Search

Background: Minor phenomena, including passage phenomena, feeling of presence, and illusions, are common and may represent a prodromal form of psychosis in Parkinson's disease (PD). We examined the prevalence and clinical correlates of minor phenomena, and their potential role as a risk factor for PD psychosis. Methods: A novel questionnaire, the Psychosis and Mild Perceptual Disturbances Questionnaire for PD (PMPDQ), was completed by Fox Insight cohort participants with and without PD. Additional assessments included the Non-Motor Symptoms Questionnaire (NMSQuest), REM Sleep Behavior Disorder Single Question Screen (RBD1Q), Movement Disorder Society-Unified Parkinson Disease Rating Scale Part II, demographic features, and medication usage. For participants with PD, we used regression models to identify clinical associations and predictors of incident psychosis over one year of follow-up. Results: Among participants with PD (n = 5950) and without PD (n = 1879), the prevalence of minor phenomena was 43.1% and 31.7% (P <.001). Of the 3760 participants with PD and no baseline psychosis, independent correlates of minor phenomena included positive responses on the NMSQuest apathy/attention/memory (OR 1.7, 95% CI 1.3-2.1, P <.001) or sexual function domain (OR 1.3, 95% CI 1.1-1.6, P =.01) and positive RBD1Q (OR 1.3, 95% CI 1.05-1.5, P =.01). Independent risk factors for incident PD psychosis included the presence of minor phenomena (HR 3.0, 95% CI 2.4-3.9, P <.001), positive response on the NMSQuest apathy/attention/memory domain (HR 1.8, 95% CI 1.3-2.6, P <.001), and positive RBD1Q (HR 1.5, 95% CI 1.1-1.9, P =.004). Conclusions: Minor phenomena are common, associated with specific non-motor symptoms, and an independent predictor of incident psychosis in PD. [ABSTRACT FROM AUTHOR]

Background: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea‐acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease‐specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. Objective: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea‐acanthocytosis). Methods: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. Results: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62‐ and ubiquitin‐positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. Conclusions: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off‐label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. Results: Twenty‐two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease‐modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Dopamine agonist withdrawal syndrome ( DAWS) has been reported in patients with Parkinson's disease (PD) who rapidly decrease or stop their dopamine agonist (DA) treatment. Retrospective studies suggest a high prevalence of DAWS (14%-18%) in PD, but there are no prospective studies. We report data from the first pilot European multicenter prospective study addressing the frequency of probable DAWS (Rabinak-Nirenberg criteria) in PD patients. The self-completed Nonmotor Symptoms Questionnaire (which addresses the core features of DAWS) was administered at clinical follow-up at 1 month in 51 patients (33 male; mean age: 73.0 ± 9.9 years; PD duration: 12.2 ± 6.3 years) who had discontinued dopamine agonists. Twelve out of fifty-one patients (24%) met clinical criteria for DAWS, the most common symptoms of which were anxiety (91.7%), pain (50%), sweating (41.7%), and anhedonia (16.7%), after the withdrawal of a DA (ropinirole, pramipexole, or cabergoline). In this first prospective evaluation of DAWS in the clinic, preliminary data indicate a high rate after discontinuation of a range of DAs, particularly in the context of impulse control disorders. Larger, controlled studies are required to establish a definitive management pathway. [ABSTRACT FROM AUTHOR]

Summary Parkinson’s disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation ( GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins’ fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of “footprint-free” iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ∼50% GBA enzymatic activity, ∼3-fold elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin’s neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized α-synuclein and dopamine levels, suggesting a combination therapy for the affected twin. [ABSTRACT FROM AUTHOR]

Aim: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD. Methods: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [ABSTRACT FROM AUTHOR]

Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized complication of dopamine replacement therapy in Parkinson's disease (PD). Other impulsive-compulsive behaviors have been linked to dopaminergic medications; these include punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), particularly at higher dosages; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Risk factors for ICDs may include male sex; younger age; younger age at PD onset; a pre-PD history of ICD(s); personal or family history of substance abuse; bipolar disorder; gambling problems; and impulsive personality traits. The primary treatment of ICDs in PD is discontinuation of DA therapy. Not all patients can tolerate this, however, due to worsening motor symptoms and/or DA withdrawal syndrome (a severe, stereotyped drug withdrawal syndrome similar to that of other psychostimulants). While psychiatric medications are frequently used to treat ICDs in the general population, there is no empirical evidence to suggest that they are effective in PD. Given the paucity of treatment options and potentially serious consequences of ICDs in PD, it is critical for patients to be monitored closely for their development. As empirically validated treatments for ICDs emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The cerebellar variant of multiple system atrophy (MSA-C) has overlapping clinical features with the hereditary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late-onset, rapidly progressive neurodegenerative disorder consistent with MSA-C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA-C was confirmed by identification of numerous alpha-synuclein-containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA-C. [ABSTRACT FROM AUTHOR]

SYDENHAM'S CHOREA (SC) IS A FEMALE-PREDOMINANT CHILDHOOD-onset neurological disorder characterized by chorea, hypotonia, and psychiatric/behavioral changes such as emotional lability or obsessive-compulsive disorder (OCD). The symptoms of SC are acute or subacute in onset and occur in the setting of acute rheumatic fever. Tourette's syndrome (TS), in contrast, is a chronic, familial, male-predominant childhood-onset motor and vocal tic disorder with frequent psychiatric comorbidity (including OCD, anxiety disorders, and attention deficit-hyperactivity disorder). SC is believed to be an autoimmune disorder, attributable to cross-reactivity between group A beta-hemolytic streptococcus (GABHS) and antigens expressed on basal ganglia neurons. Given the clinical similarities between SC and TS, it has been postulated that some cases of TS may have a similar underlying cause. The term PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection) has been used to describe cases in which tic disorders, OCD, or related neuropsychiatric disorders abruptly develop and/or markedly worsen after GABHS infection. Despite extensive study, however, a causal relationship between GABHS and TS/OCD has not been clearly demonstrated, and the existence of PANDAS remains controversial. The goal of the current study was to test the hypothesis that IgG autoantibodies from patients with SC -- but not those from patients with TS or PANDAS -- would cross-react with neuronal cell surface antigens. Serum samples were obtained from subjects with SC (n = 11, 9 female), PANDAS (n = 12, 2 female), TS (n = 11, 2 female), healthy controls, and children with non-inflammatory neurological diseases. Flow cytometry (fluorescence-activated cell sorting) then was used to detect and quantitate antibody binding to neuronally differentiated SH-SY5Y cells. The authors found that the mean IgG cell surface binding to SH-SY5Y cells was significantly higher in the SC group compared with all other groups (P < 0.001). In contrast, IgG cell surface binding in the PANDAS and TS groups was similar to that of controls. The findings confirm the autoimmune nature of SC, but show no evidence to support a similar underlying cause for TS or PANDAS. [ABSTRACT FROM AUTHOR]

IN 2005, A STUDY PUBLISHED IN NEUROLOGY DEMONSTRATED the usefulness of a simple bedside test, known as the "three clap test," in distinguishing progressive supranuclear palsy (PSP) from both frontotemporal dementia (FTD) and idiopathic Parkinson's disease (PD). The test consists of asking the patient "to clap three times as quickly as possible after demonstration of the examiner." When patients clap more than three times, an "applause sign" is present; this is felt to be a sign of motor perseveration and/or apraxia. The authors of this prior study found that the applause sign occurred commonly in PSP and was absent from those with PD or FTD, and therefore concluded that the test is useful for distinguishing between these disorders. A subsequent study concluded that the three clap test was not specific for PSP, but instead was a highly specific marker of Parkinsonian disorders in general. In the current study, the authors reexamined the applause sign, with the goal of determining whether the sign also may occur in neurodegenerative disorders that spare the basal ganglia, such as Alzheimer's disease (AD) or FTD without parkinsonism. The authors evaluated for the presence of the applause sign in 77 subjects--10 with PSP, 15 with sporadic behavioral variant FTD, 29 with AD, and 23 healthy controls. Neurological diagnoses were determined based on standard clinical diagnostic criteria. A secondary goal of the study was to test the hypothesis that the applause sign is a marker for motor perseveration rather than apraxia; for this reason subjects with apraxia were excluded from enrollment. In addition, all studies underwent neuropsychiatric testing to determine the characteristics that correlated with the presence of an applause sign. The authors found that the applause sign occurred in all of the neurodegenerative disorders that were examined (80% in PSP, 70% in FTD, and 31% in AD), and they were able to distinguish subjects with neurodegenerative disease from healthy controls. The three clap test also distinguished between PSP and AD. There were no statistically significant differences when comparing PSP with FTD, nor were there differences when comparing FTD with AD. The presence of an applause sign correlated with executive dysfunction on neuropsychiatric testing. Based on their findings, the authors conclude that the applause sign is a nonspecific sign of frontal lobe dysfunction that occurs not only in basal ganglia disorders, but also in cortical dementias such as AD. [ABSTRACT FROM AUTHOR]

THE EVALUATION AND TREATMENT OF PARKINSON'S DISease (PD) is mainly focused on the well-recognized motor features of the disease, such as rest tremor, rigidity, and bradykinesia. In recent years, however, there has been increasing recognition of the high prevalence and major clinical impact of the non-motor symptoms of PD. Anxiety is one of the most common and treatable of these non-motor symptoms, and yet one about which there has been surprisingly little clinical research. One of the major impediments to the study of anxiety in PD has been the lack of recommended PD anxiety rating scales. To address this problem, a task force was commissioned by the Movement Disorder Society to systematically evaluate the clinimetric properties of anxiety rating scales that had been previously validated or used in peer-reviewed publications about PD. Based on a literature search, the authors identified and evaluated 6 of these scales. These included the Beck anxiety inventory (BAI), hospital anxiety and depression scale (HADS), Zung self-rating anxiety scale (SAS) and anxiety status inventory (ASI), Spielberger state trait anxiety inventory (STAI), and Hamilton anxiety rating scale (HARS). They also examined item 5 (anxiety) on the neuropsychiatric inventory (NPI) because of the frequency with which it has been used in PD; other multidimensional scales were excluded. Each rating scale was critically reviewed by two task force members. Rating scales were then classified as "recommended" (used in PD beyond the original developers, with successful clinimetric testing), "suggested" (used in PD beyond the original developers or used in PD with successful clinimetric testing in this population), or "listed" (used in PD only by the original developers, with no successful clinimetric testing in PD). A brief summary of their findings was presented in the printed version of the journal article, with greater detail presented in the accompanying on-line version. The BAI was "suggested" as a screening test for episodic anxiety disorders (such as panic attacks), for studying the epidemiology and biomarkers of anxiety symptoms, and for evaluating responses to changes in treatment. The HADS had limited clinimetric information, and was therefore "suggested" for use in screening for anxiety, but not for studying the phenomenology of anxiety disorders in PD. The Zung SAS had been used in epidemiological studies in PD, but not validated in this population, and the ASI has only been used in one study in PD; neither has been used in PD treatment studies. These studies were therefore also classified as "suggested" for use in PD. The STAI has not been validated in PD, but was found to be particularly useful for evaluating sustained anxiety disorders such as generalized anxiety disorder, and was "suggested" for use in screening for anxiety, studying anxiety biomarkers, and as an outcome measure in PD. The HARS has not been validated in PD, nor is there any information about its clinimetric properties in PD, but it has been used in studies of the epidemiology and symptomatology of anxiety in PD patients and, therefore, met criteria as "suggested" for use in PD. The NPI anxiety subscale also had almost no data about its clinimetric properties in PD, but was "suggested" for use in PD, and may be most useful as a screening tool for anxiety, or for estimating the severity of anxiety in patients with dementia. In the final analysis, the task force classified all of the above anxiety rating scales as "suggested" and none of them as "recommended" for use in PD. This was because none of the rating scales had undergone successful clinimetric testing and in PD. The task force concluded that further study was needed before any of these rating scales could be specifically recommended for use in PD, and that if none of these scales prove to be acceptable, then it may be necessary to devise a new PD-specific anxiety rating scale. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) has been closely linked to both genetic and environmental factors. In prior studies, environmental exposures associated with PD have included pesticides, well water consumption, and residency in rural areas; inverse risk factors have included smoking and coffee use. Some studies have implicated solvents in PD risk, but data have been lacking about whether (and which) solvents may be involved. In this study, the authors examined the potential association between PD and exposure to six specific solvents. They used a case-control study design, with 99 pairs of twins who were discordant for PD status. Study subjects, all of whom were male, were recruited from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort. Structured questionnaires were used to obtain detailed lifetime occupational and hobby histories from each subject. Expert raters, blinded to PD status, then used this information to infer each subject's lifetime exposure to these six solvents. The authors found that ever exposure to trichloroethylene (TCE) was associated with an increased risk of PD (odds ratio [OR], 6.1; P = 0.034). There also were non-significant trends toward increased PD risk with ever exposure to perchloroethylene (PERC; OR, 10.5; P = 0.053) or carbon tetrachloride (CCl4; OR, 2.3; P = 0.088). There were similar findings when they examined the duration of exposure and cumulative lifetime exposure to these solvents. Based on these findings, the authors conclude that solvents, and TCE in specific, are associated with an increased risk of PD. [ABSTRACT FROM AUTHOR]

LEVODOPA AND DOPAMINE AGONISTS ARE HIGHLY EFFECTIVE treatment for Parkinson's disease (PD) and alleviate many of the disabling motor and non-motor disease manifestations. Over time, however, patients begin to develop motor and behavioral complications of chronic dopaminergic therapy. Motor complications such as end-of-dose wearing off and dyskinesias are most closely associated with the use of levodopa. In contrast, behavioral complications such as impulse control disorders (ICDs) are predominantly related to use of dopamine agonists such as pramipexole and ropinorole. There are a number of similarities between levodopa-induced dyskinesias (LID) and ICDs, including potential improvement after deep brain stimulation (DBS), either as a direct effect of DBS and/or due to concomitant reduction of dopaminergic medications. Prior studies have identified a distinct pattern of electrophysiological activity in the motor portion of the subthalamic nucleus (STN) that occurs in subjects with a history of LID. In the current study, the authors examined whether a comparable electrophysiological pattern occurs in subjects with ICDs. Subjects who underwent STN DBS within the past five years were divided into three groups based on clinical presentation -- those with ICDs and no significant LID (PD-ICD; n = 10), those with LID but no ICDs (PD-LID; n = 9), and those with neither ICDs nor LID (PD controls; n = 9). Subjects with ICDs were instructed to discontinue dopamine agonist treatment and add a selective serotonin reuptake inhibitor and/ or atypical antipsychotic medication 1-2 months prior to DBS surgery, but all reported ongoing ICDs. The power spectrum of subthalamic activity and subthalamo-cortical coherence patterns were examined in each of the study subjects. All subjects were examined in the medication "off" and "on" states. The three groups of subjects had comparable oscillatory activity in the STN when they were in the medication "off" state, but distinct patterns of oscillatory activity when in the medication "on" state. PD-ICD subjects had theta-alpha (4-10 Hz) activity (mean peak = 6.71 Hz) in a relatively ventral portion of the STN (2-8 mm below the intercommissural line). In contrast, PD-LID subjects had theta-alpha activity that peaked at a higher mean frequency (8.38 Hz) in a more dorsal portion of the STN (0-2 mm below the intercommissural line). Neither of these patterns was present in PD control subjects. In PD-ICD subjects, cortico-subthalamic coherence (as evaluated with scalp electrodes) was more frequent in the 4-7.5 Hz range in the region of the premotor/dorsolateral prefrontal cortex. In contrast, in PD-LID subjects, it was more frequent in the 7.5-10 Hz range in leads overlying the primary motor and supplementary motor areas. Together, these findings implicate the ventral (associative limbic) portion of the STN in the pathophysiology of ICDs, and confirm the role of the dorsal (motor) portion of the STN in that of LID. [ABSTRACT FROM AUTHOR]

PARKINSON'S DISEASE (PD) IS A CLINICALLY AND GENETICALly heterogeneous disorder, with striking variability in its presentation and rate of progression. Factors such as young age of onset and tremor predominance have been associated with an overall favorable prognosis. In contrast, features such as later age of onset, dementia, and prominent postural instability-gait disturbance tend to predict a more malignant disease course. Given this clinical heterogeneity, it is not surprising that there is also tremendous variability of life expectancy in PD. For this reason, it is of considerable clinical interest to determine factors associated with increased mortality in PD. In this study, the authors examined clinical and demographic predictors of increased mortality in PD. The study population was a large (n = 230), prospective, community-based cohort in Norway. Subjects underwent serial motor and non-motor assessments between 1993 and 2005. The vital status of all study subjects was obtained from a national registry in 2009; this included the date of death for subjects who were deceased. Kaplan-Meier analysis was used to examine unadjusted survival after motor onset. Cox proportional hazards models were used to determine the independent predictors of mortality in the cohort. Within the study period, 211 subjects (92%) died. Survival times ranged from 2.2-36.6 years, with a mean survival of 15.8 years from motor onset. The mean age of death was 81.1 ± 6.3 years (79.8 ± 6.1 for men vs. 82.4 ± 6.3 for women). Independent predictors of mortality included older age at onset, higher chronological age, male sex, higher Unified Parkinson's Disease Rating Scale (PDRS) motor scores (indicative of greater motor impairment), the presence of psychotic symptoms, and the presence of dementia. The use of atypical antipsychotics, however, was not an independent predictor of mortality. The authors conclude that treatments that prevent motor progression, dementia, and psychosis might reduce mortality in PD. [ABSTRACT FROM AUTHOR]

MUTATIONS IN THE PTEN-INDUCED PUTATIVE KINASE 1 (PINK 1) GENE ARE THE second most common cause of autosomal recessive, early-onset Parkinson's disease (PD). Patients with homozygous PINK1 mutations nearly always develop PD. Little is known, however, about whether heterozygous PINK1 mutations may also cause progressive signs and symptoms of parkinsonism. In this study, the authors performed a longitudinal analysis of four homozygous PINK1 mutation carriers (all with clinically definite PD) and 10 asymptomatic heterozygous PINK1 mutation carriers (five unaffected; five with examination findings consistent with possible or probable PD) in a single German kindred, to test the hypothesis that there is a progressive phenotype that occurs in carriers of heterozygous PINK1 mutations. All study subjects were evaluated at baseline and three years later. Baseline assessments included a videotaped Unified Parkinson's Disease Rating Scale (UPDRS) motor examination, and smell and color discrimination tasks. After three years, most of the study subjects also completed fluorodopa positron emission tomography (FDOPA PET) scans. Heterozygous PINK1 mutation carriers were compared with both homozygous PINK1 mutation carriers and healthy control subjects. Over the three-year study period, three of the five previously unaffected heterozygous PINK1 mutation carriers had developed new signs of possible PD. At the follow-up visit, seven heterozygous PINK1 mutation carriers had hyposmia, and four had diminished color discrimination. Hyposmia, but not impairment of color discrimination, was significantly more common in PINK1 mutation heterozygotes than in control subjects. PET scans at the follow-up visit showed a 20% autumnal FDOPA uptake reduction in heterozygous PINK1 mutation carriers compared with healthy controls; this was a significant difference, but mild in comparison with the 60% FDOPA uptake reduction seen in subjects with homozygous PINK1 mutations. Overall, the degree of FDOPA uptake reduction correlated with severity of UPDRS motor impairment. Together, the findings suggest that heterozygous PINK1 mutations may increase susceptibility to hyposmia and motor signs of PD, but to a lesser degree than homozygous PINK1 mutations. [ABSTRACT FROM AUTHOR]

LEVODOPA AND DOPAMINE AGONISTS (DAS) ARE commonly used treatments for Parkinson's disease (PD). Although DAs tend to have more side effects than levodopa, they are often favored as initial therapy because this strategy delays the onset of motor complications such as wearing off and dyskinesias. Later in the disease, DAs are frequently used as an adjunct to levodopa, to increase "on" times and reduce end-of-dose "wearing-off." While the benefits of combined DA/levodopa therapy are well established, it is unclear whether this is simply an additive benefit, or if there are also pharmacodynamic interactions between these drugs. The goal of the current study was to examine the effects of pramipexole, a DA, on the motor response to levodopa in PD. The authors used a double-blind, randomized, placebo-controlled, crossover design to evaluate subjects with PD who were experiencing dyskinesias and motor fluctuations as a complication of long-term levodopa therapy. Each of the 13 study subjects was treated with pramipexole (3 mg/day) or placebo for a four-week period, and then with two-hour intravenous levodopa infusions on each of two consecutive days (after overnight discontinuation of oral levodopa). Blinded neurological assessments were performed concomitant with each levodopa infusion. Subjects were then switched to the other oral agent (placebo or pramipexole) for another four weeks, after which the same levodopa infusions and examinations were repeated. The primary outcome measure was finger-tapping speed, a marker for bradykinesia. Secondary outcome measures included quantitative analyses of dyskinesias and walking speed. All measures were compared at baseline (before levodopa infusion) versus during levodopa infusion, to adjust for the direct benefits of pramipexole on motor function. Of the 13 study subjects, 10 completed the study and were included in the analysis; three dropped out (two because they were unable to tolerate DA taper during attempted crossover to placebo). Among those 10 subjects, pramipexole with levodopa treatment increased the mean finger-tapping speed beyond the change in baseline, more than doubled the area under the curve for finger-tapping speed, increased the mean peak fingertapping speed, and improved mean walking speed. In addition, pramipexole prolonged the duration of response after levodopa infusion, and shortened the time to "on." Unfortunately, pramipexole therapy was also associated with increased mean baseline and peak dyskinesia scores. Based on these findings, the authors conclude that pramipexole "augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia." [ABSTRACT FROM AUTHOR]

EPIDEMIOLOGICAL STUDIES HAVE IMPLICATED PESTICIDES AS A possible environmental cause for Parkinson's disease (PD), but little is known about the specific toxins that may be to blame. Organochlorine pesticides are potential candidates, because they are lipophilic, highly persistent in the environment, and neurotoxic to dopaminergic neurons in rodent models. High levels of specific organochlorine pesticides have also been identified in the postmortem brains of PD patients. In this study, the authors used a case-control study design to test the hypothesis that high serum levels of specific organochlorine pesticide(s) are associated with PD. They examined blood samples from subjects with PD (n=50) at a tertiary movement disorders center, and compared them with those of subjects with Alzheimer's disease (AD) (n=20), and healthy controls (n=43). They then used gas chromatography-mass spectrometry to test the samples for the presence of 16 different organochlorine pesticides, restricting further analysis to pesticides that were detected in at least half of the subjects with PD. The pesticide that was most commonly detected in the serum of PD patients was β-hexachlorocyclohexane (β-HCH), which was present in 38/50 (76%) of PD patients, compared with 17/43 (40%) of healthy controls and 6/20 (30%) AD patients. The median level of β-HCH was also significantly higher in subjects with PD (0.36 ng/mL) than in either control subjects (0 ng/mL) or subjects with AD (0 ng/mL). The findings raise the possibility that β-HCH may play a role in the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

IN RECENT YEARS, IT HAS BECOME INCREASINGLY CLEAR that Parkinson's disease (PD) consists of much more than the well-known motor features attributed to nigrostriatal dopamine deficiency. In this review paper, the authors provide a detailed discussion of these extranigral symptoms, as well as their underlying anatomy, biochemistry, and pathophysiology. They note that many of the symptoms of PD are attributable to the dysfunction of dopaminergic cells outside the substantia nigra, and/or the more widespread involvement of non-dopaminergic neurons throughout the nervous system. The authors first discuss motor symptoms of PD that are unresponsive to levodopa. While two of the early cardinal features of PD -- rigidity and bradykinesia -- are highly responsive to dopaminergic medications, rest tremor is often partially or completely unresponsive. As the disease advances, more devastating, levodopa-unresponsive motor symptoms develop, largely due to extranigral neurodegeneration. These include postural instability/ falls, freezing of gait, dysarthria, and dysphagia. They next discuss the "premotor" symptoms of PD, which begin years, and sometimes decades, before the motor symptoms develop. These may include hyposmia, sleep disorders (REM sleep behavior disorder, excessive daytime sleepiness), psychiatric symptoms (depression, anxiety), autonomic impairment (constipation, erectile dysfunction, cardiac sympathetic denervation, orthostatic hypotension, urinary urgency), and executive dysfunction. These premotor symptoms are attributable to involvement of extranigral brain regions that occur before file substantia nigra is clinically affected. After that, the authors discuss symptoms that occur in PD as a consequence of dopaminergic therapy. These include levodopa-induced dyskinesias and end-of-dose wearing off, both of which commonly develop with chronic levodopa use. They note that wearing-off symptoms include both motor deficits and non-motor manifestations such as anxiety, dysphoria, apathy, diaphoresis, urinary urgency, and pain. Other side effects of dopaminergic medications may include impulse control disorders such as compulsive eating, compulsive buying, pathological gambling, and hypersexuality; these are most commonly associated with dopamine agonists. More rarely, patients may become "'addicted" to levodopa or other dopaminergic medications, a phenomenon referred to as dopamine dysregulation syndrome. Finally, they discuss the extranigral features of advanced PD. As the disease spreads to limbic and cortical areas, dementia and visual hallucinations develop. Patients also develop increased "midline symptoms" levodopa-unresponsive motor symptoms such as postural instability, falls, freezing of gait, dysarthria, and dysphagia. Together, these symptoms are associated with markedly increased morbidity and mortality. [ABSTRACT FROM AUTHOR]