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Statistically and clinically significant cognitive declines are observed in a small subset of individuals with Parkinson's Disease (PD) following treatment with Deep Brain Stimulation (DBS).We examine the association between multi-domain cognitive decline (MCD) and demographic and baseline clinical variables and the incidence of serious adverse events (SAE) arising within a six-month interval following DBS for PD.Study participants with PD who displayed MCD at 6-month follow-up evaluation after DBS (n = 18) were contrasted with individuals with PD from the same study who did not show cognitive decline after DBS (n = 146). Logistic regression analyses were employed to assess relationship between predictors, including age (70 years old), pre-DBS cognitive screening test performance, SAE, and MCD. MCD+ and MCD-groups were also compared on other baseline clinical and demographic variables.MCD showed modest association with older age and lower baseline neurocognitive screening performance, whereas the groups did not differ on most other baseline clinical and demographic variables. SAEs during the study interval were the most robust predictor of MCD in the DBS group. A variety of SAEs were documented in study participants experiencing MCD after DBS surgery, including, but not limited to, infections and small intracranial hemorrhages.Older age and lower baseline cognition measured prior to treatment are associated with MCD measured at six-months after DBS. SAE occurring following DBS surgery are also predictive of MCD. These predictors may reflect aspects of "frailty" in advanced PD. Risk factors for SAE warrant careful consideration in clinical trials.

Background Rapid eye movement (REM) sleep behavior disorder (RBD) is present in around 40% of Parkinson's disease (PD) patients. Definitive diagnosis requires a polysomnogram, but that is costly, time intensive, and not practical for large-scale studies. Therefore, we assessed using a questionnaire-based diagnostic approach. Methods The patient-administered RBD questionnaire and bed-partner-administered question 1 of the Mayo questionnaire were prospectively validated. Results Seventy-five PD patients (51 male, 68 Hoehn and Yahr stages I and II) participated. Forty-eight had a clinical history of RBD. Sensitivity was 100% (95% CI, 86.3%–100%) when a combination of both questionnaires was compared with the gold standard of polysomnogram-confirmed RBD. Among those who achieved REM sleep (n = 65), specificity was highest for the patient questionnaire used alone, at 82.4% (95% CI, 64.8%–92.6%). Conclusions A combination of patient and bed-partner questionnaires is a useful tool to detect RBD. © 2013 Movement Disorder Society

An early Internet developer takes a personal look back at the 1990 start-up of one of the early social networks, Echo. Horn discusses the challenges she faced building an online community at a time when if people had even heard of the Internet, they thought it was something to do with computers and only of interest to socially challenged geeks. She talks about coming up with ways to deal with all the problems that continue to plague the Internet today: trolls, harassment, bullying, basically all the evils of society. Horn also covers how she got women online when the Internet was 90% male, or large institutions, such as the Whitney Museum of American Art, when talk on the net was mostly tech.

The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The e4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥ 10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE e4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Summary Background The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding St Jude Medical Neuromodulation Division.

Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation).At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events.Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months.Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Pregnant patients are rarely encountered in the movement disorders clinic, but they present significant dilemmas regarding treatment and counseling for neurologists. While movement disorders in pregnancy once described those disorders arising de novo during pregnancy, such as chorea gravidarum or restless leg syndrome, advancing maternal age in Western countries will likely increase the number of women in whom pregnancy complicates a pre-existing movement disorder. Physicians treating these women must be aware of the impact of the movement disorder and its treatment on fertility, pregnancy, fetal development, lactation, and infant care. This review summarizes retrospective series and case reports to both guide clinicians and to stimulate and direct the design of prospective studies.

As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinson's disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self-administered screening questionnaire for ICDs and other compulsive behaviors in PD. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism, and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP-S) was then explored. The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling = 0.95, sexual behavior = 0.97, buying = 0.87, eating = 0.88, punding = 0.78, hobbyism = 0.93, walkabout = 0.79). On post hoc analysis, the QUIP-S ICD section had similar properties (ROC AUC: gambling = 0.95, sexual behavior = 0.96, buying = 0.87, eating = 0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP-S to detect an individual with any disorder was 96 and 94%, respectively. Scores on the QUIP appear to be valid as a self-assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.

Cognitive impairment insufficient to meet criteria for dementia (mild cognitive impairment (MCI)) has been reported to occur in 20% to 30% of patients with Parkinson’s disease (PD),1–5 even in newly diagnosed patients.4,5 Identification of initial impact or MCI in PD is important, because it predicts future cognitive decline, including development of PD dementia (PDD),2,3,6,7 and deterioration of health-related quality of life.8 Impairments in executive function, attention, visuospatial skills, and memory characterize the “typical” cognitive profile in PD, whereas language and praxis are thought to be relatively spared.3,4,9 The memory impairment associated with PD is classically considered a retrieval deficit (i.e., subcortical memory profile) as opposed to an encoding deficit (i.e., cortical memory profile). There is substantial overlap in the pattern of observed cognitive deficits in PD without dementia and PDD. Studies enrolling both groups of patients have shown qualitatively similar, but quantitatively greater, impairments in patients with PDD in executive function, visuospatial abilities, attention, and psychomotor skills.10 In longitudinal studies of patients without dementia at baseline, verbal memory deficits11 and executive or visuospatial impairments12 have been shown to predict development of PDD on long-term follow-up. Given the aforementioned high prevalence of MCI in PD and its association with future development of dementia, it is important that patients with PD, even those with mild disease, be screened regularly for cognitive impairment.12 An ideal cognitive screening instrument in PD should be brief, assess a range of cognitive domains, simple to administer, sensitive to the initial stage of cognitive impairment, and unaffected by motor impairment. Few screening instruments have been validated or developed to assess global cognition in PD. The Scales for Outcomes of Parkinson’s Disease—Cognition was recently developed and has been shown to be valid and reliable in differentiating patients with PD with and without dementia,13,14 but its performance, specifically in patients without significant global cognitive impairment, has not been reported. The Cambridge Cognitive Examination—Revised distinguishes between patients with PD with and without dementia and detects cognitive impairment in patients with PD with an MMSE score less than 25,15 but it takes approximately 60 minutes to administer. The Mini-Mental State Examination (MMSE)16 remains the most commonly used screening instrument for global cognition. The MMSE is used extensively in PD, but its use in this population has been questioned,17,18 in part because the MMSE primarily assesses memory and language skills and also may not be sensitive to detect many cases of MCI. The Montreal Cognitive Assessment (MoCA)19 is a new cognitive screening instrument that was designed to address some of the limitations of the MMSE. It assesses a broader range of cognitive domains than the MMSE and is more challenging from a cognitive standpoint overall. The MoCA and the MMSE both have items that require motor skills that core PD symptoms potentially affect (5/30 points on the MoCA and MMSE). The MoCA has been shown to be more sensitive than the MMSE for the detection of MCI and mild Alzheimer’s disease in the general population, and a score less than 26 was found to be the optimal cutoff point for a diagnosis of cognitive impairment.19 There have been two studies using the MoCA in PD, and in one, the MoCA was found to be more sensitive than the MMSE in detecting cognitive impairment in this population,17 although a MMSE score less than 26 was used to classify patients as having cognitive impairment, and this cutoff has not been validated for PD. In addition, the authors did not examine differences in MoCA subscores in impaired and unimpaired groups or examine correlates of MoCA performance. In the other study, the MoCA was found to have good test–retest reliability, interrater reliability, and convergent validity with a neuropsychological battery in a small sample of patients with PD.20 This study presents results on the frequency and correlates of cognitive impairment using the MoCA in patients with PD. These patients were a priori defined as not meeting criteria for global cognitive impairment when evaluated with the MMSE. It was hypothesized that a substantial proportion of patients with PD would be impaired (score

Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson’s disease (PD). Little is known about optimal management strategies or the long-term outcomes of affected patients. To report on the clinical interventions and long-term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow-up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self-rated changes in their ICD symptomatology. Baseline and follow-up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow-up interview. At follow-up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = -3.1, P = 0.002) and a higher daily levodopa dosage (Z = -1.9, P = 0.05), but a similar total LEDD dosage (Z = -0.47, P = 0.64) with no changes in Unified Parkinson’s Disease Rating Scale motor score (Z = -1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self-report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms.

Background: Silas Weir Mitchell (1829 to 1914), one of the most important neurologists in American Medicine, was known for his seminal work on the phantom limb syndrome, causalgia, and nerve injuries. He was also a prolific writer of novels and short stories. The neurologic content of this fiction has not been studied. Objective: To assess the extent that references to neurologic topics were present in Mitchell9s fiction, whether these neurologic references reflected Mitchell9s scientific interests and contributions, and whether his fictional accounts of neurologic topics would precede those in his scientific writings. Methods: The authors read Silas Weir Mitchell9s novels and short stories. Results: Seventeen (63.0%) of 27 fictional works contained neurologic references. Fifty-five (69.6%) of 79 references were brief (a single word or sentence). In two works, a neurologic theme was central to the plot. Some of the neurologic content was sophisticated (aphasia, brain laterality). Phantom limb syndrome, causalgia, and nerve injuries were not prominent in his fiction. Neurologic consequences of battle injuries were featured in 10 (37.0%) works. With the exception of “The Case of George Dedlow” (i.e., phantom limb syndrome), Mitchell9s fictional accounts of neurologic topics followed his presentation of these topics in the scientific literature. Conclusions: The majority of Mitchell9s fictional works contained references to neurologic topics but most contained brief references. The number of references to Mitchell9s specific scientific interests (phantom limb syndrome, causalgia) was small, although more generally, references to the neurology of battle injuries occurred more frequently.

The medical treatment of Parkinson’s disease (PD) is challenging at every phase of the illness. Clinicians have many drugs to choose from, each with its own specific indications, symptomatic properties, and adverse effects. It is important to understand the comparative efficacy of anti-parkinsonian drugs and to consider the long-term effects of therapeutic interventions. The goal of therapy of PD is to maximize control of symptoms while minimizing the long-term consequences of the disease and treatment-related complications. It is appropriate to divide the therapy of PD into treatments that may slow the progression of the disease (putative neuroprotective treatments), the treatment of early PD, and the treatment of advanced PD. This article compares the current medical options for the treatment of all phases of PD. The term “neuroprotection” remains controversial but is used here to consider therapeutic strategies that might modify the course of PD by interfering with the underlying disease process. To date, no agent has been convincingly shown to be “neuroprotective,” but an increasing number of compounds have been studied. These agents are difficult to compare because each has a different effect on the symptoms of PD. Moreover, neuroprotective studies have been replete with difficulties stemming from the unknown etiology of PD, its variable nature, the ambiguity of chosen end points and the symptomatic effects of many of the tested therapies. All of these factors have confounded the interpretation of neuroprotective studies. The first agent tested as a putative neuroprotective agent was selegiline, a monoamine oxidase (MAO) inhibitor. Selegiline is an irreversible inhibitor of MAO-B. The DATATOP trial (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) was a large-scale, double-blind, placebo-controlled trial by the Parkinson’s Study Group.1 The primary end point of this trial was time to disability and requirement for treatment with levodopa. Although patients treated with selegiline …

Background Deep brain stimulation (DBS) improves motor symptoms in Parkinson9s disease (PD), but questions remain regarding neuropsychological decrements sometimes associated with this treatment, including rates of statistically and clinically meaningful change, and whether there are differences in outcome related to surgical target. Methods Neuropsychological functioning was assessed in patients with Parkinson9s disease (PD) at baseline and after 6 months in a prospective, randomised, controlled study comparing best medical therapy (BMT, n=116) and bilateral deep brain stimulation (DBS, n=164) at either the subthalamic nucleus (STN, n=84) or globus pallidus interna (GPi, n=80), using standardised neuropsychological tests. Measures of functional outcomes were also administered. Results Comparison of the two DBS targets revealed few significant group differences. STN DBS was associated with greater mean reductions on some measures of processing speed, only one of which was statistically significant in comparison with stimulation of GPi. GPi DBS was associated with lower mean performance on one measure of learning and memory that requires mental control and cognitive flexibility. Compared to the group receiving BMT, the combined DBS group had significantly greater mean reductions at 6-month follow-up in performance on multiple measures of processing speed and working memory. After calculating thresholds for statistically reliable change from data obtained from the BMT group, the combined DBS group also displayed higher rates of decline in neuropsychological test performance. Among study completers, 18 (11%) study participants receiving DBS displayed reliable decline by multiple indicators in two or more cognitive domains, a significantly higher rate than in the BMT group (3%). This multi-domain cognitive decline was associated with less beneficial change in subjective ratings of everyday functioning and quality of life (QOL). The multi-domain cognitive decline group continued to function at a lower level at 24-month follow-up. Conclusions In those with PD, the likelihood of significant decline in neuropsychological functioning increases with DBS, affecting a small minority of patients who also appear to respond less optimally to DBS by other indicators of QOL. Trial registration number NCT00056563 and NCT01076452.

Treatment of movement disorders has expanded beyond traditional therapies with oral medications to include injection of drugs like botulinum toxin and the use of surgical interventions in cases that do not respond to medical therapy. This article provides an overview to the diagnosis and treatment of tremor and dystonia. The distinguishing features of rest, postural, and kinectic tremor are detailed with medical and surgical modalities for treatment. A discussion of idiopathic and secondary dystonia with focus on diagnosis and medical and surgical treatments encompasses the second part of the article.

Background Poor nocturnal sleep is common in Parkinson's disease (PD) and negatively impacts quality of life. There is little data on how dopaminergic drugs influence nocturnal sleep in PD, particularly in relation to medication timing. We examined the association between dopaminergic medications and subjective and objective nocturnal sleep in PD. Methods Individuals with PD were recruited from the outpatient clinic. Demographics and disease information were collected. Patients underwent one-night polysomnography and responded to SCOPA-SLEEP, a self-administered questionnaire which includes a section on nighttime sleep and an overall measure of sleep quality; higher scores indicate worse sleep. Medication intake, including medication timing in relation to bedtime, was obtained and converted to levodopa equivalents. Results 41 Males and 21 females, median age 63.9 years, participated. Median disease duration was 5 years. After adjusting for age, sex, disease severity, and disease duration, greater total levodopa equivalent intake within 4 h of sleep was associated with higher total SCOPA-nighttime score (p = 0.009) and greater wake time after sleep onset (p = 0.049). Greater dopaminergic medication intake prior to sleep was also associated with less rapid eye movement (REM) sleep as a percent of total sleep time (p = 0.004). Conclusions Higher amounts of dopaminergic medications taken prior to sleep were associated with poor sleep quality and less REM sleep. Although poor nocturnal sleep in PD is likely multi-factorial in etiology, our findings suggest that timing and dose of medications prior to sleep need to be considered in its management.

Rapid eye movement (REM) sleep behavior disorder (RBD) is present in around 40% of Parkinson's disease (PD) patients. Definitive diagnosis requires a polysomnogram, but that is costly, time intensive, and not practical for large-scale studies. Therefore, we assessed using a questionnaire-based diagnostic approach.The patient-administered RBD questionnaire and bed-partner-administered question 1 of the Mayo questionnaire were prospectively validated.Seventy-five PD patients (51 male, 68 Hoehn and Yahr stages I and II) participated. Forty-eight had a clinical history of RBD. Sensitivity was 100% (95% CI, 86.3%-100%) when a combination of both questionnaires was compared with the gold standard of polysomnogram-confirmed RBD. Among those who achieved REM sleep (n=65), specificity was highest for the patient questionnaire used alone, at 82.4% (95% CI, 64.8%-92.6%).A combination of patient and bed-partner questionnaires is a useful tool to detect RBD.

Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinson9s Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p p p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients ( p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology ® 2012;79:55–65

The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P0.001) in total score and an increased risk of a ≥ 10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Objectives: Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. Methods: A total of 55 subjects with PD and an Inventory of Depressive Symptomatology–Clinician (IDS-C) score ≥22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (>50% decrease in IDS-C score or Clinical Global Impression–Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. Results: There were no between-groups differences in a priori–defined response rates. Using a more liberal response criterion of >40% decrease in IDS score from baseline, there was a trend ( p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition ( p = 0.003) and daytime sleepiness ( p = 0.001), and atomoxetine was well-tolerated. Conclusions: Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. Classification of evidence: This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.

Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients.To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy.Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (70 years vsor = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stageor = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006.Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists.The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events.Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P.001). Motor function improved significantly (P.001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P.001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P.001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage.In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events.clinicaltrials.gov Identifier: NCT00056563.

Parkinson's disease (PD) is a chronic neurodegenerative disease associated with substantial morbidity, increased mortality, and high economic burden. Of importance to managed care is that the number of cases of PD are on the rise, paralleling the advancing age of the population, and misdiagnosis is common. Effective management of PD can minimize disability and potentially improve long-term outcomes, which would minimize long-term healthcare costs and medical resource utilization. This article provides a brief review of the epidemiology, pathophysiology, clinical course, and burden of PD.

The nonmotor neuropsychiatric symptoms of Parkinson's disease, particularly depression, psychosis, and cognitive impairment/dementia, are major contributors to disability and a decline in quality of life. Their effect on patients may be more disabling than motor symptoms. Increasing awareness of the importance of recognizing and treating neuropsychiatric symptoms of this disease in the medical community is a focus of specialists and organizations. This article looks at useful screening measures to help clinicians recognize neuropsychiatric symptoms and offers suggestions for their effective treatment.

In the absence of a cure, the primary goals in managing Parkinson's disease (PD) are to preserve functionality and health-related quality of life. Meeting these goals can minimize healthcare-resource utilization and long-term healthcare costs. Although effective treatment of motor symptoms of the disease is a central consideration to facilitate improved outcomes, management of nonmotor symptoms is now recognized as an equally important target of intervention, since nonmotor symptoms can contribute greatly to disability. The article addresses the current treatment options of choice for reducing motor symptoms of PD and their most rational use. Cost-effectiveness is a major consideration for managed care and is also analyzed for many available treatment options.

The authors investigated the early women physicians of the New York Infirmary for Women and Children and their role in shaping the career and accomplishments of their student and later colleague, Dr. Sarah J. McNutt. These influences eventually led McNutt to be inducted into the American Neurologic Association (ANA). McNutt was educated at the New York Infirmary for Women and Children by early women physicians including Drs. Elizabeth and Emily Blackwell and Mary Putnam Jacobi. McNutt worked to improve the educational opportunities for practicing physicians and nurses by developing postgraduate lectures and organizations. With her early colleagues she developed the New York Infirmary for Women and Children into a reputable hospital and woman's medical college. One of the consultants to the New York Infirmary for Women and Children was Royal W. Amidon, secretary of the ANA in 1883. McNutt's close association with the Clinical Society of the New York Post Graduate Medical School and Hospital brought her into direct contact with other prominent ANA members including C.L. Dana and W.A. Hammond. In 1884, McNutt was nominated by Amidon and Hammond as the first woman member to the ANA and was elected. Her ANA thesis was Double Infantile Spastic Hemiplegia. McNutt was elected into the ANA at a time when women physicians were first being recognized and included into mainstream medicine. Her historic election acknowledged her accomplishments and highlighted the proactive role of the early ANA in forging new medical policies in the United States.

Importance Biochemical abnormalities present in GBA ( mut/wt ) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD). Objective To determine whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression. Design and Setting Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups. Participants The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA -associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing. Main Outcome Measures Biochemical profiling was available for all 20 GBA -associated PD cases, as well as a subset (87 of 242) of the GBA -negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations. Results Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset ( P = .04) and were more likely to demonstrate cognitive dysfunction ( P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 ( P = .001), monocyte chemotactic protein 1 ( P = .008), and macrophage inflammatory protein 1α ( P = .005). The association between interleukin 8 and GBA mutation status was replicated ( P = .03) in a separate cohort of patients having PD with vs without GBA mutations. Conclusions and Relevance Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations.

Context Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. Objective To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. Design, Setting, and Patients Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age ( Intervention Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. Main Outcome Measures The primary outcome was time spent in the “on” state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. Results Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P Conclusion In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. Trial Registration clinicaltrials.gov Identifier: NCT00056563