Grasping the big picture: impact analysis of screening tools for timely referral for device-aided therapies.

Several screening tools are available to assist general neurologists in the timely identification of patients with advanced Parkinson's disease (PD) who may be eligible for referral for a device-aided therapy (DAT). However, it should be noted that not all of these clinical decision rules have been developed and validated in a thorough and consistent manner. Furthermore, only a limited number of head-to-head comparisons have been performed. Available studies suggest that D-DATS has a higher positive predictive value and higher specificity than the 5-2-1 criteria, while the sensitivity of both screening tools is similar. However, unanswered questions remain regarding the validity of the decision rules, such as whether the diagnostic performance measures from validation studies are generalizable to other populations. Ultimately, the question is whether a screening tool will effectively and efficiently improve the quality of life of patients with PD. To address this key question, an impact analysis should be performed. The authors intend to set up a multinational cluster randomised controlled trial to compare the D-DATS and 5-2-1 criteria on the downstream consequences of implementing these screening tools, with a particular focus on the impact on disability and quality of life.

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation.

BACKGROUND: To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients. METHODS: This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire. DISCUSSION: Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease. TRIAL REGISTRATION: NCT05830396. Registration date: March 20, 2023.

Intermuscular coherence as a biomarker of subthalamic nucleus deep brain stimulation efficacy in Parkinson's disease.

OBJECTIVE: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment in advanced Parkinson's disease (PD). However, the clinical outcome after STN-DBS is variable. The aim of this study was to explore the coherence of antagonistic muscles measured with electromyography (EMG) as novel biomarker of STN-DBS efficacy in PD. METHODS: EMG of bilateral wrist and upper arm antagonistic muscles of 21 PD patients was recorded during three standardized motor tasks. Patients were measured one day prior to DBS surgery (pre-DBS) and 6 months afterwards (post-DBS). Coherence analyses were performed on the antagonistic muscle pairs. Pearson correlations between intermuscular coherence and clinical performance were calculated. RESULTS: Intermuscular coherence during each of the different co-contraction tasks significantly correlated to UPDRS-III bradykinesia scores (p < 0.01). In other words, higher intermuscular coherence is associated with more severe PD symptoms. Moreover, coherence changes (pre-DBS - post-DBS coherence) correlated to clinical score changes after DBS (p < 0.01) and pre-DBS coherence correlated to this clinical score change as well (p < 0.01). CONCLUSIONS: Higher pre-DBS coherence of antagonistic arm muscles is correlated to worsening of clinical PD state and higher intermuscular coherence predicts enhanced clinical improvement. SIGNIFICANCE: We propose that pre-DBS intermuscular coherence could be developed into a predictor of STN-DBS clinical outcome. It could aid patient selection and adaptive stimulation algorithms for DBS.

Radiation of parotid or submandibular glands is effective for drooling in patients with parkinsonism; a randomised double-blind placebo-controlled trial.

BACKGROUND: Drooling is a common symptom in patients with parkinsonism, causing physical and emotional distress. It is unknown which major salivary glands are the best candidates for irradiation to reduce drooling with minimal adverse events. Therefore, this study assessed the efficacy and safety of submandibular and parotid salivary gland irradiation to reduce drooling. METHODS: A prospective, randomised, double-blind, placebo-controlled trial was conducted at the University Medical Center Groningen, the Netherlands. After informed consent, 31 patients with parkinsonism and severe drooling according to the Unified Parkinson Disease Rating Scale (UPDRS) were included in this study. Exclusion criteria consisted of the use of anticholinergic drugs, the existence of salivary gland diseases, and/or an history of (pre)malignancies of the salivary glands. Patients were randomized for parotid-, submandibular- or sham irradiation (2x6 Gy with one week interval). Patients were evaluated at 1, 3, 6 and 12 months after radiation. Primary outcome measure was drooling severity according to the UPDRS. Secondary outcomes measures consisted of stimulated glandular salivary secretion rates and adverse effects. FINDINGS: Overall 31 parkinsonian patients were included. Initially 11 patients were radiated on the parotid glands, 10 patients on the submandibular glands and 10 patients were sham-radiated. After 6 months, the sham-radiated patients were actively treated after a second randomisation. One patient in the parotid radiation group discontinued his participation after three months due to physical deterioration. Radiation of parotid or submandibular glands significantly improved the existing drooling, as compared to placebo radiation. Parotid- and submandibular radiation was equally effective, but more patients in the submandibular radiated group reported sticky saliva vs. patients treated by parotid radiation (33∙33% vs. 13∙33%). INTERPRETATION: Major salivary gland radiation significantly improves drooling in parkinsonian patients with few adverse effects. However, parotid gland radiation is accompanied by fewer side effects and therefore is the preferred mode of radiation in this patient population.

Faecal Transplantation, Pro- and Prebiotics in Parkinson's Disease; Hope or Hype?

Faecal microbiome transplantation (FMT) is an attractive technique, because the administration is relatively simple and in general has a mild adverse effect pattern. Moreover, FMT consists of a broad mixture, which could be beneficial, because at this moment it is not known what type of changes in the microbiome are needed. However, except from a few cases no clinical data in Parkinson's disease (PD) is available yet. There is some indication that FMT might be beneficial in severe constipated PD patients, but the clinical data to support this are very scarce. So, actually there are no good data in the public domain to support FMT at this moment in PD patients. FMT at this moment is a black box with too many unanswered questions, also with respect to safety concerns. Only the administration of species of Lactobacillus and Bifidobacterium over a time period of four to twelve weeks has repeatedly proven to be effective in treating constipation in PD. Also, no solid clinical data are available about the possible effects of probiotic treatment on motor symptoms or progression of PD. Therefore, also probiotic treatments in PD should wait until better clinical data become available, in order to select the right target populations and to have good estimates of the clinical effects to be expected.

Visual hallucinations in psychosis.

The Dutch version of the Visual Hallucination Questionnaire was used to assess lifetime visual hallucinations (VH) characteristics in 27 patients with psychosis. Our results confirmed substantial variance in many VH characteristics. Most patients reported multiple VH types. Complex VH were most prevalent, mainly consisting of people and animals, followed by simple, then geometric VH. Few patients experienced only simple VH. The VH generally had features resembling real perceptions. Insight was usually reduced. VH ranged from 'appropriate' and neutral to peculiar and delusion-associated. VH accompanied by fright and sound seem to be related to experiencing complex or multiple types of VH.

The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Learning from Parkinson's patients: Usability of the Cyclops dry powder inhaler.

Effective inhaler therapy requires correct handling of the inhaler, including being able to prepare the inhaler for use. Motor function impairment and cognitive disabilities, may impose problems on patients with Parkinson's disease when they have to prepare medication, such as inhalers, for use. The aim of the present study was to examine whether Parkinson's patients are able to correctly prepare the Cyclops inhaler for use. At first, 12 patients, 6 in an off state and 6 in an on state, were asked to open 5 inhalers with ascending peel resistance of the cover foil. It was investigated up to which peel resistance they were able to successfully pull the foil from the inhaler. For the second part of the study, 48 participants, 24 on and 24 off, were asked to open 2 pouches and the 2 inhalers selected in part 1. For pouch 1, 70.8% of the patients in an on state and 58.3% in an off state were able to open the pouch correctly. For pouch 2, this was 79.2% and 75.0%, respectively. Both Cyclops inhalers were opened correctly by 95.8% of the participants in the on state and 91.7% of the participants in the off state.

Direct comparison of oscillatory activity in the motor system of Parkinson's disease and dystonia: A review of the literature and meta-analysis.

OBJECTIVE: To outline the current knowledge of (sub)cortical oscillations in Parkinson's Disease (PD) and dystonia, and to quantitatively summarize the results of direct comparisons of local oscillatory power between both diseases in the resting state, without medication or stimulation, in both the low-frequency (LF, ±4-12 Hz) and beta (±13 to ∼30 Hz) range. METHODS: Eight relevant studies were included. Recordings from 127 dystonia-, and 144 PD-patient hemispheres were analyzed. Ratios of LF and beta power between diseases were obtained. RESULTS: Beta oscillations in dystonia were lower when compared to beta oscillations in PD, ratio = 0.72, Z = 3.56, p = 0.0004, 95% CI [0.60, 0.86]. Subgroup analyses showed significant differences only in the GPi, whilst conflicting evidence was shown in the STN. LF oscillations in PD were lower when compared to LF oscillations in dystonia, ratio = 0.77, Z = 2.45, p = 0.01, 95% CI [0.63, 0.95]. Subgroup analyses showed significant differences in the GPi and the STN, but not in the M1. CONCLUSIONS: LF and beta oscillations are present in the resting-state motor network of both PD and dystonia patients. However, the power distribution of those oscillations differs between diseases. SIGNIFICANCE: This meta-analysis provides high-level evidence which supports the presence of exaggerated oscillations across the parkinsonian/dystonic motor networks.

How typical are 'typical' tremor characteristics? Sensitivity and specificity of five tremor phenomena.

INTRODUCTION: Distinguishing between different tremor disorders can be challenging. Some tremor disorders are thought to have typical tremor characteristics: the current study aims to provide sensitivity and specificity for five 'typical' tremor phenomena. METHODS: Retrospectively, we examined 210 tremor patients referred for electrophysiological recordings between January 2008 and January 2014. The final clinical diagnosis was used as the gold standard. The first step was to determine whether patients met neurophysiological criteria for their type of tremor. Once established, we focused on 'typical' characteristics: tremor frequency decrease upon loading (enhanced physiological tremor (EPT)), amplitude increase upon loading, distractibility and entrainment (functional tremor (FT)), and intention tremor (essential tremor (ET)). The prevalence of these phenomena in the 'typical' group was compared to the whole group. RESULTS: Most patients (87%) concurred with all core clinical neurophysiological criteria for their tremor type. We found a frequency decrease upon loading to be a specific (95%), but not a sensitive (42%) test for EPT. Distractibility and entrainment both scored high on sensitivity (92%, 91%) and specificity (94%, 91%) in FT, whereas a tremor amplitude increase was specific (92%), but not sensitive (22%). Intention tremor was a specific finding in ET (85%), but not a sensitive test (45%). Combination of characteristics improved sensitivity. CONCLUSION: In this study, we retrospectively determined sensitivity and specificity for five 'typical' tremor characteristics. Characteristics proved specific, but few were sensitive. These data on tremor phenomenology will help practicing neurologists to improve distinction between different tremor disorders.

A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity.

AIMS: Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB. METHODS: Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 µg and an optional dose of 100 µg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model. RESULTS: All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 µg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed-effect model. CONCLUSIONS: ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level.

The prevalence of visual hallucinations in non-affective psychosis, and the role of perception and attention.

BACKGROUND: Little is known about visual hallucinations (VH) in psychosis. We investigated the prevalence and the role of bottom-up and top-down processing in VH. The prevailing view is that VH are probably related to altered top-down processing, rather than to distorted bottom-up processing. Conversely, VH in Parkinson's disease are associated with impaired visual perception and attention, as proposed by the Perception and Attention Deficit (PAD) model. Auditory hallucinations (AH) in psychosis, however, are thought to be related to increased attention. METHOD: Our retrospective database study included 1119 patients with non-affective psychosis and 586 controls. The Community Assessment of Psychic Experiences established the VH rate. Scores on visual perception tests [Degraded Facial Affect Recognition (DFAR), Benton Facial Recognition Task] and attention tests [Response Set-shifting Task, Continuous Performance Test-HQ (CPT-HQ)] were compared between 75 VH patients, 706 non-VH patients and 485 non-VH controls. RESULTS: The lifetime VH rate was 37%. The patient groups performed similarly on cognitive tasks; both groups showed worse perception (DFAR) than controls. Non-VH patients showed worse attention (CPT-HQ) than controls, whereas VH patients did not perform differently. CONCLUSIONS: We did not find significant VH-related impairments in bottom-up processing or direct top-down alterations. However, the results suggest a relatively spared attentional performance in VH patients, whereas face perception and processing speed were equally impaired in both patient groups relative to controls. This would match better with the increased attention hypothesis than with the PAD model. Our finding that VH frequently co-occur with AH may support an increased attention-induced 'hallucination proneness'.

A Method for Automatic and Objective Scoring of Bradykinesia Using Orientation Sensors and Classification Algorithms.

Correct assessment of bradykinesia is a key element in the diagnosis and monitoring of Parkinson's disease. Its evaluation is based on a careful assessment of symptoms and it is quantified using rating scales, where the Movement Disorders Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is the gold standard. Regardless of their importance, the bradykinesia-related items show low agreement between different evaluators. In this study, we design an applicable tool that provides an objective quantification of bradykinesia and that evaluates all characteristics described in the MDS-UPDRS. Twenty-five patients with Parkinson's disease performed three of the five bradykinesia-related items of the MDS-UPDRS. Their movements were assessed by four evaluators and were recorded with a nine degrees-of-freedom sensor. Sensor fusion was employed to obtain a 3-D representation of movements. Based on the resulting signals, a set of features related to the characteristics described in the MDS-UPDRS was defined. Feature selection methods were employed to determine the most important features to quantify bradykinesia. The features selected were used to train support vector machine classifiers to obtain an automatic score of the movements of each patient. The best results were obtained when seven features were included in the classifiers. The classification errors for finger tapping, diadochokinesis and toe tapping were 15-16.5%, 9.3-9.8%, and 18.2-20.2% smaller than the average interrater scoring error, respectively. The introduction of objective scoring in the assessment of bradykinesia might eliminate inconsistencies within evaluators and interrater assessment disagreements and might improve the monitoring of movement disorders.

Transcutaneous port for levodopa/carbidopa intestinal gel administration in Parkinson's disease.

OBJECTIVE: To evaluate the safety and tolerability of the T-Port(®) for intestinal infusion of levodopa/carbidopa gel in patients with advanced Parkinson's disease (PD). METHODS: This prospective study was carried out in 24 patients with PD (15 males, mean age 61.8 years, mean duration PD 18.7 years). All adverse device effects were evaluated at 2 weeks, 3 months and 6 months and until explantation or death. RESULTS: Post-operative complications were similar to endoscopic gastrojejunostomy placement (four peritoneal irritation, one pocket pain). Eight patients with prior experience with the endoscopic gastrojejunostomy preferred the T-Port. The total device experience was 83.6 years, and the average survival time was 3.6 (range 1.1-5.2) years. Six T-Ports were still in use, and two patients had died due to non-device-related reasons. Sixteen T-Ports had been explanted due to 15 stoma reactions (14 inflammations and one infection) and one tilting of the T-Port. The T-Ports were replaced with endoscopic gastrojejunostomy system as replacements with T-Ports were not part of the study. Only two device malfunctions occurred (one catheter breakage at 3 year post-implant and one T-Port leakage of levodopa/carbidopa gel). No tube kinking, dislocation or blockage occurred. The number of adverse device effects proved to be significantly lower as compared to the endoscopic gastrojejunostomy literature data. CONCLUSIONS: The T-Port is safe and well tolerated, and the low number of tube problems is a potential advantage compared with the endoscopic gastrojejunostomy system. Proper cleaning and local treatment of the stoma site around the T-Port are essential to prolong its longevity.

Parkinson's patients' executive profile and goals they set for improvement: Why is cognitive rehabilitation not common practice?

Impairments in executive functions (EF) are the core cognitive impairment in patients with Parkinson's disease (PD). Surprisingly, cognitive rehabilitation is not routinely offered to patients with PD. However, in patients with acquired brain injury (ABI), cognitive rehabilitation, in particular strategic executive training, is common practice and has been shown to be effective. In this study, we determined whether PD patients have different needs and aims with regard to strategic executive training than ABI patients, and whether possible differences might be a reason for not offering this kind of cognitive rehabilitation programme to patients with PD. Patients' needs and aims were operationalised by individually set goals, which were classified into domains of EF and daily life. In addition, patients with PD and ABI were compared on their cognitive, in particular EF, profile. Overall, PD patients' goals and cognitive profile were similar to those of patients with ABI. Therefore, based on the findings of this study, there is no reason to assume that strategic executive training cannot be part of standard therapy in PD. However, when strategic executive training is applied in clinical practice, disease-specific characteristics need to be taken into account.

Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson's disease: the LEAP-study.

BACKGROUND: The aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson's disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed. METHODS: To differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson's Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson's Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks. DISCUSSION: The LEAP-study will provide insights into the possible disease modifying effects of early levodopa. TRIAL REGISTRATION: ISRCTN30518857, EudraCT number 2011-000678-72.

Parkinson bradykinesia correlates with EEG background frequency and perceptual forward projection.

BACKGROUND: To deal with processing-time in the nervous system, visuomotor control requires anticipation. An index for such anticipation is provided by the 'flash-lag illusion' in which moving objects are perceived ahead of static objects while actually being in the same place. We investigated the neurophysiological relation between visuomotor anticipation and motor velocity in Parkinson's disease (PD) and controls. METHODS: Motor velocity was assessed by the number of keystrokes in 30s ('kinesia score') and visuomotor anticipation in a behavioural flash-lag paradigm while electroencephalography data was obtained. PD patients (n = 24) were divided in a 'PDslow' and a 'PDfast' group based on kinesia score. RESULTS: The PDslow group had a lower kinesia score than controls (resp. 40.3 ± 1.7 and 64.9 ± 4.6, p < 0.001). The flash-lag illusion was weaker in the PDslow group than in controls (resp. fractions 0.32 ± 0.04 and 0.50 ± 0.09 of the responses indicating perceived lagging, p = 0.03). Furthermore, the magnitude of the flash-lag illusion correlated with the kinesia score (cc = 0.45, p = 0.02). Finally, electroencephalography background frequency was lower in the PDslow group than in controls (resp 8.24 ± 0.24 and 9.1 ± 0.32 Hz, p = 0.01) and background frequency correlated with the kinesia score (cc = 0.58, p = 0.001). CONCLUSIONS: The decreased flash-lag illusion and lower electroencephalography background frequency in more bradykinetic PD patients provides support for disturbed visuomotor anticipations, putatively caused by reduced, sub-cortically mediated, network efficiency. This suggests a link between anticipation in early-stage visual motion processing and motor preparation.

Prolonged use of extracorporeal membrane oxygenation combined with prone positioning in patients with acute respiratory distress syndrome and invasive Aspergillosis.

Extracorporeal membrane oxygenation (ECMO) is increasingly being used in patients with severe acute respiratory distress syndrome. In two large cohorts of such patients, the median duration of treatment with ECMO was 9 and 10 days. We describe two patients, both with H1N1 pneumonia complicated by invasive Aspergillosis, who required ECMO support significantly longer at 45 and 52 days, but eventually made a full recovery. In both patients, prone positioning was used during ECMO treatment.

Turning principles into practice in Alzheimer's disease.

The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer's Disease International (ADI) launched a Global Alzheimer's Disease Charter, which comprises six principles that underscore the urgency for a more ambitious approach to diagnosis, treatment and care. This review highlights some of the most important aspects and challenges of dementia diagnosis and treatment. These issues are reviewed in light of the six principles of the recent ADI Charter: promoting dementia awareness and understanding; respecting human rights; recognizing the key role of families and caregivers; providing access to health and social care; stressing the importance of optimal diagnosis and treatment; and preventing dementia through improvements in public health. The authors continue to hope that, one day, a cure for Alzheimer's disease will be found. Meanwhile, healthcare professionals need to unite in rising to the challenge of managing all cases of dementia, using the tools available to us now to work toward improved patient care.

Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion.

STUDY DESIGN: Pilot study. OBJECTIVE: To study the effect of pulsatile bolus infusion of intrathecal baclofen (ITB) on daily ITB dose, in patients showing dose increases, probably due to tolerance. SETTING: Department of neurology and neurosurgery, University Medical Center Groningen, the Netherlands. METHODS: Data on dosages and clinical efficacy were gathered from four patients who were switched from continuous to pulsatile bolus infusion of ITB, because of the probable diagnosis of tolerance to ITB. RESULTS: Switching from continuous to pulsatile bolus infusion resulted in a decrease of the daily ITB dose, while the clinical effect could be kept stable, without introducing adverse events. CONCLUSION: Pulsatile bolus infusion of ITB seems to be an effective and safe treatment strategy to reverse the need for increasing ITB dosages in patients with the probable diagnosis of tolerance to ITB.