Respiratory Dysfunction in Parkinsons Disease

A number of studies have provided evidence, through various aerodynamic measurements, for disordered respiratory function in individuals with PD. These disorders include reduced vital capacity, reduced total amount of air expended during maximum phonation tasks, reduced intraoral air pressure during consonant vowel productions, and abnormal airflow patterns (48-50). The origins of these airflow abnormalities are not clear but they may be related to variations in airflow resistance due to...

Dopamine Agonists And Dopamine Receptors

The dopamine agonists used in the treatment of PD include apomorphine, bromocrip-tine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, and rotigotine. All of these agents activate D2 receptors, whereas pergolide has been shown to be a mild D1 agonist, and pramipexole may have higher affinity for D3 receptors (Table 1). Five subtypes of dopamine agonist receptors have been identified and may be classified into striatal (D1 and D2) receptors or cortical (D3, D4, and D5) receptors. The...

[123IMetaiodobenzylguanidine Scintigraphy

123I Metaiodobenzylguanidine (MIBG) is a norepinephrine analog, which is transported into and stored in the terminals of sympathetic nerve endings. MIBG uptake is expressed as a ratio of single photon emission computed tomography signal in heart to that of the upper mediastinum. The lower the ratio, the fewer are the functioning sympathetic nerve terminals in the heart. A number of studies have looked at the sympathetic innervation of cardiac muscle in PD patients using this technique, and all...

Acoustic Measures of Abnormal Voice and Speech in Parkinsons Disease

Acoustic analyses of voice and speech in individuals with PD have confirmed the perceptual descriptions of hypokinetic dysarthria. Fox and Ramig (33) documented reduced vocal sound pressure level (vocSPL) by 2 to 4 dB (at 30 cm) on a number of speech tasks in 29 individuals with PD, compared with age- and gender-matched controls, which is equal to a 40 change in vocal loudness. Ho et al. (34) found vocSPL in PD to decay much faster than in neurologically normal speakers. They interpreted this...

Advanced Parkinsons Disease

Selegiline has mild to moderate benefit as adjunct therapy to levodopa in advanced PD patients and is approved by the FDA in the United States for this indication. In a small double-blind placebo-controlled trial (79) of selegiline 10mg day in PD subjects (n 38) on stable levodopa doses, selegiline reduced daily levodopa dosage requirements (P < 0.05) and significantly improved tremor (P 0.02) over eight weeks. Thirty subjects (selegiline n 18, placebo n 12) completed a 16-month follow-up...

Anatomy The Basics For Circuitry

This section reviews the basic anatomical interconnections between neurons that make up the basal ganglia-thalamic-cortical circuits. The anatomy is discussed only to a level of detail necessary for conceptual understanding of current models of function and dysfunction and for possible futures theories. This section will neither cover a fine-grained analysis of interconnections nor the histology for reviews see Refs. (8-12) . Traditional approaches to the anatomy of the basal ganglia have been...

Anticholinergics and Cholinesterase Inhibitors

Anticholinergic medications used to treat motor symptoms in PD potentially produce adverse effects on memory, executive functions, and global cognitive abilities. In placebo-controlled studies, Bedard et al. (114,115) found anticholinergics to induce executive deficits in PD, but not in control participants. Although anticholinergic-induced memory decrements are observable even in patients without preexisting cognitive impairments (116), Saint-Cyr (117) found that confusional states are more...

Assessment of Efficacy

Overall, based on clinical experience and the available scientific data, SSRIs and TCAs may be considered useful for the treatment of depression in PD, and the agent that provides the best overall clinical benefit-to-risk profile should be selected (168). Amoxapine and lithium should be avoided, given the propensity of these agents to worsen motor symptoms and the availability of safer agents (169,170). Additionally, the nonselective MAO inhibitors (e.g., isocarboxazid, phenelzine, and...

Attention and Executive Functions

Attention and executive deficits in PD are most often ascribed to frontal lobe dysfunction secondary to striatofrontal deafferentation and, in particular, pathophysio-logical alterations in the basal ganglionic-dorsolateral frontal loops with medial nigral dopamine depletion impacting the caudate and its frontal projections (31). Performance on simple tasks of attention, for example, forward digit span, is most often preserved in patients with PD (32). On the other hand, deficits on tasks,...

Atypical Antipsychotics

Atypical antipsychotics are typically used to treat psychosis in PD. Table 1 provides a summary of atypical antipsychotic studies in PD. The United States Food and Drug Administration (FDA) recently asked all atypical antipsychotic manufacturers to add a boxed warning to their product labels, saying that atypical antipsychotics, when used in elderly patients with dementia, were associated with a higher risk of mortality (54). However, since the deaths were primarily due to cardiovascular or...

Autonomic Dysfunction and Management

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Although Parkinson's disease (PD) is commonly regarded as a disorder of dopamine deficiency, it is actually a multisystem degenerative disorder. As nondopaminergic brain pathways are involved in the genesis of many symptoms, these cannot be successfully treated by merely increasing brain dopaminergic stimulation. The auto-nomic symptoms fall into this category, and thus management is often...

Ayurvedic Medicine

Ayurvedic medicine is the traditional medical system in India, which has existed for over 5000 years. The term Ayurveda literally means science of life or life knowledge. PD is documented to have existed in ancient India and was called Kampavata. Similar to the TCM system, physical illness is thought to result from emotional imbalance, unhealthy lifestyle, and toxins that ultimately upset the balance of the three doshas or regulatory systems of a person (5). These three doshas are vata, which...

Basal Ganglia Selection Theory

This theory posits that the basal ganglia are involved in the selection of motor programs. Bradykinesia and akinesia of PD results in the failure to select or engage appropriate motor programs, whereas levodopa-induced dyskinesia and other hyperkinetic disorders of the basal ganglia fail to suppress inappropriate motor programs (33). The genesis of this theory lies in the observations that most all interactions between nuclei of the basal ganglia are inhibitory with the exception of the output...

Behavioral Speech Voice And Swallowing Treatment For Parkinsons Disease

Although the incidence of speech and voice disorders in individuals with PD is extremely high, only 3 to 4 receive speech treatment (112). One explanation for this is that carryover and long-term treatment outcomes have been disappointing and consequently the primary challenges in the treatment of hypokinetic dysarthria associated with PD. Clinicians have long been aware that when dysarthric PD patients are receiving direct stimulation, prodding, or feedback from the speech clinician or an...

Cholinesterase Inhibitors

In multiple AD trials, cholinesterase inhibitors had mild-to-moderate benefits in both cognition and psychosis (101,102). Cholinesterase inhibitors are also effective for psychosis in DLB patients and are a potential alternative to the atypical antipsy-chotics for PD psychosis. An early open-label study with tacrine showed that five of seven demented PD patients had complete resolution of psychotic symptoms (103) however, the use of this drug has been limited because of hepatic toxicity....

Complementary Therapies For Parkinsons Disease What Do We Really Know

There are very few well-designed studies and consequently very little evidence to support or refute the use of most complementary therapies for the treatment of PD. This does not mean that alternative therapies cannot help someone with PD, but for Western-trained healthcare providers treating someone with PD who is considering alternative therapies, it is difficult to know what and how to advise them. The first rule in medicine is do no harm, so if a particular therapy such as massage therapy...

Deep Brain Stimulation Of The Globus Pallidus Interna

Surgery targeting the internal segment of the globus pallidus has been shown to improve all of the cardinal features of PD including bradykinesia, rigidity, and tremor as well as levodopa-induced dyskinesia. Due to concerns of complications related to speech, balance, and cognition with bilateral pallidal lesions, bilateral DBS of the GPi is preferred to pallidotomy. Multiple studies have reported the efficacy of GPi stimulation for PD (15-20) (Table 1). Many of these studies have a small...

Deep Brain Stimulation

Nonablative surgical procedures for treatment of PD involve either unilateral or bilateral implantation of high-frequency stimulation electrodes into deep brain nuclei. Studies detailing neuropsychological outcomes after unilateral globus pallidus (GPi) deep brain stimulation (DBS) have supported the neurobehavioral safety of this technique (113,157), although a few studies have demonstrated minor postoperative declines in verbal fluency (158-160). The majority of studies indicate that even...

Depression Epidemiology

Depressive symptomatology may occur at any stage of PD and is a major factor related to poor quality of life for both patients and caregivers, with caregiver distress highly correlated with the patient's severity of depression (8,12,63,64). Depressive disorders are common in PD. In a community-based study, the prevalence of depressive symptomatology in PD patients was six times that of healthy age- and sex-matched controls (2). In a registry-based study of 211,245 patients, Nilsson et al. (65)...

Detection and Recognition

No standardized tool or method has been specifically developed to detect and assess anxiety in the PD population. Detection may be problematic, because several symptoms of anxiety overlap with mental and somatic symptoms commonly associated with PD. The Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for GAD in the general population includes a period of at least six months with prominent tension, worry, and feelings of apprehension about everyday events...

Disordered vs Compensated Rate of Speech in Parkinsons Disease

Disordered rate of speech has been reported in some individuals with PD, and rapid rate or short rushes of speech have been reported in 6 to 13 of individuals with PD. Palilalia or stuttering-like speech disfluencies have been observed in a small percent of individuals with parkinsonism (30,31). The discrepant findings of speech rate in parkinsonian speech (slow vs. rapid) may be related to the presence or absence of compensatory mechanisms. Caliguiri (55) found, using kinematic analyses, that...

Drugs For Dyskinesia Sarizotan

Sarizotan (Merck KgaA) is a novel compound belonging to the aminomethyl chro-mane chemical group, which was initially developed as an atypical antipsychotic, but is now being evaluated to treat dopaminergic-induced dyskinesia in PD. The drug has affinity for 5-HT1A, D2, D3, and D4 receptors. After oral ingestion, it is rapidly absorbed and highly protein bound, but readily crosses the blood-brain barrier. The terminal serum T1 2 is approximately seven hours, and the drug is extensively...

Effect Of Medical Treatments For Parkinsons Disease On Speech And Swallowing

Although neuropharmacologic and neurosurgical approaches have had positive effects on the primary symptoms of PD, their effects on voice, speech, and swallowing have been inconsistent. Several studies have assessed the effects of levodopa and dopamine agonists on voice and speech functions in PD. Gallena et al. (47) studied the effects of levodopa on laryngeal function in six persons with early PD who were not receiving medication. They found that levodopa reduced excessive laryngeal muscle...

Effect Of Surgical Treatments For Parkinsons Disease On Speech And Swallowing Deep Brain Stimulation

Many studies of deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus internus (GPi), and ventral intermediate (Vim) nucleus of the thalamus have reported dysarthria and dysphagia as side effects (88-90). Several studies examined specific aspects of voice, speech, swallowing and related orofacial, and respira-tory-laryngeal functions associated with DBS treatment of PD. Santens et al. (91) found that left-brain stimulation had a profound negative effect on prosody,...

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is an effective treatment for primary psychiatric disorders, especially treatment-resistant depression. Experience with ECT for PD psychosis, however, is limited to case studies. ECT has been demonstrated to be beneficial in PD patients with psychosis (112-114), and can transiently improve parkinsonian motor symptoms, but may require a period of hospitalization, and result in significant confusion. ECT should only be considered when patients are resistant to...

Excessive Daytime Sleepiness

In PD, severe EDS needs treatment, and first concurrent medications that may be sedating should be eliminated or reduced (Table 5). Modafinil (100-400 mg day), a nonaddictive sleep-wake cycle activator, is nonstimulating and the only drug that has shown efficacy in improving EDS in double-blind, placebo-controlled trials (87,88). A seven-week, double-blind, placebo-crossover study of modafinil (200 mg) followed by a four-week open-label extension (200 and 400 mg) study by Adler et al. (88)...

Frequency Of Autonomic Dysfunction In Parkinsons Disease

Although the focus of routine follow-up visits between PD patients and neurologists is typically on motor symptoms of the disease, autonomic problems are frequently present and can be identified if patients are specifically asked. In one study of 48 men with PD, 89 had at least one autonomic symptom compared with 43 of elderly control subjects (2). Autonomic symptoms seen in these men with PD included erectile dysfunction (60 ), urinary urgency (46 ), constipation (44 ), dysphagia (23 ), and...

Guam Parkinsondementia Complex

A characteristic parkinsonism with dementia Parkinson dementia complex (PDC) with a number of features that overlap with PSP (50) has been reported in the native Chamorro population of Guam since the 1950s (51). The frequency of PDC is declining in recent years for unknown reasons, and the etiology is unknown. The gross findings in PDC are notable for cortical atrophy affecting frontal and temporal lobes, as well as atrophy of the hippocampus and the tegmentum of the rostral brainstem (52)....

Incidence Prevalence and Risk Factors

Estimates of incidence and prevalence of dementia in PD vary widely because of different definitions, methods of ascertainment, and study designs. Prevalence rates of dementia in hospital- or clinic-based cohort studies range from 11 to 22 (123-125), whereas population-based estimates are somewhat higher, ranging from 18 to 44 (9,126-129), perhaps reflecting referral bias. A recent systematic review of the literature estimated that the prevalence of dementia in PD ranges from 25 to 31 (130)....

Intensive Voice Treatment for Parkinsons Disease

It is hypothesized that there are three features underlying the voice disorder in individuals with PD (i) an overall amplitude scale down (75,76) to the speech mechanism (reduced amplitude of neural drive to the muscles of the speech mechanism), which results in hypophonia, hypoprosodia, and hypokinetic articulation (ii) problems in the perception of vocal loudness and effort (77), which prevent the individuals with PD from accurately monitoring and scaling their vocal output and (iii)...

Is There an Association Between Levodopa Therapy and Melanoma

The connection between levodopa therapy, PD, and malignant melanoma has been a matter of debate for three decades. It originally derived from the biochemistry of the drug. Levodopa is a substrate for the development of dopamine, which, in turn, develops into neuromelanin in CNS nigral neurons. It is the dopaquinones derived from levodopa that are oxidized to form neuromelanin in these cells (126). Hence, it has been proposed that levodopa may also affect the activity of melanocytes in the skin,...

Kelly E Lyons and Rajesh Pahwa

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A. Stereotactic surgeries for movement disorders were introduced in the late 1940s (1-3) but were not widely accepted due to significant morbidity, mortality, and limited knowledge of the appropriate target for symptomatic benefit. With advances in pharmacological therapy, particularly the availability of levodopa, these surgeries were rarely performed for Parkinson's disease (PD) until the late 1980s (4)....

Levodopa and Dopamine Agonists

Findings concerning the impact of levodopa on cognitive functions are inconsistent, with studies showing improvement, decrements, and an absence of significant cognitive changes associated with levodopa therapy or its withdrawal (124). Despite these inconsistent findings, evidence is accumulating that levodopa has short-term effects on certain aspects of memory and executive functions, perhaps as mediated by disease stage. Kulisevsky et al. (125) reported that short-term improvements in...

Levodopa Methyl Ester

Levodopa methyl-ester carbidopa effervescent tablets (CNP-1512) are currently approved for rescue therapy in PD in Italy (Chiesi Farmaceutici). Outside of Italy, the drug (V1512) is owned by Vernalis Pharmaceuticals. This preparation is approximately 250 times more soluble in water and can thus be easily dissolved and orally administered. Studies comparing the drug with standard levodopa preparations demonstrate a faster onset of action (by a mean of 8.5 minutes) and a longer total duration of...

Long Term Outcome of Treatment for Psychosis

Goetz and Stebbins (5) described 11 PD patients in a nursing home with hallucinations, all of whom were never discharged from the nursing home and died within two years. In an open-label extension of the U.S. double-blind clozapine trial, only 25 of completers died over a 26-month observational period. Forty-two percent were in nursing homes, 68 were demented, and 69 were still psychotic (4). A separate study of 39 parkinsonian patients, treated with clozapine for psychosis, found that only 15...

Mechanisms

The underlying mechanism for depression in PD remains poorly understood, but the phenotypic expression of depressive disorders has been attributed to a combination of medical, neurochemical, and psychosocial phenomena. Depression may be a reactive response or demoralization phenomenon associated with the diagnosis of PD and its relative disability. However, when compared with patients with other chronic disabling conditions matched for functional disability, patients with PD exhibit greater...

Methyl4Phenyl1236Tetrahydropyridine

The inadvertent self-administration of MPTP by heroin addicts in the 1980s induced an acute form of parkinsonism whose clinical and biochemical features were indistinguishable from idiopathic PD (35,36). Like PD, this MPTP cohort demonstrated an excellent response to levodopa and dopamine agonist treatment but developed motor complications within weeks. The rapidity with which these motor complications appeared presumably reflected the severity of substantia nigra neuronal degeneration induced...

Midbrain Dopamine Neurons That Express Calcium Binding Proteins

Calcium binding proteins (CaBPs) are intracellular Ca2+ sensors that bind to Ca2+ and form a Ca2++CabP complex, which facilitate the activation of several enzymes and proteins and play a significant role in neurotransmission and the regulation of transcription factors (26). Among the numerous CaBPs, within the dopaminergic neurons of the midbrain, Calbindin D28K (CB), Calretinin (CR), and Parvalbumin (PV) are the most abundant (27). A significant number of CB-immunoreactive neurons have been...

Mortality of Parkinsons Disease with Levodopa

Several studies performed in the 1970s demonstrated that levodopa therapy improved mortality in PD. These studies compared the survival of levodopa-treated patients to the mortality rate demonstrated in the pre-levodopa Hoehn and Yahr study (122), which demonstrated that mortality was three times greater than the normal population. Nearly all studies indicated that levodopa improved survival with rates of 1.4 to 2.4 (119,120,123,124). Some investigators suggested that survival approached...

Multiple System Atrophy

MSA refers to a neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, and orthostatic hypotension (31). There is no known genetic risk factor or genetic locus in MSA. The MSA brain shows varying degrees of atrophy of the cerebellum, cerebellar peduncles, pons and medulla, as well as atrophy and discoloration of the posterolateral putamen and pigment loss in the substantia nigra. The histopathological findings include neuronal loss, gliosis, and microvacuolation, involving...

Neuronal Mechanisms Of Subthalamic Nucleus Deep Brain Stimulation

One of the first hypotheses regarding the neuronal mechanism of action of DBS is that DBS inhibits activities within the stimulated target. A number of studies demonstrated that activity in structures receiving input from the DBS target was consistent with increased, not decreased, output from the stimulated structure. An example of GPi activity before, during, and after STN DBS in a nonhuman primate is shown in Figure 4. Note in this example, there is a significant reduction of neuronal...

Neuropsychological Aspects Of Parkinsonplus Syndromes And Essential Tremor

Parkinson-plus syndromes traditionally include PSP, MSA, and corticobasal degeneration (CBD). Although sparse, preliminary neuropsychological studies indicate that the cognitive impairment profiles likely differ across the parkinson-plus syndromes (172). A summary of key differences is presented in Table 4. TABLE 4 Comparison of Neurobehavioral Features of Parkinson's Disease with Dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Multiple System...

Neuropsychological Dysfunction in Parkinsons Disease with Dementia

The annual incidence of clinically diagnosed dementia in PD (PDD) is about 3 for individuals younger than 60 years and 15 or less for those 80 years and older (66,67). Estimates of dementia prevalence in patients with PD vary between 9 and 93 , depending on which diagnostic criteria, ascertainment methods, and sampling methods are implemented (24). The methodologically soundest studies yield prevalence estimates of about 25 (68). Dementia is very rarely present early in the disease course...

Neuropsychological Dysfunction in Parkinsons Disease Without Dementia

In reviewing the PD literature, Lieberman (29) reported that 17 to 53 of treated and untreated PD patients without dementia demonstrate cognitive dysfunction. Unfortunately, few of the studies reported formal criteria for determining what did or did not constitute dementia, thus making it difficult to determine whether patients were in the early stages of dementia. As noted earlier, more recent studies suggest that formal neuropsychological testing may uncover mild cognitive deficits in 25 to...

Neuropsychological Findings In Parkinsons Disease

Parkinson (20) contended that patients with shaking palsy did not exhibit significant intellectual changes however, by the late 1800s, investigators had begun to recognize the presence of cognitive deficits in patients with PD (21). Mild neuropsychological changes are widely accepted to occur in early PD. Increasingly, it is recognized that cognitive alterations, especially in executive functions and or memory, may already be present at the time of disease diagnosis. Recent studies estimate...

Neuropsychology Behavioral Neurology And Neuropsychiatry

Sir William Osler first used the term neuropsychology in 1913 however, neuropsychology, at least as a clinical endeavor, did not emerge as a subdiscipline of psychology until the 1940s, largely in response to demands for the assessment and rehabilitation of brain-injured soldiers in World War II (1). The likely first published use of a clinical neuropsychological test with persons having parkinsonian syndrome is Shaskin et al.'s (2) administration of the Wechsler Bellevue Scale, an intelligence...

Neurotoxicantinduced Models Of Parkinsons Disease 6Hydroxydopamine

6-OHDA or 2,4,5-trihydroxyphenylethylamine is a specific catecholaminergic neu-rotoxin structurally analogous to both dopamine and noradrenalin. Acting as a false-substrate, 6-OHDA is rapidly accumulated in catecholaminergic neurons. The mechanism of 6-OHDA toxicity is complex and involves alkylation rapid auto-oxidization leading to the generation of hydrogen peroxide, superoxide, and hydroxyl radicals and impairment of mitochondrial energy production (5,6). The 6-OHDA-induced rat model of PD...

Other Pharmacologic Agents

Few other pharmacologic strategies for specifically treating dementia in PD have even been reported. Because noradrenergic depletion could contribute to executive dysfunction in PD, Bedard et al. (170) conducted a trial of naphtoxazine (SDZ-NVI-085), a selective noradrenergic alpha 1 agonist, versus placebo in nondemented patients with PD. The results of the study demonstrated improved performance on tasks of set-shifting and cognitive flexibility, such as the Stroop and Odd-Man-Out tests....

Other Trials in Early Parkinsons Disease

Palhagen et al. (72) reported a study of selegiline in 157 de novo PD subjects. Selegiline 10 mg day delayed the need for levodopa by four months compared with placebo (P 0.028). There was a wash-in effect at six weeks and three months, with total and motor UPDRS scores significantly better in the selegiline group. At six months, the rate of disease progression was significantly slower for both total UPDRS (-1.9 vs. 3.5 P < 0.001) and motor UPDRS (-1.5 vs. 2.5 P < 0.001) (negative numbers...

Parkinsons Disease Dementia

Pathological findings considered to account for dementia in PD include severe pathology in monoaminergic and cholinergic nuclei that project to the cortex producing a subcortical dementia (39 ), coexistent Alzheimer's disease (AD) (29 ), and diffuse cortical Lewy bodies (26 ) (22). The basal forebrain cholinergic system is the subcortical region most often implicated in dementia, and neurons in this region are damaged in both AD and Lewy body dementia. Neuronal loss in the basal nucleus is...

Parkinsons Disease Diagnosis Accuracy

The diagnosis of PD is currently based primarily on clinical judgment. However, the variability of disease presentation, progression, and response to medications often makes the diagnosis uncertain. In a population-based study, at least 15 of patients with a diagnosis of PD did not meet strict diagnostic criteria, and approximately 20 of patients with PD who had medical attention had not been diagnosed with PD (48). Prevalence studies of parkinsonism suggest a diagnostic accuracy of 80 after...

Parkinsons Disease Progression

The rate of clinical progression of PD is highly variable and unpredictable (77). In clinical studies, several clinical endpoints for progressive functional decline in PD have been used, including the Unified Parkinson's Disease Rating Scale (UPDRS) in the defined off state or after drug washout up to two weeks, time to need for dopaminergic therapy, or time to development of motor fluctuations (85-89). Clinical rating scales are extremely useful, but ratings may be investigator-dependent and...

Pathophysiology of Dementia

There is controversy regarding which features are the primary contributors to dementia in PD. PD is characterized by cell loss in the substantia nigra pars compacta (SNc), resulting in loss of dopaminergic input into the striatum. Several pathological and functional imaging studies have shown that in PD, there is greater depletion in the lateral compartment of the SNc, which projects to the putamen, than in the medial compartment, which projects to the caudate (139-141). Cognitive impairment is...

Physiologic Measures of Laryngeal Dysfunction in Parkinsons Disease

Disordered laryngeal function has been documented in a number of videoendo-scopic and videostroboscopic studies. Hansen et al. (22) reported vocal fold bowing resulting in poor glottic closure in 94 of 32 PD patients, together with greater amplitude of vibration and laryngeal asymmetry. Smith et al. (41), using videostro-boscopic observations, found that 57 of 21 PD patients had a form of glottal incompetence (bowing, anterior or posterior chink) on fiberoptic examination. Perez et al. (42)...

Perceptual and Phonetic Characteristics of Voice and Speech Disorders in Parkinsons Disease

Darley et al. (3) reported one of the first systematic descriptions of perceptual characteristics of speech and voice in individuals with PD (3,31,32). They identified reduced loudness, monopitch, monoloudness, reduced stress, breathy, hoarse voice quality, imprecise articulation, and short rushes of speech as the most characteristic of the speech and voice disorders in PD. They termed these symptoms hypoki-netic dysarthria. Logemann et al. (2) used phonetic and perceptual analyses to...

Pharmacologicalinduced Models Of Parkinsons Disease

Pharmacological manipulation of the dopaminergic system can take on two basic forms either targeting dopamine biosynthesis or destruction of nigrostriatal dopaminergic neurons. Both reserpine and alpha-methyl-para-tyrosine (AMPT) interfere with dopamine production and result in a temporary dopamine depletion lasting hours to days, whereas neurotoxicants such as 6-hydroxydopamine (6-OHDA) and (MPTP) result in midbrain dopaminergic cell death. Methamphetamine (METH) is a class of compound that...

Postencephalitic Parkinsonism

Parkinsonism following encephalitis lethargica during the influenza pandemic between 1916 and 1926 is known as postencephalitic parkinsonism (PEP). During the recovery phase of the acute viral encephalitis, parkinsonian rigidity developed with the most characteristic clinical features being oculogyric crises. The PEP brain has NFTs in the cortex, basal ganglia, thalamus, hypothalamus, substantia nigra, brainstem tegmentum, and cerebellar dentate nucleus (48). The distribution of the pathology...

Preclinical Parkinsons Disease

Estimates based on postmortem studies suggest that for every patient who presents with PD, there may be up to 15 cases of preclinical PD (development of Lewy body pathology without clinical signs of PD) (111). Neuroreceptor imaging studies provide a window into this preclinical period of PD, the time during which neurodegeneration has begun, but symptoms have not yet become manifest. Preclinical identification of affected subjects is particularly important if intervention exists, which may...

Progressive Supranuclear Palsy

Prevalence rates of dementia in PSP range from 50 to 80 , but some authors contend that these numbers reflect over-diagnosis due to bradyphrenia, emotional problems, and visual dysfunction that accompany PSP. Cognitive deficits are seen in approximately 50 of patients with PSP (172), with the neuropsychological profile being typical of diseases with subcortical involvement, including slowed information processing, executive dysfunction, and information retrieval deficits (173). As compared to...

Rapid Eye Movement Behavior Disorder and Restless Legs Syndrome

The treatment of choice for RBD is clonazepam, a benzodiazepine, although the mechanism is unknown and there are no controlled trials (13). Other drugs thought to be helpful for RBD include pramipexole, levodopa, carbamazepine, donepezil, and melatonin (64,89-91). Caution needs to be exercised with the use of clonazepam, as in some cases, RBD may be confused with sleep apnea, which can be worsened by clonazepam. Nighttime dosing with drugs such as selegiline may aggravate RBD. Others have...

Risk Factors for Dementia in Parkinsons Disease

Various demographic and disease variables predict PDD (Table 3). More recent work suggests that neuropsychological evaluation may also facilitate early identification of PDD. Jacobs et al. (91) and Mahieux et al. (92) noted that poorer performance by TABLE 3 Risk Factors for Dementia in Parkinson's Disease Diminished cognitive test performance Executive Attention Verbal fluency Visuoperceptual List learning Lower socioeconomic status Family history of Parkinson's dementia Disease severity...

Selegiline and Rasagiline

Selegiline and rasagiline, selective monoamine oxidase-B (MAO-B) inhibitors, have been hypothesized to exert a neuroprotective effect in PD by way of reducing physiologic stress associated with MAO-B oxidation of dopamine. Along with improvement in motor functions, several small, uncontrolled studies have found selegiline to be associated with improved global cognitive functioning, P300 latencies, and or memory in patients with PD (137-140). In contrast, selegiline was reported not to...

Sexual Dysfunction

Though PD patients rarely complain of sexual difficulties, if specifically asked, dysfunction in this area is very common. Bronner et al. (65) performed a comprehensive assessment of sexuality in 75 patients (32 women, 43 men) with PD who did not complain of problems in this area. Using specific sexual function scales, they asked patients to rate their sexuality currently and retrospectively before the onset of their PD. They found that in men, 68 had erectile dysfunction, 65 were dissatisfied...

Specific Occupations And Parkinsonism

Numerous epidemiologic studies have attempted to detect occupations at high risk for developing PD. Fall et al. (65) performed an occupation case-control study and found an increased risk of PD in carpenters (OR 3.9), cabinet-makers (OR 11), and cleaners (OR 6.7), compared to a population-based control group. Tanner et al. (66) performed a case-control study (nonpopulation-based) of occupational exposures and PD in People's Republic of China and found that occupations involving industrial...

Side Effects

Amantadine is generally well tolerated. The most common idiosyncratic side effects include livedo reticularis and pedal edema. Livedo reticularis is a mottled bluish-red reticular skin discoloration, which blanches to pressure. It is observed in more than 5 of patients receiving amantadine. It is more common in women (30) and is usually predominant in the lower extremities. The appearance is nonspecific, and skin biopsies of the area are normal (31). Livedo reticularis usually appears after...

Spontaneous Rodent Models for Parkinsons Disease

There are several naturally occurring spontaneous mutations in rodents that are of particular interest in PD. Spontaneous rodent models include the weaver, lurcher, reeler, Tshrhyt, tottering, and coloboma mice and the AS AGU and circling (ci) rat. These models possess unique characteristics that may provide insight into neurodegener-ative processes of PD and related disorders. Several of these spontaneous rodent models display altered dopaminergic function or neurodegeneration, and have...

Swallowing Treatment for Parkinsons Disease

Treatment of swallowing disorders in PD has not been well studied. Conventional techniques have included oral motor exercises to improve muscle strength, range of motion and coordination, and behavioral modifications such as effortful breath-hold, chin positioning, double swallow, the Mendelsohn maneuver, swallow cough, effortful swallow, and diet and liquid modifications (13,127). Effectiveness of these techniques varies and can be dependent on patient motivation and cooperation, family...

Transcription Factor Pitx3

Yet another clue to the factor(s) that render the dopamine neurons of the SNpc vulnerable to neurodegeneration in PD is obtained from the studies on the role of the transcription factor Pitx3 in aphakic mice. Aphakic mice have small eyes with no lens and a loss of development of the anterior chamber of the eye (57,58). The clinical features of the aphakic mice result from a deletion of a large segment of the promotor region, exon 1, and intron regions of the Pitx3 gene (58). In addition to the...

Treatment

There is a poor evidence base for the treatment of sleep problems in PD, and the issue is complicated by the fact that treatment of sleep problems in PD needs to take into account the multifactorial nature of sleep disturbances in PD. A review by the Movement Disorder Society Task Force reported that there were no robust trials of dopaminergic agents for the treatment of nonmotor symptoms in PD, including sleep (80). Only modafinil (for EDS) and melatonin (for insomnia) have been studied in...

Urinary Bladder Dysfunction

The most frequent urinary complaints in PD patients are frequency, urgency, urge incontinence, and nocturia. Hobson et al. (58) performed a community-based questionnaire survey in Wales, U.K., and found that bladder problems were reported in 51 of 123 PD patients returning the survey compared to 31 of 92 controls. The calculated relative risk of developing bladder symptoms in PD patients compared to controls was 2.4. Lemack et al. (59) performed a similar questionnaire-based assessment of...

Vesicular Monoamine Transporter And Dopamine Transporters In The Substantia Nigra Pars Compacta

Vesicular transporters transport neurotransmitters into vesicles of nerve terminals and neuroendocrine cells and make them available for regulated release. VMAT1 is localized predominantly in the neuroendocrine cells, whereas VMAT2 is widely distributed in monoaminergic terminals and dendrites. In the dopaminergic nerve terminal, VMAT2 transports cytoplasmic dopamine and 1-methyl-4-phenylpyridium (MPP+) into the vesicles (16). Dopamine that is not incorporated into the vesicles gets oxidized...

Visuospatial Perception

Visuoperceptual impairments are thought to occur in early PD, even when motoric task demands are minimized (62,63) however, some argue that visuoperceptual impairments are secondary to deficits in set-shifting, spatial memory, bradyphrenia, and dexterity (34,64). Visuospatial impairments do not appear to improve with dopamine replacement and do not reliably vary with motor on and off periods. Thus, if dopamine impacts visuoperceptual abnormalities in PD, it is probably in conjunction with other...

Welding

Some materials safety data sheets (MSDS) for welding consumables list parkinsonism as a potential hazard of welding, although the data upon which this claim is based is unclear. There are several clinical reports (80,83-85) of parkinsonism in welders, although many patients had atypical features, including cognitive abnormalities, disturbances of sleep, peripheral nerve complaints, and mild motor slowing. In a study of magnetic field exposed workers, Noonan et al. (70) found that welders were...

Pramipexole

Pramipexole was approved in the United States in 1997 and is a synthetic, nonergot dopamine agonist. Like the ergot-derived dopamine agonists, this agent is active at the D2, D3, and D4 receptors. Pramipexole also has affinity for a- and P-adrenoreceptors, acetylcholine receptors, and 5-HT receptors (Table 1). The drug is available in 0.125, 0.25, 0.5, 1.0, and 1.5 mg tablets, and the usual dosage is 3.0 mg d in three divided doses titrated over five weeks (Table 3) (15). This drug reaches peak...

Levodopa And Homocysteine

An evolving concern with levodopa therapy relates to its association with elevated homocysteine (HC) levels. Since the late 1990s, several studies have indicated that levodopa dose correlates with elevation of HC. Postuma and Lang (131) reviewed this literature, and the relevance of the increase of HC to PD and patient health remains unclear. The concern relates to data suggesting that elevated HC levels increase the risk of stroke, coronary artery disease, and dementia (132-134). HC is...

Hardware Related Complications

Several reports have also focused on hardware complications related to DBS. Beric et al. (46) examined complications for 86 DBS patients and found electrode failure in 3.5 (n 3), extension wire failure in 4.7 (n 4), IPG malfunction in 1.2 (n 1), and pain at the IPG in 1.2 (n 1). Kondziolka et al. (49) examined hardware complications in 66 patients undergoing unilateral thalamic DBS for either essential tremor, parkinsonian tremor, multiple sclerosis, or other forms of tremor. There were a total...

Clinical Uses

Amantadine is generally considered as a mild antiparkinsonian agent, with effects on tremor, rigidity, and bradykinesia, and a well-tolerated side-effect profile. It is used in early PD when considering levodopa sparing strategies or when symptoms are mild enough not to warrant more aggressive therapy. Amantadine has been studied in early PD as monotherapy, and in combination with anticholinergics in limited series and small controlled studies, with relatively short follow-up (18-20). However,...

Piribedil

Piribedil is a nonergoline selective D2 D3 agonist with alpha-1 antagonist activity. Oral doses of this medication range between 80 and 250 mg d. Once blood levels are stabilized with a piribedil dose of at least 150 mg d, it has a mean half-life of approximately 21 hours. Simon et al. (54) assessed the efficacy of a single intravenous infusion of piribedil in 10 subjects with PD who received escalating doses of piribedil (2, 4, 8, and 16 mg) or placebo. These subjects continued their PD...

Conclusion

Sleep disorders in patients with PD are common (94). They are a key component of the nonmotor symptom complex of PD and remain under-diagnosed and under-treated. Sleep problems may arise from uncontrolled motor symptoms, degeneration of the neuroanatomical substrates responsible for the sleep-wake cycle or unwanted medication side effects. Routine assessment of patients with PD should include inquiry regarding the quality of sleep and sleep-related symptoms. Use of validated bedside clinical...

Geographic Differences In Rates Of Parkinsons Disease

Population-based prevalence and incidence studies can provide an indirect indication of potential environmental etiologies of PD, although it is impossible to compare between studies of different populations, given that genetic differences could account for the differing prevalence. Within a population, however, these studies can provide critical clues to environmental risk factors. A higher prevalence of PD in rural environments implicates regional farming practices, including pesticides,...

The Role Of Neuropsychology In The Management Of Parkinsons Disease

Neuropsychology provides an important contribution to the management of patients with PD. Neuropsychological evaluation delineates the nature and extent of cognitive changes, if any, and a profile of relative neuropsychological strengths and weaknesses. Such knowledge is helpful in the determination of the most probable etiology of mild- and new-onset cognitive changes development and formulation of strategies or treatments to ameliorate the impact of cognitive deficits on functioning guidance...

Entacapone

Entacapone is readily absorbed across the intestinal mucosa and does not seem to be significantly affected by first-pass metabolism in the liver. The bioavailability of an oral dose of entacapone ranges from 30 to 46 (18,37-40). It is highly (98 ) protein bound and metabolized via glucuronidation. Most reports place the elimination half-life of entacapone between 0.4 and 0.7 hours (18,37-39). Entacapone does not cross the blood-brain barrier to any significant extent and appears to exert its...

Measuring Sleep Disorders

Until 2002, there were no specific instruments to clinically assess sleep problems of PD in a comprehensive and holistic fashion. Existing sleep scales for other disorders, such as the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale, or the Karolinska Sleepiness Scale, are not specific for PD and have problems related to scale clinimetrics in relation to complexity and face validity when these are used in PD (66, 71-73). For instance, the PSQI, although quantifiable, does not...

References

Proton MRS GABA and glutamate. Adv Neurol 2000 83 261-271. 2. Fazekas F, Barkhof F, Filippi M, et al. The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 1999 53 448-456. 3. Baird A, Warach S. Imaging developing brain infarction. Curr Opin Neurol 1999 12 65-71. 4. Phelps M. Positron emission tomography (PET). In Mazziota J, Gilman S, eds. Clinical Brain Imaging Principles and Applications. F.A. Davis Philadelphia,...

Clinical Trials Of Levodopa

The initial therapeutic studies of levodopa in PD were carried out in the 1960s and early 1970s. The subjects were of varying disease durations, some quite advanced with dementia, and standard measures such as the Unified Parkinson's Disease Rating Scale (UPDRS) were not yet devised however, the results were dramatic (3). In 1967, Cotzias et al. (11) demonstrated the definitive effectiveness of high-dose L-Dopa (as opposed to D, L-Dopa). These investigators examined 28 patients in an open-label...

Benzodiazepines

Although benzodiazepines are commonly used in the management of anxiety, only one randomized controlled trial addressed this in the PD population (40). Bromazepam, a long-acting benzodiazepine, was reported to improve psychic and somatic (i.e., tremor) symptoms of anxiety. Anecdotally, other benzodiazepines have also been noted to be effective. Clonazepam was reported to be effective in a patient with anxiety and panic attacks that were refractory to alprazolam, lorazepam, and numerous...

Pathophysiology of Psychosis and Risk Factors

The pathophysiology of psychosis in PD is poorly understood, but dopaminergic and serotonergic mechanisms have been proposed. One theory is that chronic excessive stimulation of dopamine receptors, particularly in the mesolimbic mesocorti-cal pathways, causes hypersensitization, resulting in psychosis when patients are treated with dopaminergic agents (36). However, exogenous dopamine supplementation by itself is not the only factor in the development of psychosis since all PD medications...

Levodopa Preparations

Levodopa is available with carbidopa as immediate release carbidopa levodopa 10 100, 25 100, and 25 250. It is also available in a sustained-release form as car-bidopa levodopa 25 100 and 50 200. An orally dissolvable form of immediate release carbidopa levodopa (Parcopa ) is available as 10 100, 25 100, and 25 250. Finally, levodopa is available with the COMT inhibitor, entacapone, in the following combinations Stalevo 50 (carbidopa 12.5mg levodopa 50mg entacapone 200 mg), Stalevo 100...

Massage Therapy

Massage therapy involves the use of a therapist's hands and sometimes elbows and knees or in some cases hand-held wooden thumbs or rocks along with special ointments and aromas that are directly applied to the body's muscles and soft tissues (5). Its origins date back to over 4000 years as a form of TCM therapy to promote health and prevent disease. It is also a primary treatment in the Ayurvedic system. Similar to acupuncture theory, the direct manipulation of the body tissues is thought to...

Parkinsons Disease Differential Diagnosis And Severity

The initial questions of an imaging ligand are whether it reliably distinguishes between subjects with and without a known pathology (a marker for disease trait) and whether the changes in the imaging outcomes correlate with disease severity (a marker for disease state). In several studies, dopamine and vesicular transporter ligands and 18F-DOPA discriminated between individuals with PD and healthy subjects, with a sensitivity greater than 95 (11,13,20,72-74). These studies take advantage of...

Pharmacokinetics and Dosing

Amantadine is an aliphatic primary amine formulated as a hydrochloride salt for clinical use, as an oral preparation. It is a relatively inexpensive drug available as a 100-mg tablet or capsule and a 50-mg mL liquid. Other than some anticholinergics and apomorphine, it is also one of the few PD medications available in a parenteral formulation (amantadine-sulfate). This intravenous preparation, however, is not available for use in the United States (8). The bioavailability of amantadine is 86...

Conclusions

DBS is an effective and relatively safe treatment for levodopa-responsive PD patients with medication resistant motor fluctuations and dyskinesia. DBS of the thalamus clearly reduces parkinsonian tremor however, bradykinesia, rigidity, and dyskinesia are not significantly affected. Therefore, VIM DBS is reserved for disabling tremor predominant PD. DBS of the GPi and STN both significantly improve all of the cardinal symptoms of PD as well as dyskinesia. DBS of the STN often results in a...

Introduction

Nearly 90 of individuals with Parkinson's disease (PD) develop voice and speech disorders during the course of their disease (1,2). These disorders are characterized by reduced voice volume (hypophonia) a breathy, hoarse, or harsh voice quality (dysphonia) imprecise consonant and vowel articulation due to reduced range of articulatory movements (hypokinetic articulation) and a tendency of these movements to decay and or accelerate toward the end of a sentence reduced voice pitch inflections...

Clinical Trials Of Selegiline Datatop

The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study (70) evaluated 800 PD subjects randomized to receive selegiline 10mg day or placebo. The total Unified Parkinson's Disease Rating Scale (UPDRS) scores were improved in the selegiline-treated group compared with placebo at one month (2.1 vs. 0.1 P < 0.001) and at three months (1.6 vs. -1.3 P < 0.001). The motor UPDRS scores also improved significantly in the selegiline compared with the placebo group at one...

Tremor

Tremor, although less specific than bradykinesia, is one of the most recognizable symptoms of PD. However, only half of all patients present with tremor as the initial manifestation of PD, and 15 never have tremor (45). Although tremor at rest (4-6 Hz) is the typical parkinsonian tremor, most patients also have tremor during activity, and this postural tremor (5-8 Hz) may be more disabling than the resting tremor. Postural tremor without parkinsonian features and without any other known...

Detection and Assessment

There are no reliable and empirically derived criteria for recognition of depression in PD. Therefore, it is not surprising that depression remains under-detected and under-treated in the PD population (15,71). In a clinic-based study, nearly two-thirds of patients with clinically significant depressive symptomatology were not receiving antidepressant therapy (11). Older individuals often underreport depressive symptoms and are likely to focus on somatic or vegetative complaints (e.g., fatigue...

Does Tolerance Develop to Levodopa

The lay literature is replete with information suggesting that levodopa loses its effect after about five years. This leads to some trepidation on the part of the patient and physician in initiating therapy. If that were the case, it would indicate that tolerance is a possible concern and would argue for delaying treatment. It is conceivable that, when all nigrostriatal cells are depleted, levodopa would lose all effectiveness since these are the cells that convert levodopa and release...

Parkinsons Disease

The clinical features of Parkinson's disease (PD) include bradykinesia, rigidity, tremor, postural instability, autonomic dysfunction, and bradyphrenia. The most frequent pathologic substrate for PD is Lewy body disease (2). Some cases of otherwise clinically typical PD have other disorders, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) or vascular disease, but these are uncommon, especially when the clinical diagnosis is made after several years of clinical...

Initiation Of Dopamine Agonist Therapy

Dopamine agonists provide substantial improvement in PD symptoms while delaying the development of motor fluctuations and dyskinesia (32,42,58). Similar trials comparing dopamine agonists (pergolide, pramipexole, ropinirole) to levodopa in a randomized fashion suggest possible long-term benefit according to the functional imaging measures (2,3). The reduction in striatal and nigral decline in F-dopa and -CIT uptake suggest these agents have some benefit over levodopa for up to 46 months of...

Selective Serotonin Reuptake Inhibitors

Results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD (42-44). In an open-label study (n 10), Menza et al. (42) reported that citalopram (mean dose 19mg d) improved anxiety in depressed PD patients. In a study of 30 patients, paroxetine (20 mg twice daily) reduced psychic and somatic anxiety symptoms, as well as depressive symptoms after six weeks (43). Sertraline was also found to have anxiolytic effects in PD patients (44). Although these data are derived from...