Molecular and behavioural abnormalities in the FUS-tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti-inflammatory therapies.

Genetic mutations in FUS, a DNA/RNA-binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1-359]-tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1-359]-tg mouse displays behavioural and brain pro-inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre-symptomatic FUS[1-359]-tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD-like syndrome. FTLD-related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre-symptomatic FUS[1-359]-tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS-like syndrome in the mutants. We used anti-ALS drug riluzole (8 mg/kg/d), or anti-inflammatory drug, a selective blocker of cyclooxygenase-2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro-Cells, 500 000-CD34+ ), which showed anti-inflammatory properties. Signs of elevated anxiety, depressive-like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS-tg-treated animals. Applied treatments have normalized protein expression of interleukin-1ß (IL-1ß) in the prefrontal cortex and the hippocampus, and of Iba-1 and GSK-3ß in the hippocampus. Thus, the pre-symptomatic FUS[1-359]-tg mice demonstrate FTLD-like abnormalities that are attenuated by standard and new ALS treatments, including Neuro-Cell preparation.

Treatment of rats with spinal cord injury using human bone marrow-derived stromal cells prepared by negative selection.

BACKGROUND: Spinal cord injury (SCI) is a highly debilitating pathology without curative treatment. One of the most promising disease modifying strategies consists in the implantation of stem cells to reduce inflammation and promote neural regeneration. In the present study we tested a new human bone marrow-derived stromal cell preparation (bmSC) as a therapy of SCI. METHODS: Spinal cord contusion injury was induced in adult male rats at thoracic level T9/T10 using the Infinite Horizon impactor. One hour after lesion the animals were treated with a sub-occipital injection of human bmSC into the cisterna magna. No immune suppression was used. One dose of bmSC consisted, on average, of 2.3 million non-manipulated cells in 100 µL suspension, which was processed out of fresh human bone marrow from the iliac crest of healthy volunteers. Treatment efficacy was compared with intraperitoneal injections of methylprednisolone (MP) and saline. The recovery of motor functions was assessed during a surveillance period of nine weeks. Adverse events as well as general health, weight and urodynamic functions were monitored daily. After this time, the animals were perfused, and the spinal cord tissue was investigated histologically. RESULTS: Rats treated with bmSC did not reject the human implants and showed no sign of sickness behavior or neuropathic pain. Compared to MP treatment, animals displayed better recovery of their SCI-induced motor deficits. There were no significant differences in the recovery of bladder control between groups. Histological analysis at ten weeks after SCI revealed no differences in tissue sparing and astrogliosis, however, bmSC treatment was accompanied with reduced axonal degeneration in the dorsal ascending fiber tracts, lower Iba1-immunoreactivity (IR) close to the lesion site and reduced apoptosis in the ventral grey matter. Neuroinflammation, as evidenced by CD68-IR, was significantly reduced in the MP-treated group. CONCLUSIONS: Human bmSC that were prepared by negative selection without expansion in culture have neuroprotective properties after SCI. Given the effect size on motor function, implantation in the acute phase was not sufficient to induce spinal cord repair. Due to their immune modulatory properties, allogeneic implants of bmSC can be used in combinatorial therapies of SCI.

70th Birthday symposium of Prof. Dr. Riederer: autologous adult stem cells in ischemic and traumatic CNS disorders.

Ischemic and traumatic insults of the central nervous system both result in definite chronic disability, only to some extent responsive to rehabilitation. Recently, the application of autologous stem cells (fresh bone marrow-derived mononuclear cells including mesenchymal and hematopoietic stem cells) was suggested to provide a strategy to further improve neurological recovery in these disorders. During the acute phase, stem cells act mainly by neuroprotection with prevention of apoptosis, whereas during the chronic situation they provide neurorestoration by transdifferentiation and/or the secretion of neurotrophic factors. To reach these goals, in the acute phase, stem cells (10 million mononuclear cells per kg body weight) might be best applied intravenously, as during the first 7 days after the lesion, the blood-brain barrier permits passage of cells from the blood into the brain or the spinal cord. In the more chronic situation, though, those cells might be applied best intrathecally by lumbar puncture. Based on the reported results so far, it seems justified to develop well-designed clinical double-blind trials in chronic spinal cord injury and ischemic stroke patients, as efficacy and safety concerns might not be answered by preclinical studies.

Autologous stem cells in neurology: is there a future?

Stem cells seem very promising in the treatment of degenerative neurological diseases for which there are currently no or limited therapeutic strategies. However, their clinical application meets many regulatory hurdles. This article gives an overview of stem cells, their potential healing capacities as well as their identified and potential risks, such as tumor formation, unwanted immune responses and the transmission of adventitious agents. As there is no clinical experience with embryonic and induced pluripotent stem cells (as the result of their unacceptable risk on tumor formation), most attention will be paid to fresh autologous adult stem cells (ASCs). To evaluate eventual clinical benefits, preclinical studies are essential, though their value is limited as in these studies, various types of stem cells, with different histories of procurement and culturing, are applied in various concentrations by various routes of administration. On top of that, in most animal studies allogenic human, thus non-autologous, stem cells are applied, which might mask the real effects. More reliable, though small-sized, clinical trials with autologous ASCs did show satisfying clinical benefits in regenerative medicine, without major health concerns. One should wonder, though, why it is so hard to get compelling evidence for the healing and renewing capacities of these stem cells when these cells indeed are really essential for tissue repair during life. Why so many hurdles have to be taken before health authorities such as the European Medicine Agency (EMA) and/or the Food and Drug Administration (FDA) approve stem cells in the treatment of (especially no-option) patients.

Tauroursodeoxycholic Acid Reduces Neuroinflammation but Does Not Support Long Term Functional Recovery of Rats with Spinal Cord Injury.

The bile acid tauroursodeoxycholic acid (TUDCA) reduces cell death under oxidative stress and inflammation. Implants of bone marrow-derived stromal cells (bmSC) are currently under investigation in clinical trials of spinal cord injury (SCI). Since cell death of injected bmSC limits the efficacy of this treatment, the cytoprotective effect of TUDCA may enhance its benefit. We therefore studied the therapeutic effect of TUDCA and its use as a combinatorial treatment with human bmSC in a rat model of SCI. A spinal cord contusion injury was induced at thoracic level T9. Treatment consisted of i.p. injections of TUDCA alone or in combination with one injection of human bmSC into the cisterna magna. The recovery of motor functions was assessed during a surveillance period of six weeks. Biochemical and histological analysis of spinal cord tissue confirmed the anti-inflammatory activity of TUDCA. Treatment improved the recovery of autonomic bladder control and had a positive effect on motor functions in the subacute phase, however, benefits were only transient, such that no significant differences between vehicle and TUDCA-treated animals were observed 1-6 weeks after the lesion. Combinatorial treatment with TUDCA and bmSC failed to have an additional effect compared to treatment with bmSC only. Our data do not support the use of TUDCA as a treatment of SCI.

Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson's disease.

Objective Olfactory dysfunction is an early and common symptom in Parkinson disease (PD). Previously, the authors demonstrated that idiopathic olfactory dysfunction in first-degree relatives of PD patients is associated with an increased risk of developing PD within 2 years. The aim of the present study was to determine the value of combined olfactory testing and SPECT scanning in predicting future PD in the same population of relatives over a 5-year period. Methods In a cohort of 361 non-parkinsonian, non-demented first-degree relatives of PD patients, a combination of olfactory processing tasks was used to select groups of hyposmic (n=40) and normosmic (n=38) individuals for a 5-year clinical follow-up evaluation and sequential SPECT scanning, using a dopamine transporter ligand to assess nigrostriatal dopaminergic function at baseline and 5 years from baseline. A validated questionnaire, sensitive to the presence of parkinsonism, was used in the follow-up of the remaining 283 relatives. Results Five years from baseline, five out of the 40 hyposmic relatives fulfilled clinical diagnostic criteria for PD. None of the other 349 relatives available for follow-up developed PD. All hyposmic individuals developing PD had an abnormal baseline SPECT scan. Discussion In conclusion, idiopathic hyposmia in first-degree relatives of PD patients is associated with an increased risk of developing clinical PD of 12.5% over a 5-year period. The present data suggest that a two-step approach using olfactory testing followed by SPECT scanning in hyposmic individuals has a very high sensitivity and specificity in detecting PD. The usefulness of this two-step approach needs to be confirmed in larger populations.

Neuro-Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice.

AIMS: Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants. METHODS: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39 × 106 mesenchymal and hemopoietic human stem cells, containing 5 × 105 of CD34+ cells), which showed anti-inflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle. RESULTS: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Cell-treated mutants had reduced muscle atrophy and lumbar motor neuron degeneration. This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3ß (GSK-3ß). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group. CONCLUSION: The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation.

Hyposmia and executive dysfunction as predictors of future Parkinson's disease: a prospective study.

Olfactory deficits and executive dysfunction are early and common symptoms in Parkinson's disease (PD). Previous studies have shown that hyposmia can be a first sign of PD. The aim of the present study was to determine which of three olfactory tests and two selected tests of executive function would be the best predictor of future PD over a 5 year period. In a cohort of 361 nonparkinsonian, nondemented first-degree relatives of PD patients, in whom alternative causes of olfactory dysfunction were excluded, we measured baseline performance on three olfactory and two executive function tasks. Five years from baseline, clinical neurological evaluation and/or a screening questionnaire, sensitive to the presence of Parkinsonism, were used to detect individuals developing clinical PD. Our results show that in first degree relatives of PD patients worse performance on each of three olfactory processing tasks was associated with an increased risk of developing PD within 5 years, whereas performance on selected tests of executive dysfunction was not associated with an increased risk of developing PD. Interestingly, impaired odor discrimination was the best predictor for future PD.

Extended testing across, not within, tasks raises diagnostic accuracy of smell testing in Parkinson's disease.

The aim of this study was to determine whether extended olfactory testing within a single olfactory task and/or across olfactory tasks increases diagnostic accuracy of olfactory testing in Parkinson's disease (PD). Olfactory function was assessed using an extended version of the "Sniffin' Sticks", comprising 32-item odor identification and discrimination tasks, and a detection threshold task in 52 PD patients and 50 controls, all aged between 49 and 78 years. ROC curves based on sensitivity and specificity estimates were used to compare the diagnostic accuracy of extended and combined olfactory testing. There was no significant difference in diagnostic accuracy between the 16-item and the 32-item versions of the odor identification or discrimination test. The single olfactory test that was best in discriminating between PD patients and controls was a 16-item odor identification test. A combination of the 16-item identification test and the detection threshold task had a significantly higher area under the curve than the 16-item odor identification test alone. In conclusion, extended testing across, and not within, olfactory tasks increases diagnostic accuracy of olfactory testing in PD. A combination of an odor detection threshold task and a 16-item odor identification test had the highest sensitivity and specificity in distinguishing between PD patients and controls.

Effects of rivastigmine on tremor and other motor symptoms in patients with Parkinson's disease dementia: a retrospective analysis of a double-blind trial and an open-label extension.

BACKGROUND AND AIM: Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson's disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson's disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD. METHODS: The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine. RESULTS: During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson's Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worsening parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Post-hoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study. CONCLUSION: Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.

Variability in the clinical expression of Parkinson's disease.

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson's disease (PD). Symptoms of PD are due to a progressive loss of nigral neurons causing striatal dopaminergic denervation. However, nigral degeneration is only a part of the underlying synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, fatigue, pain, autonomic dysfunction, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms, as discussed in this paper, might be explained by the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites. Better insight in the clinicopathological correlations of this disease may help to further develop early diagnosis and adequate therapeutic strategies.

Management of non-motor symptoms in advanced Parkinson disease.

Progress in pharmacology has markedly improved the treatment of early Parkinson's disease. The management of advanced Parkinson's symptoms, however, remains a challenge. These symptoms are divided into motor and non-motor symptoms. Non-motor symptoms may appear early or late in the disease and sometimes even before the onset of the first motor symptoms confirming the diagnosis. The spectrum of non-motor symptoms encompasses autonomic dysfunctions, sleep disorders, mood disorders, impulse control disorders, cognitive dysfunction, dementia, paranoia and hallucinations. They are often less appreciated than motor symptoms but are important sources of disability for many PD patients. This review describes these non-motor symptoms and their managements.

Impairment of complex upper limb motor function in de novo Parkinson's disease.

The aim of the present study was to evaluate complex upper limb motor function in newly diagnosed, untreated Parkinson's disease (PD) patients. Four different unimanual upper limb motor tasks were applied to 13 newly diagnosed, untreated PD patients and 13 age- and sex-matched controls. In a handwriting task, PD patients had significantly reduced sentence length and writing velocity, and decreasing letter height in the course of writing. Furthermore, PD patients performed an aiming task slower with than without target, and showed increased transposition in a pointing task. The results of this study extend previous observations of impaired complex upper limb movements to newly diagnosed, untreated PD patients.

Case studies in the advancement of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disease following Alzheimer's disease. As there is no biomarker or diagnostic test available for the diagnosis of Parkinson's disease, diagnosis of this disorder can be challenging. Parkinson's disease symptoms include both motor and non-motor symptoms. Non-motor symptoms may require special attention, such as the impulse control disorders that can be devastating to patients and their families. This Expert Review Supplement presents three cases that illustrate different aspects of Parkinson's disease, including diagnosis, non-motor symptoms, and treatment.

Managing Parkinson's disease with continuous dopaminergic stimulation.

The pathophysiology of Parkinson's disease is marked by the loss of dopaminergic neurons, which leads to striatal dopaminergic deficiency. This causes resting tremor, hypokinesia, rigidity, bradykinesia, and loss of postural reflexes. Most current treatments for Parkinson's disease aim to restore striatal dopamine signaling by increasing the supply of dopamine with oral levodopa (L-dopa), stimulating dopamine receptors directly using dopamine agonists, or inhibiting the reuptake of endogenous dopamine. L-dopa is standard therapy for patients with Parkinson's disease. However, with continued treatment and disease progression, the response to oral dopaminergic drugs becomes unstable and motor fluctuations emerge, including off periods and dyskinesia. Direct duodenal-administered infusible L-dopa/carbidopa is effective for the management of refractory motor fluctuations in some patient populations. However, enteral infusions cannot mimic the function of the normal dopaminergic brain, and around-the-clock constant-rate administration carries the risk of causing refractory off periods associated with severe immobility and hyperpyrexia. Subthalamic nucleus (STN) deep brain stimulation (DBS) is also a promising treatment. DBS passes a high-frequency electrical current into the target area, mimicking the effect of lesioning the stimulated area. However, this treatment requires invasive surgery and is appropriate for a limited segment of the patient population. This supplement provides a rationale for the use of continuous dopaminergic receptor stimulation and offers guidelines on the individualization of treatment decisions, with special focus on continuous L-dopa infusion and STN DBS. Erik Wolters, MD, PhD, offers an introduction to the impact of continuous L-dopa infusion. Andrew J. Lees, MD, FRCP, provides an overview of the physiologic response to L-dopa and reviews clinical pharmacologic studies of intravenous and intraduodenal L-dopa. Jens Volkmann, MD, discusses selection criteria for STN DBS and duodenal L-dopa/carbidopa infusion. Teus van Laar, MD, PhD, and Ad Hovestadt, MD, discuss the first data from a Dutch cohort study of duodenal L-dopa/carbidopa.

Rivastigmine for dementia associated with Parkinson's disease.

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.

Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease.

Patients receiving oral levodopa, the standard treatment for Parkinson's disease (PD), eventually develop motor fluctuations and dyskinesias. Treatment options for patients with these symptoms include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous dopaminergic stimulation (CDS). STN-DBS is the prevalent surgical therapy for PD and has shown efficacy, but behavioural disorders, including cognitive problems, depression and suicidality have been reported. CDS can be achieved with oral dopamine agonists with a long half-life, transdermal or subcutaneous delivery of dopamine agonists, or intestinal levodopa infusion. Of these, duodenal levodopa infusion appears to be the most promising option in terms of both efficacy and safety.

Abnormal susceptibility to distracters hinders perception in early stage Parkinson's disease: a controlled study.

BACKGROUND: One of the perceptual abnormalities observed in Parkinson's disease (PD) is a deficit in the suppression of reflexive saccades that are automatically triggered by the onset of a peripheral target. Impairment of substantia nigra function is thought to lead to this reduced ability to suppress reflexive saccades. METHODS: The present study examined whether this perceptual deficit is also present in early stage PD when using hardly noticeable task-irrelevant stimuli. Eleven non-demented de novo, untreated PD patients (mean age 57 yr, range 44-70) participated in the study as well as 12 age-matched controls. Performance on an 'oculomotor capture' task, in which in half of the trials an irrelevant stimulus with sudden onset was added to the display, was compared between patients and controls. Analysis of variance (ANOVA) was performed with group (patients/controls) and age (< 61 yrs/> or = 61 yrs) as independent factors and type of trial (control/distracter) as repeated measurements factor. The factor sex was used as covariate. RESULTS: With respect to Reaction Time (RT), a significant interaction between group and condition was found. RTs increased under the 'irrelevant stimulus' condition in both groups, the patients exhibiting a significantly larger increase in RTs than the control group. Also, a significant interaction effect between group and condition for number of correct responses was found. The number of correct responses was reduced in the onset distracter condition, the reduction being larger in the patients. In the patient group, contrary to the control group, a higher age was associated with fewer correct responses at baseline and in the onset distracter condition, suggesting that perceptual functions in PD are highly susceptible to the effects of ageing. The increased reaction times and larger number of incorrect responses of the PD patients in the onset distracter condition may be related to impairments of substantia nigra function and lower brain stem. CONCLUSION: The capture task seems to be a sensitive instrument to detect early perceptual deficits in PD. The magnitude of the observed deficits suggests that perceptual functions in early stage PD are so substantially impaired that this may interfere with daily activities.

Bimanual coordination dysfunction in early, untreated Parkinson's disease.

Bimanual coordination involves the simultaneous performance of either symmetrical (in-phase) or asymmetrical (anti-phase) movements with both hands and is known to be impaired in Parkinson's disease (PD). At present, it is unclear whether this aspect of motor function is already impaired in early stage, untreated PD patients. Therefore, we investigated the accuracy of bimanual coordination in 13 early stage, untreated PD patients and 13 age- and sex-matched healthy controls. Each subject performed bimanual coordination tasks at two different movement frequencies (1 and 1.75 Hz) and with two different phase relationships (in-phase and anti-phase). The percentage of unsuccessful trials (as a measure of overall task performance) in PD patients was significantly higher than in healthy subjects. PD patients performed high frequency in-phase and anti-phase bimanual coordination tasks less accurately with their non-dominant hand than healthy subjects. Furthermore, PD patients had more difficulty than healthy subjects in maintaining a constant phase relationship between the hands in the anti-phase condition at low movement frequency. This study demonstrates that bimanual coordination dysfunction is a very early sign of PD. Bimanual coordination tasks, in particular those involving high frequency anti-phase movements, might prove useful in the early diagnosis of PD.

Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging.

Rotenone has been reported to induce various degrees of Parkinsonism in rats. We tested whether advancing age alters the sensitivity of dopaminergic neurons to rotenone. A low, systemic dose of rotenone had no effect on young rats, but led to a 20-30% reduction of tyrosine hydroxylase-positive neurons in the substantia nigra of older rats. The effect was specific to nigral dopaminergic neurons and may be associated with the increase of glial cell activation in older rats. These data suggest that age enhances the sensitivity of dopaminergic neurons to rotenone and should be considered when assessing models of Parkinson's disease.