions of the PPN, although producing akinesia (see Section 8.7.2), fail to reproduce the tremor of Parkinson's disease (Kojima et al., 1997). It is however clear that parkinsonian tremor cannot be adequately understood just in terms of the relative over- or underactivity of neurons in the various subdivisions of the basal ganglia, although that is certainly an important factor. One of the possible implications is that the pattern of firing, as well as the...

Druginduced Parkinsonism

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

Peripherally Induced Tremor And Parkinsonism

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

Developmental Forms Of Parkinsonism

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

Structural Lesions Causing Parkinsonism

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

Other Unusual Causes Of Secondary Parkinsonism

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

Parkinsons Disease Summary

The symptoms of Parkinson's disease are many and varied and are not to be explained by a single pathophysiological mechanism. As far as striatal dopamine depletion is responsible, a variety of symptoms can be explained in terms of the widespread over-activity of striatal medium spiny neurons, the origin of both the direct and indirect pathways, and the consequent difficulty in selectively releasing or selectively suppressing specific pieces of behavior. These abnormal processes, acting in different parts of the striatum, can act on behavior at different levels. Macrobehavior and microbehavior reflected in symptoms presumably involve similar dynamic mechanisms, but in different parts of the striatum. Thus some of the symptoms of excessive release and excessive suppression are exerted at the level of bodily movements, others at the level of cognitive processes. In the case of the latter, it becomes more difficult than in the normal situation to activate separately different...

Neurophysiological Correlate Of Parkinsonism

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

Neurophysiological Tests In The Assessment Of Atypical Parkinsonian Disorders

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

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

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

Parkinsonism And Movement Disorders

Since degeneration of the nigrostriatal system occurs in all parkinsonian disorders, drugs targeting the principal transmitter deficiency, DA, remain the treatment of choice for associated motor dysfunction, especially rigidity and bradykinesia. Positron emission tomography (PET) studies have shown decreased striatal 18flourodopa uptake and decreased striatal regional blood flow indicative of the loss of nigral dopaminergic neurons (1,2). Moreover, a preferential loss of postsynaptic DA-D2 receptors in the posterior putamen occurs in relation to levodopa resistance, suggesting the additional degeneration of striatal spiny neurons (3,4). Similarly, 123I-iodobenzamide (IBZM) single photon emission computed tomography (SPECT) studies indicate lower mean striatal DA-D2 receptor binding in patients with atypical parkinsonian disorders than in those with PD (5). A comparison using 123I p-CIT SPECT reveals a reduction of striatal DA transporter density in parkinsonian disorders, including PD...

Hemiparkinsonismhemiatrophy

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

Rasagiline Parkinsons Disease [7987

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

Metabolic Causes Of Parkinsonism

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

The Impact Of Parkinsonism On Healthrelated Quality Of Life

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

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

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

Toxic And Metabolic Parkinsonism

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

The Goad And The Halter In Parkinsons Disease

Oliver Sacks is of the clear opinion that the above-mentioned symptoms are not the core features of Parkinson's disease. In the introduction to Awakenings, he mentions that the very first qualities of Parkinson's disease to be described were festination and pulsion. In objective terms these consist of hurried movements (e.g., of gait or in writing), although the hurried movements may become smaller and smaller in amplitude and so come to an uncontrolled halt. Subjectively they are often accompanied by a sense of motor urgency and impatience. Sacks quotes Charcot's phrase cruel restlessness to describe Parkinson's disease. Of a similar nature is the symptom of akathisia, more commonly seen in psychiatric patients as an unpleasant side effect of treatment with neuroleptic drugs. This is manifested objectively as excessive restlessness and fidgetiness, often accompanied by a subjective sense of restlessness. These symptoms represent release of large-scale behavior, rather than of simple...

Direct Connections From Basal Ganglia To Brain Stem And Their Role In Parkinsonian Akinesia And Rigidity

Two symptoms given prominence in descriptions of Parkinson's disease akinesia and rigidity are improved little by thalamotomy, unlike the symptom of tremor (see Section 8.6), although all three symptom classes are alleviated by STN lesions. Akinesia and rigidity are often associated in Parkinson's disease, and appear to represent a subtype different from that in which tremor predominates (see Section 8.1). Jellinger (1999) suggests, on the basis of neuropathological studies, that in this subtype, dopamine cell loss is predominantly in the lateral part of substantia nigra, which innervates the motor part of the striatum (dorsal putamen). It is difficult to incorporate this finding in detail into the scheme of functional circuits through the basal ganglia (mentioned in Section 2.2), without fuller data on dopamine loss in parts of the basal ganglia (such as STN) additional to the striatum. Nevertheless, the fact that akinesia and rigidity change little with thalamotomy suggests that...

Infectious Causes Of Parkinsonism

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

Alzheimer and Parkinson Diseases

Subthalamic Nucleus Anatomy

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

Parkinsonism Without Prominent Rest Tremor

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

Postanoxic Parkinsonism

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

Early Concepts Of Atypical Parkinsons Disease

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

Inflexibility Of Adjustments Of Posture And Gait In Parkinsons Disease

The previous section was concerned with selection of dimensions for attention and of behavior-related cell assemblies. Behavioral output should include automatic adjustments of gait or posture, normally thought of as motor functions. In Parkinson's disease there are, besides the classic motor symptoms, many abnormalities in gait and posture. Often these normal functions and their abnormalities in Parkinson's disease are spoken of in terms of postural reflexes. However, there are several indications that these adjustments are not reflexes as commonly understood, but are generated by mechanisms similar to those underlying the cognitive processes just described. In Parkinson's disease, these automatic adjustments are impaired. For unpredictable toe-up tilts, parkinsonian subjects cannot adjust the size of the response to the expected size of the tilt nor can they chose the larger (safer) response size as a default when the size of the perturbation is uncertain (Bloem et al., 1995b)....

Parkinsonism Owing To Toxin Exposure

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

Parkinsonism

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

Of Parkinson

According to Kosaka (34,35), the topography of the Lewy bodies is organized in three different distributions. An X rectangle means presence of Lewy bodies. The brainstem type is commonly found in Parkinson's disease. The diffuse type is usually associated with DLB. In the transitional type, cognitive symptoms are common they may be primary or complicate IPD. The borders between the three types may be difficult to draw. It has been shown that even in cases of apparently uncomplicated IPD, the presence of a few Lewy bodies in the isocortex is common (42). Striatonigral degeneration (69,70) was initially an autopsy finding since the symptoms are very similar to those of IPD, except that there is a resistance to treatment by L-dopa (71). The gross examination shows a peculiar and often severe atrophy along with a green discoloration of the putamen that is distinctive of the disease. The substantia nigra is pale. As already mentioned by Adams et al. ( D g n rescences nigro-stri es et c r...

Series Editors Introduction

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

Corticobasal Degeneration

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

Multiple System Atrophy

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

Prevalence of PSP and MSA

Measures of the prevalence of PSP vary from 0.97 to 6.54 per 100,000 (eight studies) and for MSA from 2.29 to 39.3 per 100,000 (five studies) (Table 1). A study from Sicily (8) reported one of the highest rates of 28.6 per 100,000 but this was for unspecified parkinsonism, so this category may have included cases other than MSA and PSP. The results presented in Table 1 are simple crude rates for the whole population rather than age-standardized rates. Though some studies do report such standardized rates, each study generally uses a different standard population and some studies fail to present age-specific rates making it impossible to restandardize the rates to a single population. The purpose of standardization is to remove any confounding effect owing to the age structure of the population. As all the studies except one from Libya (7) have been undertaken in a developed world population, it is likely that such confounding is not too large. In fact, differences between the crude...

Implications From Prevalence and Incidence Data

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

Risk Factors For Psp And

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

Excitatory Network Substrate For Cell Assemblies And Associative Operations

The mammalian forebrain consists of various macrostructures of which the cerebral cortex is the largest. This laminated sheet of gray matter comprises both the neocortex and other laminated components, including notably, the hippocampal formation. In addition there are nonlaminated structures in the forebrain, including the thalamus, and a variety of other entities (striatum, globus pallidus, subthalamus), which, together with the substantia nigra in the midbrain make up the complex known as the basal ganglia.

Dementia With Lewy Bodies

Although it has long been recognized that a significant proportion of PD patients develop dementia (12), the pathological substrate for this cognitive dysfunction remained uncertain. In 1961, Okazaki reported finding LBs in the cerebral cortex of two patients with PD and atypical dementia (27). Although subsequent cases of diffuse Lewy body disease (DLBD) were published, the condition was initially considered rare. In the late 1980s, with greater awareness of cortical LBs and the development of more sensitive staining methods, several groups reported finding cortical LBs in 15-25 of elderly demented patients, both with and without parkinsonism (28,29). It has recently been proposed that dementia associated with Lewy bodies (DLB) represents a recognizable clinicopathological syndrome that may be distinguishable during life from other causes of dementia (30). The proposed diagnostic criteria are purely clinical however, and recommendations as to how to quantitate LBs are only designed...

The Spectrum Of Lb Disorders

There is striking clinical and pathological overlap between PD and DLB. Up to one-third of patients with a clinical diagnosis of PD will develop dementia (9,12,42) and most (but not all) patients with DLB display some degree of parkinsonism (30). LBs are the defining histopathological feature of both conditions. In PD, LBs are most numerous in subcortical nuclei and it is the associated loss of dopaminergic neurons that is largely responsible for the characteristic extrapyramidal features. However, small numbers of cortical LBs may be found in virtually all cases of PD, even in the absence of dementia (31). In DLB, cortical LBs are usually more numerous and some studies have shown a

Progressive Supranuclear Palsy

In the original description of this disease entity, patients with supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, rigidity, and mild cognitive deficits were found to have abundant NFTs in subcortical nuclei (91). The clinical phenotype is now recognized to be much more variable and includes both pure parkinsonism and frontotemporal dementia with no movement abnormality (1,2,4,5,71). The macroscopic changes are quite variable. The cerebral cortex often appears normal but may show significant frontotemporal atrophy that may be quite circumscribed (Fig. 5A). The midbrain and pontine tegmentum are often atrophic whereas the globus pallidus is the most commonly affected part of the basal ganglia (Fig. 5B). Microscopic degeneration with neuronal loss and gliosis also tends to be more widespread and severe in PSP than CBD, with substantia nigra, locus ceruleus, globus pallidus, subthalamic nucleus, midbrain tegmentum, cerebellar dentate nucleus, and pontine nuclei usually...

The Motor Thalamus Target Of Executive Decisions

Within the CTH network, the region that holds greatest promise as the site at which the symmetry of the excitatory network is broken are certain thalamic nuclei (loosely, the motor thalamus ). In most thalamic nuclei, the main informational input is conveyed exclusively by excitatory influences. In ultrastructural terms, these excitatory inputs to thalamic principal cells are of two sorts (Steriade et al., 1990). The first of these are recognizable in electron microscope pictures as small round terminals, located mainly on distal dendrites, and derived from all regions of the neocor-tex (Jones and Powell, 1969 Jones, 1985 Steriade et al., 1990). The other variety of excitatory terminals are the large round boutons (Jones and Powell, 1969 Jones, 1985) located mainly on proximal dendrites, which are derived either from ascending sensory pathways (e.g., Guillery, 1969) or other ascending pathways (Harding, 1973 Somogyi et al., 1978) or (in some nuclei) directly from the cortex itself...

Other Neurodegenerative Conditions

Many other common idiopathic neurodegenerative conditions have parkinsonism as an inconsistent or minor clinical feature. Extrapyramidal symptoms are very common in AD and may take the form of true parkinsonism (135-137). Many patients with a clinical diagnosis of AD and parkin-sonism are found to have coexisting LB pathology at autopsy, either restricted to subcortical structures or also involving the cerebral cortex (35,136,138). The correct terminology for these cases is uncertain, because of the lack of universally accepted neuropathological diagnostic criteria for both AD and DLB (see subheading Dementia with Lewy Bodies). Interpretation is further complicated by recent reports of LBs as a common incidental finding in AD patients, even in the absence of extrapyramidal features (139). However, parkinsonism also occurs in some AD patients who have only SP and NFT pathology (136,138,140). SPs are a consistent finding in the striatum and are occasionally seen in the substantia nigra...

Transgenic Mice Expressing Ftdp17associated P301l Mutant Tau Transgenes

Models expressing the P301L human tau protein have been utilized in three novel ways to support the role of amyloid in the development of human AD. Additionally, results from one P301L model suggests that tau and synuclein pathology may be linked, supporting a role for tau in Parkinson's disease (PD). It is possible that the inclusion of the P301L mutation in these mice, which has not been identified in human AD or PD, may complicate these results however, attempts to reproduce these findings using wild-type tau may be unsuccessful given the abbreviated life-span of the model organism. Nonetheless, the pathology of many of these P301L models at the cellular level closely recapitulates the tau pathological features of human AD and other tauopathies.

The 3 and 4R Tauopathies

Alzheimer's-type pathology is the only detectable lesion in a significant proportion of cases in which the diagnosis of IPD has been made premortem (20,164,165). This observation raises the possibility that Alzheimer's disease, in the absence of dementia, causes the parkinsonian symptoms by a direct involvement of the nigrostriatal pathway (165). It is not the place to review here the pathology of Alzheimer's disease suffice it to say that extracellular deposition of Ap peptide and intracellular accumulation of both 3R and 4R tau isoforms are the principal lesions. Tau accumulates in three compartments the neuronal cell body (NFT), the dendrites (neuropil threads), and the axonal component of the corona of the senile plaques (their neuritic component). Ap deposition, without a neuritic component, does not correlate with symptoms or only weakly, whereas tau pathology usually strongly does. The abundance of Ap peptide deposits in the striatum has been known for a long time (166) but it...

Definition And Identification Of Key Neuropsychiatry Symptoms

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

Measuring Psychiatric Symptoms

A number of different instruments have been used to measure neuropsychiatry symptoms in patients with parkinsonian disorders. These can be divided into clinical interviews that focus upon a broad range of symptoms or more focused scales. Examples of the first group include the Present Behavioural Examination (PBE) (6), Neuropsychiatric Inventory (NPI) (7), and Brief Psychiatric Rating Scale (BPRS) (8). The PBE is a lengthy interview with a detailed assessment of behavior in patients with dementia, and requires a trained observer. The NPI is a highly structured, caregiver-based interview, which can be completed in a relatively short time depending on the amount of disturbances (see below). The BPRS was constructed essentially for schizophrenic states, and requires a trained rater. Examples of scales that assess specific syndromes in more detail are the Hamilton Depression Rating Scale (HAM-D) (9) and self-rating scales completed by the patients themselves (i.e., Beck Depression...

The Neuropsychiatry Of The Basal Ganglia

The basal ganglia are involved in two major brain systems associated with the regulation of emotions, mood, and behavior (a) the limbic structures with widely distributed brainstem, striatal, and paralimbic sites, with rich reciprocal connections to the basal ganglia, in particular between the amygdalae and caudate (17) and (b) five frontosubcortical circuits, linking frontal lobe regions to subcortical structures, including the basal ganglia, and back to frontal lobe areas (18). These circuits receive input from brainstem nuclei, including dopaminergic input from substantia nigra and pars compacta. In addition to motor and eye movement control, the frontosubcortical circuits subserve Since parkinsonian disorders usually involve several subcortical structures, particularly at more advanced disease stages, focal lesions may provide a better opportunity to unravel the relationship between different basal ganglia regions and neuropsychiatry symptoms. In a literature review, Bhatia and...

Psychiatric Aspects Of Dementia With Lewy Bodies

DLB is characterized clinically by dementia, visual hallucinations, and fluctuating consciousness in addition to parkinsonism. Neuropathological characteristics include alpha-synucleinopathy, such as Lewy bodies and Lewy neurites in the brainstem, particularly the substantia nigra, subcortical structures, limbic cortex, and neocortex. Some amyloid deposition is also found in most patients. Neurochemically marked cholinergic deficits are reported in addition to a moderate nigro-striatal dopaminergic, and monoaminergic deficits have also been reported. It is estimated that at least 80 of DLB patients experience some form of neuropsychiatric symptoms (23), such as visual hallucinations, auditory hallucinations, delusions, delusional misidentification, and depression. These visual hallucinations are consistently reported to be more frequent in DLB than in AD, also in samples diagnosed at autopsy, and constitute one of the key diagnostic features of the disorder. Although rates vary from...

Management Of Neuropsychiatric Symptoms

Pharmacological Treatment of PD In light of the high prevalence and clinical importance of neuropsychiatric symptoms in patients with parkinsonian disorders, relatively few adequately designed clinical trials have been reported. In a recent evidence-based review of management of PD, including psychosocial treatments, produced by The Movement Disorder Society (112), the only neuropsychiatric treatment that was concluded to be efficacious was the atypical antipsychotic agent clozapine for hallucinations psychosis. In addition, the tricyclic antidepressant nortriptyline was considered to be likely efficacious. Too few or methodologically inadequate studies precluded positive conclusions for other treatments. To our knowledge, only nine randomized, placebo-controlled studies of neuropsychiatric symptoms in parkinsonian disorders have been reported four trials with cholinergic agents in DLB (rivastigmine) (113), PD (donepezil) (114), and PSP (donepezil and RS-86, a cholinergic agonist)...

Pharmacological Treatment Of

Several open-label studies suggest that atypical antipsychotic agents can improve psychotic symptoms in DLB (125,126). However, DLB sufferers seem to be particularly vulnerable to a specific type of adverse reaction to neuroleptic agents. Patients develop severe parkinsonism, impairment of consciousness, autonomic instability, and frequently experience falls and a marked drop in their level of cognitive performance and functioning (127,128). Furthermore, even in DLB patients who do not experience severe neuroleptic sensitivity, there is some evidence that neuronal loss in the caudate and putamen may be exacerbated by neuroleptic treatment (129). Given the major concerns regarding severe neuroleptic sensitivity reactions, neuroleptic agents cannot be considered to be the first-choice management approach for neuropsychiatric symptoms, but may possibly still have a role in severe and intractable cases with psychosis. A number of case reports and case series indicate that cholinesterase...

Future Research Issues

Study the diagnostic properties of the neuropsychiatric profile in parkinsonian disorders. 3. Exploring the neurochemical underpinnings of neuropsychiatric symptoms in patients with parkinsonian disorders. 6. Systematic studies of non-pharmacological strategies should be conducted for patients with parkinsonian disorders.

Distribution Of The Apraxias In Other Body Parts

Truncal or whole body apraxia is a disorder of axial movements neither attributable to elementary motor (e.g., extrapyramidal) or sensory deficit nor to dementia. Patients have difficulties dancing or turning around and may be unable to adapt the body to the furniture patients have difficulty sitting down in a chair, showing hesitation, sitting in a wrong position (e.g., on the edge of the chair) and in incorrect directions (e.g., facing the back of the chair). When lying in bed, their body is not aligned parallel to the major axis of the bed and they place the pillow in an unusual position. Patients may have minimal or no difficulty in standing or getting up, in contrast to features of some basal ganglion disorders such as parkinsonism. Truncal apraxia is seen with bilateral hemispheric damage involving the parietal or parieto-temporal cortex or affecting parietofrontal connections (55,56). THE NATURE OF APRAXIA IN ATYPICAL PARKINSONISMS Corticobasal Degeneration CBD patients may not...

Dopamine in the Subthalamic Nucleus and Changes in Neural Activity There after Dopamine Denervation

It is widely accepted that Parkinson's disease arises largely or entirely from degeneration of dopaminergic axons innervating the basal ganglia. The general belief is that denervation of the dopamine supply to the striatum (specifically the putamen, according to Kish et al., 1988) is sufficient to produce the symptoms of the disease. It might, therefore, be thought that the classic motor symptoms of Parkinson's disease could be explained in terms of dynamic changes occurring primarily in the striatum, when the putamen is severely depleted of its dopamine. As discussed below (Section 3.4.5), many striatal neurons undergo an increase in firing rate in association with parkinsonian states. It is also known that firing rate of neurons in the STN is markedly elevated in animal models of Parkinson's disease (see, e.g., Miller and DeLong, 1987 Bergman et al., 1994 Kreiss et al., 1997 Magill et al., 2001 but also see Ni et al., 2001). This fact has been attributed to the increase in firing...

Diffuse Lewy Body Disease

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

Increase versus Decrease of Firing Rate in Neurons of Origin of the Direct and Indirect Pathways

It is quite plausible to suggest that decreased firing in GPe in human Parkinson's disease, or animal models of it, is due to increased firing of the inhibitory striatal cells projecting to GPe. A number of studies directly investigating firing rates in the striatum support this suggestion by showing that striatal dopamine depletion increases the firing rate of single striatal units. This is seen in anesthetized preparations (Arbuthnott, 1974 Schultz and Ungerstedt, 1978 Orr et al., 1986), paralyzed locally anesthetized preparations (Hull et al., 1974 Alloway and Rebec, 1984), and in free-moving animals (Kish et al., 1999 Chen et al., 2001).* Anesthesia reduces the firing rate, sometimes by as much as an order of magnitude, but the differential between intact and dopamine-depleted animals still applies (Schultz and Ungerstedt, 1978 Kish et al., 1999). Parkinsonian states ( catalepsy ) can also be produced acutely by administering neuroleptic drugs. This has been shown to increase...

The Scaling Of Movement Hypothesis

This hypothesis is consistent with the fact that activity in GPi neurons is usually found to be above normal in an akinetic symptom (MPTP-induced parkinsonism in monkeys) and is below normal in a hyperkinetic disorder (e.g., chorea, dyskinesia, etc.) (Section 3.4.3.1). However, chorea and dyskinesia are not simply increases in velocity and amplitude of movement Voluntary movement may in fact be slowed (Mink, 1996). Moreover it is important to note that the hypothesis of scaling of movement refers clearly to an aspect of motor coordination, rather than behavioral selection. Given this, the proposed role of the basal ganglia seems to be redundant, since the cerebellum is concerned with many of the same processes.

Directions For Future Research

Directions for future research point strongly toward the need to develop both specific and combined behavioral, pharmacotherapeutic, or neurostimulation interventions that might slow, arrest, or even reverse the progression of the speech and language manifestations of atypical parkinsonian disorders (see Table 2 for summary). For example, cholinergic stimulation using centrally active cholinesterase inhibitors may be beneficial in improving cognitive or linguistic performance in the early stages of disease progression. Transcranial magnetic stimulation (TMS) can also be used to investigate the excitability of motor cortices in neurodegenerative diseases, thus providing important information having pathophysiological and clinical relevance. For example, TMS can be used to study the effects of drugs and surgery thus introducing the possibility of monitoring the action of treatment of movement disorders (including dysarthria) on cortical excitability (79). As medical treatments become...

Epidemiologic Aspects

The incidence of PSP is closer to 10 of PD (36), making it much more common than previously recognized. Early crude incidence rates of PSP ranged from 0.3 to 0.4 per 100,000 per year (37), but an incidence study of PSP and all types of parkinsonism in Olmsted County, Minnesota, from 1976 to 1990 (1,36) found a crude incidence rate for PSP of 1.1 per 100,000 per year, which increased from 1.7 cases per 100,000 per year at age 50-59 years to 14.7 per 100,000 per year at ages 80-99 yr (1). It is thought that these figures are higher because of better methodological case finding and increased recognition of the disorder by neurologists and non-neurologists (1). Similarly, the earlier underestimated prevalence of 1.39 per 100,000 (38) has been found to be 6.0-6.4 100,000 in two population-based prevalence studies using currently accepted diagnostic criteria for PSP conducted in the United Kingdom (2,39).

Clinical Diagnostic Criteria

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

Onset And Progression

MSA usually manifests in middle age (the median age of onset is 53), affects both sexes, and progresses relentlessly with a mean survival of 6-9 yr (13,19,20). MSA patients may present with akinetic-rigid parkinsonism that usually responds poorly to levodopa. This has been identified as the most important early clinical discriminator of MSA and PD (11,21-23), although a subgroup of MSA patients may show a good or, rarely, excellent, but usually short-lived, response to levodopa (24-26). Progressive ataxia, mainly involving gait, may also be the presenting feature of MSA (27,28). A cerebellar presentation of MSA appears to be more common than the parkinsonian variant in Japan compared to Western countries (29). Autonomic failure with symptomatic orthostatic hypotension and or urogenital and gastrointestinal disturbance may accompany the motor disorder in up to 50 of patients at disease onset (20). Besides the poor response to levodopa, and the additional presence of pyramidal or...

Clinical Features Of Dementia With Lewy Bodies

From Current Clinical Neurology Atypical Parkinsonian Disorders Edited by I. Litvan Humana Press Inc., Totowa, NJ c. spontaneous motor features of parkinsonism sundowning or intermittent delirium, depending upon the severity and diurnal pattern. FC occurs in 80 or more of DLB patients. The profile of attentional impairment and fluctuating attention in DLB is indistinguishable from that recorded in PDD (8). The frequency of parkinsonian features at presentation in DLB ranges between 10 and 78 , with 40-100 of DLB cases displaying EPS at some stage of the illness (17-19), with differences likely to represent ascertainment bias, use of neuroleptic agents, and variable definition of clinical phenomenology. Louis and coworkers compared EPS in 31 DLB and 34 PD pathologically confirmed cases (17). Clinical information was obtained prospectively in some patients. DLB patients presenting with parkinsonism were, on average, 10 yr younger than the DLB patients presenting with neuropsychiatric...

Diagnostic Accuracy And Differential Diagnosis

Interrater reliability for the core clinical features of parkinsonism and hallucinations in DLB is generally good, but only poor or moderate for fluctuating cognition. The application of validated methods to recognize the latter may thus increase diagnostic accuracy. When DLB presents as a primary dementia syndrome the key differential diagnoses are AD, vascular dementia, delirium secondary to systemic or pharmacological toxicity, Creutzfeldt-Jakob disease, or other neurodegenerative syndromes characterized by EPS and dementia. The latter include PSP and corticobasal degeneration (CBD). These conditions need to be excluded as far as possible by taking a careful history (including the carer whenever possible) and performing a thorough neurological examination, supplemented where necessary by ancillary investigations (see next section, Investigation). Table 2 summarizes the key clinical features in several neurodegenerative syndromes featuring parkinsonism and cognitive impairment.

Legend To Videotape

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

Madhavi Thomas and Joseph Jankovic

Idiopathic Parkinson's disease (PD) is the most common cause of parkinsonism, accounting for about 75 of all cases. Other causes of parkinsonism include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and a variety of other neurodegenerative disorders in which rest tremor, bradykinesia, rigidity, and other parkinsonian features are present. Since these disorders are often associated with other neurological deficits, such as dysautonomia (in MSA), vertical ophthalmoparesis (in PSP), and apraxia (in CBD), they are referred to as parkinsonism plus syndromes. Whereas the above disorders are degenerative in nature, there are other forms of parkinsonism, which are secondary to a variety of etiologic factors including vascular parkinsonism (VP), hemiatrophy hemiparkinsonism, and toxic and metabolic causes. It is important to review the cardinal features of PD that form the basis for diagnosis of parkinsonism. Cardinal motor features of PD...

Major Research Issues

As discussed above, there are several forms of nondegenerative parkinsonism with variable clinical features as shown in Table 2, VP being the most common. One of the mysteries of VP is what, besides the usual stroke risk factors, predisposes the affected individual to develop VP since not everyone with hypertension, diabetes, or other stroke risk factors develops VP. Further studies of the relationship between anticardiolipin antibodies and VP (20) are needed before routine screening of these patients for these antibodies can be recommended. It is not clear why some patients improve with dopaminergic drugs whereas others do not. CSF withdrawal may benefit some patients with VP, but this improvement is transient (34). More studies are needed to determine whether CSF shunting would benefit some patients.

Future Directions

As discussed above, several of these non-degenerative forms of parkinsonism support the evidence for multiple etiologic factors leading to selective neuronal vulnerability. Investigation of neuroprotective potential of specific agents such as CPI 1189 for HIV dementia has shown some improvement with motor function, but the study is not designed for efficacy (100). Future studies in this area may help treat HIV-induced parkinsonism. Parkinsonism induced by toxic exposure or specific infectious etiology may provide a direct clue to the dysfunction in mitochondrial and other specific cellular mechanisms such as inflammation, and lysosomal dysfunction, which may help identify specific targets for therapy. Further research into the cellular mechanisms in various types of parkinsonism are needed in order to clarify the mode of insult an specific signal transduction pathways involved in disease mechanisms.

For Differential Diagnosis In Patients With

From the author's point of view, the neurophysiological tests that better characterize parkinsonism and, specifically, the APDs, are listed in Table 4. Performance of ballistic movements within a reaction time task paradigm is useful to test the mechanisms of motor preparation and execution, even though very much should still be learned on the physiology of motor preparation for the test to provide its full potential of information. Brainstem and spinal reflexes have to be conveniently modulated by the descending motor commands for them to be integrated in the subject's normal motor behavior. Although many tests have given interesting information on the abnormal brainstem and spinal reflex modulation in patients with parkinsonism, a good clinical correlate of these abnormalities is still pending. The evaluation of autonomic reflexes and the sphincter EMG provides information on specific abnormalities that can be predominant in certain groups of patients. They reflect the involvement...

Neural Dynamics In The Basal Ganglia When Dopaminergic Tone Is Elevated

There is also some evidence that different striatal units undergo increases in firing in the low- versus high-dose phases of amphetamine's actions. Whether the units whose increase in firing correlates with the small movements of focused stereotypy are really related more fundamentally with the suppression of locomotion which occurs at the same time cannot be determined. Thus, there is no clear evidence yet for a dissociation in firing rate changes compatible with proposed opposed roles in relation to the behavior for the cells of origin of direct versus indirect pathways. There is also no evidence against this proposal. The issue might be resolvable by careful combination of electrophysiological and ethological observations during behavior changes produced by a range of amphetamine doses.

Prospects For Future Research

In research on atypical parkinsonian disorders, MR investigations can be expanded in at least two main directions. Fig. 6. Vascular parkinsonism. In this 66-yr-old patient with pseudobulbar signs and progressive parkinsonism with shuffling gait, coronal T1- (A) and axial T2-weighted sections (B) show multiple lacunes or small infarcts in the basal ganglia and thalami. Hyper- and hypointensity consistent with an old, small hemorrhagic lesion is present in the right putamen (B). Fig. 6. Vascular parkinsonism. In this 66-yr-old patient with pseudobulbar signs and progressive parkinsonism with shuffling gait, coronal T1- (A) and axial T2-weighted sections (B) show multiple lacunes or small infarcts in the basal ganglia and thalami. Hyper- and hypointensity consistent with an old, small hemorrhagic lesion is present in the right putamen (B). Fig. 7. Parkinsonism in chronic manganese intoxication. Pallidal hyperintensity in Tl-weighted axial section prompted investigations on possible...

Functional Magnetic Resonance Imaging

However, the pattern of abnormal movement-related activity in frontal motor areas has been variable across studies (9-12). Since these studies used motor tasks that differed in terms of movement parameters and cognitive load, the implication is that, in PD, functional impairment of the various basal ganglia-thalamocortical motor loops is highly dependent on the motor context. In addition to motor activation studies, BOLD-sensitive fMRI has also successfully been employed to assess nonmotor functions such as attention to action and working memory in PD (12,13). Repeated fMRI measurements have also been used to image the acute effects of a therapeutic intervention. For instance, pharmacological fMRI studies have consistently demonstrated a partial normalization of movement-related activation in frontal motor areas after oral administration of levodopa (9-11). At present, there are no fMRI studies investigating atypical parkinsonian disorders. However,...

Magnetic Resonance Spectroscopy

Proton MRS has been used by several groups to study brain metabolism in nondemented PD yielding conflicting results (15-27). In general, the majority of these studies have failed to detect consistent abnormalities for NAA, Ch, or Cr in the basal ganglia (15-19,21,24,25 but see refs. 20,26,27) or the cerebral cortex (19,21,25 but see refs. 22,23). A multicenter study that included 151 patients with PD and 97 age-matched controls found no overall differences in the striatal proton spectra between groups (16). However, there was a decrease in the NAA Cho ratio in a subgroup of elderly patients (aged 51-70 yr) and patients that were not treated with levodopa (16). These findings suggest that proton MRS may reveal subtle metabolic abnormalities in patients with PD depending on age and medication. Therefore, heterogeneities of clinical features across patient groups may at least in part account for discrepancies across studies (15-27). Three out of four proton MRS studies have reported...

Diffusionweighted Magnetic Resonance Imaging

Three studies have characterized water diffusion in patients with atypical parkinsonian disorders. Patients with PSP showed an increase in ADCs in the prefrontal and precentral white matter (30) and the basal ganglia (31,32). An increase in ADCs was also found in patients with the MSA-P variant of MSA (32), but not in patients with PD (31,32). These data indicate that diffusion-weighted imaging may help to distinguish between PD and atypical parkinsonian disorders, but fails to discriminate between PSP and MSA. Because DT-MRI provides a unique approach to tracking anatomical connectivity in vivo, DT-MRI can provide important new insights into the neuroanatomical basis of atypical parkinsonian disorders linking clinical symptoms with impaired anatomical connectivity. Though no DT-MRI study has been published on atypical parkinsonian disorders at this stage, it is safe to state that DT-MRI provides a promising tool to pinpoint characteristic patterns of abnormal connectivity, especially...

Reasons For Identifying Striatal Cholinergic Cell Loss As The Origin Of The Four Syndromes

With no previous neuroleptic exposure (Owens et al., 1982 McCreadie et al., 1996). Nevertheless, patients exposed to neuroleptics have a higher incidence of TD than nonexposed patients (Jeste and Wyatt, 1981). These facts suggest that neuroleptic exposure is one amongst a number of possible contributory causes of this syndrome (Crane, 1973a). The relationship of TD to drug exposure is stronger for typical neuroleptic drugs than for the atypical drugs (serotonin-dopamine antagonists and clozapine) (Correll et al., 2004 Margolese et al., 2005). It appears more consistently if neuroleptic drugs produce prominent parkinsonism than in patients with less-severe motor side effects (Kane et al., 1986 Chouinard et al., 1986a, 1988 Tenback et al., 2006). This may be the explanation of the lower risk associated with atypical antipsychotic drugs. Abnormal dyskinetic movements also occur in some patients with Parkinson's disease during L-DOPA therapy (Barbeau, 1969 Cotzias et al., 1969 Chase et...

Autonomic Dysfunction

Most studies of autonomic dysfunction in atypical parkinsonian disorders focus on MSA, where this feature is far more common than in CBD, PSP, or DLB. Neuropathological studies reveal neuronal loss in central adrenergic pathways, especially catecholaminergic neuron depletion in the rostral ventrolateral medulla, but not in the sympathetic ganglia (67,68). Asymptomatic orthostatic hypotension generally does not require treatment in MSA, since autoregulation seems preserved down to a systolic blood pressure of 60 mmHg, a value well below the 80 mmHg at which autoregulation fails in normal subjects (69). Urinary problems also commonly afflict those with atypical parkinsonian syndromes. a1-adrener-gic receptors are present in the proximal urethra where impaired relaxation may be responsible for difficulty voiding and increased residual urine. An uncontrolled study showed that a1-adrenergic antagonists, prazosin (nonselective) and moxisylyte (selective), reduced residual urine volume,...

Cognitive Dysfunction

Drugs enhancing central cholinergic function provide a rational approach to the treatment of cognitive dysfunction associated with the Parkinson plus disorders. In PSP, however, a controlled trial of physostigmine showed only borderline changes in long-term memory (41), although improved visual attention has been reported (92). An open study of donepezil did not appear to ameliorate cognitive dysfunction (38), whereas a controlled trial suggested modest benefit in some cognitive measures but worsened mobility scores (42). A controlled trial on the direct cholinergic agonist RS-86 revealed comparable unsatisfactory results (43).

Behavioral Dysfunction

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

Efficacy Of Rehabilitation

The efficacy of rehabilitation in patients with APDs is largely unknown, however a number of studies have investigated the efficacy of physical therapy in addition to medication therapy in individuals with PD. Most studies reveal positive effects of physical therapy in patients with PD. De Goede and colleagues conducted a meta-analysis of 12 studies investigating the effects of physical therapy in addition to medications in individuals with PD (2). All studies included in the analysis were classi fied as true or quasi-experiments. The physical therapy interventions varied across studies and included gait training with external cues, behavioral training to improve activities of daily living (ADL), exercises to improve mobility, stretching, strengthening, karate, skills training, and education. A statistically significant summary effect size was found with regard to ADL (0.40), stride length (0.46), and walking speed (0.49). The summary effect size with regard to neurological signs...

Directing Rehabilitation Approaches

Therapists may choose from a variety of treatment approaches and strategy. These include treatments that target problems at the impairment or functional level, and interventions that aim to restore to a previous level of functioning or compensate for loss of previous healthy functioning. Although the literature on rehabilitation with patients with PD is not yet adequate to establish comprehensive evidenced-based guidelines, the growing body of evidence supports the efficacy of rehabilitation and suggests approaches that rehabilitation teams may use in patients with idiopathic PD and APDs. Consistent themes that arise from the research in idiopathic PD include improvements in walking ability and ADL status following rehabilitation targeting these functional areas. Task-specific training at the functional level appears to be a critical ingredient. Studies of other neurologic disorders support the notion that performance of tasks improves in relation to direct task practice (16,17)....

Overview Of A Movement Disorders Rehabilitation Program

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

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