Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer's disease in the context of a structured 5-phase biomarker development framework.

PURPOSE: In 2017, the Geneva Alzheimer's disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. METHODS: The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1-2), clinical validity (phases 3-4), and clinical utility (phase 5). RESULTS: The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. CONCLUSION: Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non)steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3ß level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1ß and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

Health-care providers' perspectives on childhood cancer treatment in Manado, Indonesia.

BACKGROUND: Childhood cancer survival in low-income countries is low. OBJECTIVE: Our study investigated health-care providers' perspectives on childhood cancer treatment in Indonesia. Their health beliefs and attitudes toward parental financial difficulties, protocol adherence, parental education, and communication were explored. METHODS: A self-administered questionnaire was filled in by 222 health-care providers (156 doctors, 51 nurses, 6 social workers, 9 administrators) RESULTS: Health of children with cancer is beyond doctor's control and determined by luck, fate or God according to 35% of health-care providers, 30% were uncertain about this statement, and 35% disagreed. Combination of chemotherapy and alternative treatment is best to achieve cure according to 15% of health-care providers, 50% were uncertain, and 35% disagreed. Prosperous parents adhere better with treatment (67%). Doctors adhere better with cancer treatment for prosperous patients (55%). When dealing with poor families, less elaborate explanation is given (62%), more difficult vocabulary is used (49%), and less cooperation is offered (46%). Reasons for non-adherence with treatment protocol were as follows: financial difficulties parents (82%), side-effects (77%), lack of motivation parents (75%), and inadequate drugs supply at pharmacy (70%). Information about cancer and treatment makes parents more afraid or depressed about future, and parents prefer not to know according to 27% of health-care providers, 20% were uncertain, and 53% disagreed. Communication with parents is hindered by differences in status and social hierarchical structures (83%). CONCLUSIONS: Health-care providers' beliefs about childhood cancer treatment are characterized by much uncertainty and contradiction. This likely affects adherence of health-care providers, parents, and childhood cancer treatment outcome.

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study.

PURPOSE: Alpha-synuclein often co-occurs with Alzheimer's disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. METHODS: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. RESULTS: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stß = 0.72) and category fluency (stß = 0.69) tests. Lower parietal R1 was related to lower delayed (stß = 0.50) and immediate (stß = 0.48) recall, VOSP number location (stß = 0.70) and fragmented letters (stß = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stß = 0.61), all p < 0.05. CONCLUSION: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.

Odor recognition memory is not independently impaired in Parkinson's disease.

The results of previous studies in small groups of Parkinson's disease (PD) patients are inconclusive with regard to the presence of an odor recognition memory impairment in PD. The aim of the present study was to investigate odor recognition memory in PD in a larger group of patients. Odor recognition memory and detection thresholds were assessed using components of the "Sniffin' Sticks" test battery in 55 non-demented PD patients (Hoehn and Yahr stages I-III) and 50 control subjects of comparable age and sex. PD patients performed slightly but significantly worse than control subjects on the odor recognition memory task. After correction for odor detection scores, however, the difference in odor recognition memory performance between PD patients and controls was no longer statistically significant. These data indicate that odor recognition memory is not independently impaired in PD patients.

Slowing of oscillatory brain activity is a stable characteristic of Parkinson's disease without dementia.

Extensive changes in resting-state oscillatory brain activity have recently been demonstrated using magnetoencephalography (MEG) in moderately advanced, non-demented Parkinson's disease patients relative to age-matched controls. The aim of the present study was to determine the onset and evolution of these changes over the disease course and their relationship with clinical parameters. In addition, we evaluated the effects of dopaminomimetics on resting-state oscillatory brain activity in levodopa-treated patients. MEG background oscillatory activity was studied in a group of 70 Parkinson's disease patients with varying disease duration and severity (including 18 de novo patients) as well as in 21 controls that were age-matched to the de novo patients. Whole head 151-channel MEG recordings were obtained in an eyes-closed resting-state condition. Levodopa-treated patients (N = 37) were examined both in a practically defined 'OFF' as well as in the 'ON' state. Relative spectral power was calculated for delta, theta, low alpha, high alpha, beta and gamma frequency bands and averaged for 10 cortical regions of interest (ROIs). Additionally, extensive clinical and neuropsychological testing was performed in all subjects. De novo Parkinson's disease patients showed widespread slowing of background MEG activity relative to controls. Changes included a widespread increase in theta and low alpha power, as well as a loss of beta power over all but the frontal ROIs and a loss of gamma power over all but the right occipital ROI. Neuropsychological assessment revealed abnormal perseveration in de novo patients, which was associated with increased low alpha power in centroparietal ROIs. In the whole group of Parkinson's disease patients, longer disease duration was associated with reduced low alpha power in the right temporal and right occipital ROI, but not with any other spectral power measure. No association was found between spectral power and disease stage, disease severity or dose of dopaminomimetics. In patients on levodopa therapy, a change from the 'OFF' to the 'ON' state was associated with decreases in right frontal theta, left occipital beta and left temporal gamma power and an increase in right parietal gamma power. Widespread slowing of oscillatory brain activity is a characteristic of non-demented Parkinson's disease patients from the earliest clinical stages onwards that is (largely) independent of disease duration, stage and severity and hardly influenced by dopaminomimetic treatment. Some early cognitive deficits in Parkinson's disease appear to be associated with increased low alpha power. We postulate a role for hypofunctional non-dopaminergic ascending neurotransmitter systems in spectral power changes in non-demented Parkinson's disease patients.

Observations on the cortical silent period in Parkinson's disease.

Transcranial magnetic stimulation is a tool in the neurosciences to study motor functions and nervous disorders, amongst others. Single pulses of TMS applied over the primary motor cortex lead to a so-called cortical silent period in the recording from the corresponding muscle, i.e. a period of approximately 100ms with no muscle activity. We here show that in Parkinson's disease (PD), this cortical silent period in some cases is interrupted by short bursts of EMG activity. We describe in detail these interruptions in two patients with PD. These interruptions may number up to 3 per cortical silent period and show a consistent frequency across trials and hemispheres within a given patient; the two patients described here do differ, however, in the time-delay of the interruptions and hence the induced frequency. For one patient, the frequency of the interruptions proved to be around 13 Hz, the other patient showed a frequency of around 17 Hz. The results corroborate earlier findings of cortical oscillations elicited by pulses of TMS and may be related to abnormal oscillatory activity found in the cortical-subcortical motor system in PD.

First case of ataxia with isolated vitamin E deficiency in the Netherlands.

We present a 36-year-old Dutch woman who suffered from a progressive form of cerebellar ataxia since school age. In her childhood she was diagnosed with Friedreich's ataxia. Genetic analysis of the frataxin gene at 34 years of age, however, had revealed no abnormal GAA triplet expansion. We identified two point mutations in the alpha-tocopherol transport protein (alpha-TTP) gene on chromosome 8q13, and the diagnosis ataxia with isolated vitamin E deficiency (AVED) was made. This report illustrates the diagnosis AVED and its relation to vitamin E metabolism. It is important to evaluate previously made diagnoses when newly developed tests can be performed for confirmation.

Resting state oscillatory brain dynamics in Parkinson's disease: an MEG study.

OBJECTIVE: The pathophysiological mechanisms of cognitive dysfunction and dementia in Parkinson's disease (PD) are still poorly understood. Altered resting state oscillatory brain activity may reflect underlying neuropathological changes. The present study using magneto encephalography (MEG) was set up to study differences in the pattern of resting state oscillatory brain activity in groups of demented and non-demented PD patients and healthy, elderly controls. METHODS: The pattern of MEG background oscillatory activity was studied in 13 demented PD patients, 13 non-demented PD patients and 13 healthy controls. Whole head MEG recordings were obtained in the morning in an eyes closed and an eyes open, resting state condition. Relative spectral power was calculated using Fast Fourier Transformation in delta, theta, alpha, beta and gamma frequency bands. RESULTS: In the non-demented PD patients, relative theta power was diffusely increased and beta power concomitantly decreased relative to controls. gamma Power was decreased in central and parietal channels. In the demented PD patients, a diffuse increase in relative delta and to lesser extent theta power and a decrease in relative alpha, beta and to lesser extent gamma power were found in comparison to the non-demented PD group. In addition, reactivity to eye opening was much reduced in the demented PD group. CONCLUSIONS: Parkinson's disease is characterized by a slowing of resting state brain activity involving theta, beta and gamma frequency bands. Dementia in PD is associated with a further slowing of resting state brain activity, additionally involving delta and alpha bands, as well as a reduction in reactivity to eye-opening. SIGNIFICANCE: The differential patterns of slowing of resting state brain activity in demented and non-demented PD patients suggests that, in conjunction with a progression of the pathological changes already present in non-demented patients, additional mechanisms are involved in the development of dementia in PD.

The effect of rhythmic somatosensory cueing on gait in patients with Parkinson's disease.

BACKGROUND AND AIMS: Gait and gait related activities in patients with Parkinson's disease (PD) can be improved with rhythmic auditory cueing (e.g. a metronome). In the context of a large European study, a portable prototype cueing device was developed to provide an alternative for rhythmic auditory cueing: rhythmic somatosensory cueing (RSC, a miniature vibrating cylinder attached to the wrist). We investigated whether PD patients could adapt their walking pattern using RSC under conditions of changing walking speed and the presence of potentially distracting visual flow while walking on a treadmill. METHODS: A total of 17 patients with PD participated (mean age 63.4+/-10.3 years; Hoehn-Yahr score 2.5+/-0.9, mean Unified Parkinson's Disease Rating Scale score 49.8+/-13.7, mean disease duration 7.7+/-5.1 years). They performed systematic walking speed manipulations under 4 conditions in a random order: (1) no cue, no visual flow, (2) no cue, visual flow, (3) cue, no visual flow and (4) cue, visual flow. Visual flow in the form of a virtual corridor that moved at the current walking speed was projected on a 2 x 2 m rear-projection screen. The cueing rhythm was set at -10% of preferred stride frequency at each speed. Stride frequency was assessed using peaks in the trajectories of thigh sagittal plane segmental angles. RESULTS: Walking with RSC resulted in lower stride frequencies, and thus larger step lengths (p-values <0.05), regardless of walking speed. The presence of visual flow did not impair the use of RSC, as evidenced by the lack of differences between conditions 3 and 4 (p>0.05). CONCLUSION: Rhythmic somatosensory cueing may be a viable alternative for auditory cueing and is robust to changes in walking speed and visual distractors.

PD-related psychosis: pathophysiology with therapeutical strategies.

Parkinson's disease (PD) is a chronic, neurodegenerative disease with degeneration of the central dopaminergic neurons in the substantia nigra, leading to a depletion of dopamine (DA) in the striatum. This depletion causes the clinical hallmarks of this disease: bradykinesia, hypokinesia, rigidity, tremor and postural instability. Besides these well known motor symptoms, non-motor symptoms may develop, such as hyposmia, sleep disorders, autonomic disturbances, depression, cognitive impairment and psychosis. Pathophysiological mechanisms underlying these symptoms not only comprise Lewy body pathology in the central dopaminergic system, but also in the noradrenergic, serotinergic and cholinergic transmittersystems. Indeed, in Parkinson's disease, about 30-40% of the patients suffers fluctuating psychotic symptoms, mainly paranoid delusions and/or visual or acoustic hallucinations, symptoms considered to represent major contributors to patient and caregiver distress and nursing home placement. Endogenous (related to the disease process itself) as well as exogenous (related to therapeutical interventions) psychotogenic factors may contribute to the development of psychotic symptoms in PD. Therapeutical strategies, therefore, are aimed to reduce both endogenous and exogenous factors. To reduce endogenous psychotogenic factors, cholinesterase inhibitors, suggested to reduce cognitive deterioration, now seem to be the drugs of choice. In exogenously induced psychotic symptoms, atypical antipsychotics are considered the most effective. However, as psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of both strategies may be preferred.

Parkinson's disease: premotor clinico-pathological correlations.

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/ akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson's disease (PD). Progressive loss of nigral neurons with Lewy bodies is considered an essential neuropathological feature. Recent studies, however, indicate that nigral degeneration is only a part of this synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, autonomic dysfunction, pain, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms suggests multiple causes and/or pathogeneses within the present diagnostic disease entity. In this article, a recently proposed staging of PD-related brain pathology will be correlated with the various clinical expressions. It will be argued that the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites, may explain the individually variable expression of this disease.

The effects of visual rhythms and optic flow on stride patterns of patients with Parkinson's disease.

This study was aimed at determining the effects of rhythmic visual cueing under changing visual conditions on stride frequency in patients with Parkinson's disease (PD; n = 21) and healthy age matched controls (n = 7) while walking at different speeds on a treadmill. Stride frequency and stride length in patients with PD as well as controls were not rigidly coupled to walking speed and could be manipulated with walking speed as well as by using spatial and temporal rhythmic visual cues.

Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Standard therapeutic interventions are aimed at replenishment of empty dopamine stores with levodopa or substitution with dopamine receptor agonists. However, in the long term this symptomatic therapy fails. Currently, various neuroprotective agents are being developed, with the intention to slow down the degeneration of dopaminergic neurons. In this context, the early identification of persons at risk to develop the disease as well as the assessment of the effectiveness of putative neuroprotective agents, are critical issues. Dopamine transporter (DAT) scintigraphy with single photon emission computed tomography (SPECT) has been used to assess the dopaminergic function in PD. Initial studies with several radioligands show significant loss of DAT binding in PD patients as compared to controls. In this paper we review the evidence on the utility of DAT imaging with SPECT in early PD detection as well as in monitoring neurprotection.

Chronic manganese intoxication.

We report six cases of chronic manganese intoxication in workers at a ferromanganese factory in Taiwan. Diagnosis was confirmed by assessing increased manganese concentrations in the blood, scalp, and pubic hair. In addition, increased manganese levels in the environmental air were established. The patients showed a bradykinetic-rigid syndrome indistinguishable from Parkinson's disease that responded to treatment with levodopa.

Multiple system atrophy and progressive supranuclear palsy. Diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM single photon emission computed tomography.

OBJECTIVE: To measure D2 dopamine receptors in the striatum in patients with multiple system atrophy and progressive supranuclear palsy by I 3-iodo-6-methoxybenzamide labeled with iodine I 123 (123I-IBZM) single photon emission computed tomography and differentiate them from control subjects. DESIGN: Survey with the following as retrospective criterion standards: (1) parkinsonism, (2) negative apomorphine test, and (3) no or only slight reaction to dopaminergic medication. SETTING: Ambulatory or hospitalized care in an academic referral center. PATIENTS AND CONTROL SUBJECTS: Twenty-one patients with parkinsonism not responding to dopaminergic medication (17 with multiple system atrophy and four with progressive supranuclear palsy) and 21 control subjects without parkinsonism. INTERVENTION: In vivo imaging by single photon emission computed tomography using the D2 dopamine receptor specific radioligand 123I-IBZM. MAIN OUTCOME MEASURE: Striatum/occipital cortex ratio of count rate density as semiquantitative measurement for striatal D2 dopamine receptor density. RESULTS: A highly significant loss of striatal uptake of 123I-IBZM was observed in the patients in comparison to the control subjects with little or no overlap between values. CONCLUSIONS: The hypothesized loss of D2 receptors in multiple system atrophy has been confirmed. Use of 123I-IBZM single photon emission computed tomography may be a cost-effective alternative to positron emission tomography in the differential diagnosis of parkinsonism and in the selection of patients for dopaminergic therapy.

Dopaminomimetic psychosis in Parkinson's disease patients: diagnosis and treatment.

Dopaminomimetic agents, which were rationally designed to reverse dopamine deficits in the substantia nigra and ventral tegmental area of the parkinsonian midbrain, effectively attenuate deficits in motor and non-motor behavior thought to be elicited by dopamine deficiencies in the striatal and frontal limbic regions, respectively. On the other hand, dopaminomimetic medications may also induce perturbations in postsynaptic peptides, causing dopaminergic hypersensitivity. Drug-induced chronic dopaminomimetic psychosis afflicts about one-fifth of PD patients on dopaminergic regimens. Although the long-held mechanism for psychosis in PD is excessive stimulation of mesocorticolimbic dopamine receptors, interactions between dopamine and serotonin, as well as participation of serotonin-modulated GABAergic neurons may also contribute to the pathophysiology. Reduction or withdrawal of anticholinergic agents, amantadine, and dopamine precursors or agonists constitutes a first approach to the problem but is often insufficient. Unfortunately, typical antipsychotic agents such as haloperidol, which selectively antagonizes dopamine D-2 receptors, can induce extrapyramidal syndromes such as tardive parkinsonism. On the other hand, emerging atypical neuroleptics such as clozapine, quetiapine, and olanzapine, which antagonize 5HT-2A receptors (among others), inhibit D-2 receptors to a lesser degree and exhibit selective binding to mesolimbic (vs. striatal) dopamine receptors. The limbic selectivity of these agents appears to be of greater magnitude than that typical of risperidone. In addition, the selective antiserotonergic agent ondansetron is a prospective therapeutic option. The pharmacologic properties of these agents are explored.

Penicillin concentrations in serum and CSF during high-dose intravenous treatment for neurosyphilis.

Eight neurosyphilitic patients (two asymptomatic, six symptomatic) were treated with intravenously administered aqueous penicillin G, 0.15 million IU/kg body weight/24 hrs for 15 days. On the 8th day of treatment, penicillin concentrations were determined in serum and CSF samples collected at hourly intervals over a period of 8 hours, using a microbiological assay method. Serum concentrations ranged from 0.26 to 100 mg/l, while CSF concentrations ranged from 0.062 to 3.0 mg/l. These results indicate that, by ensuring penicillin concentrations in CSF, which are continuously above the minimal fully treponemicidal concentration during the course of treatment, this treatment regimen should provide an adequate therapy for asymptomatic and symptomatic neurosyphilis.

Effect of corticosteroids on sciatic nerve-tibialis anterior muscle of rats treated with hemicholinium-3. An experimental approach to a possible mechanism of action of corticosteroids in myasthenia gravis.

We studied the effect of intraperitoneally administered corticosteroids on the neuromuscular transmission in the sciatic nerve-tibialis anterior muscle preparation of the anesthetized rat stimulated at a rate of 10 Hz. Administered simultaneously with hemicholinium-3 (HC-3), 80 mug per kilogram (that is, half the lethal dose for 50 percent survival), prednisolone and dexamethasone cause a marked reversal of the block of the neuromuscular transmission caused by HC-3. The effect of aldosterone is very small. The blocking action of d-tubocurarine is not antagonized by either prednisolone or dexamethasone. Choline provides total protection against the HC-3 blockade, whereas physostigmine, in a just sublethal dose, is ineffective. We tentatively conclude that in myasthenia gravis the carrier-mediated transport of choline into the nerve endings may be deficient and that the beneficial effect of corticosteroids in this condition is based on their ability to ameliorate the deficient choline transport.

Motor perseveration is an early sign of Parkinson's disease.

Perseveration in the generation of random motor behavior was examined by means of the Vienna perseverance task in groups of de novo (n = 18) and treated (n = 18) patients with early PD, and in control subjects (n = 18). In comparison with control subjects, both the de novo and treated patients with PD were relatively unable to generate random motor sequences, indicating a decreased ability to switch cortical behavioral programs in PD. An impairment of random motor generation appears to be a very early feature of PD.