[Show abstract][Hide abstract] ABSTRACT: (-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [(11)C]raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at Tmax. Parametric images of [(11)C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [(11)C]raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 μM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 μM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.Neuropsychopharmacology advance online publication, 24 September 2014; doi:10.1038/npp.2014.195.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2014; 40(2). DOI:10.1038/npp.2014.195 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) related dementia (PDD) develops in up to 80% of PD patients. The present study was performed to further unravel the underlying pathophysiological mechanisms by applying a new analysis approach that uses an atlas-based MEG beamformer to provide a detailed anatomical mapping of cortical rhythms and functional interactions. Importantly, we used the phase lag index (PLI) as a measure of functional connectivity to avoid any biases due to effects of volume conduction.
MEG recordings were obtained in 13 PDD and 13 non-demented PD patients. Beamforming was used to estimate spectral power and PLI in delta, theta, alpha, beta and gamma frequency bands. Compared to PD patients, PDD patients had more delta and theta power in parieto-occipital and fronto-parietal areas, respectively. The PDD patients had less alpha and beta power in parieto-temporo-occipital and frontal areas, respectively. Compared to PD patients, PDD patients had lower mean PLI values in the delta and alpha bands in fronto-temporal and parieto-temporo-occipital areas, respectively. In addition, in PDD patients connectivity between pairs of regions of interest (Brodmann areas) was stronger in the theta band and weaker in the delta, alpha and beta bands.
The added value of the present results over previous studies analysing frequency-specific changes in neuronal activity in PD patients, is the anatomical framework in which we demonstrated a slowing in neuronal activity and a reduction in functional connectivity in PD related dementia. Moreover, this study shows a widespread reduction in functional connectivity between different regions in PDD.
[Show abstract][Hide abstract] ABSTRACT: Extranigral neuropathological changes may precede the degeneration of nigrostriatal dopaminergic neurones in Parkinson's disease (PD). Therefore, non-motor disturbances are an interesting target for the development of tests aimed at identifying individuals with premotor PD. An impaired sense of smell occurs with high prevalence in the clinical motor stages of PD patients and has also been reported in first-degree relatives of PD patients. In a prospective study in 361 asymptomatic first-degree relatives of PD patients, we studied the value of a two-step approach, combining olfactory testing and dopamine transporter (DAT) SPECT imaging, in detecting patients in the premotor phase of PD. Unexplained hyposmia alone was associated with a 12.5% risk of developing PD within a five year period. Cox regression analysis revealed that odour discrimination performance was most strongly correlated with the risk of future PD. Furthermore, all relatives that later developed PD had both hyposmia and abnormally reduced striatal DAT binding at baseline. The results of our studies provide the proof-of-principle that a two-step approach of olfactory testing and DAT SPECT imaging may serve to diagnose PD in its premotor phase. Yet, the low positive predictive value of hyposmia indicates that a wider application of this approach for screening purposes would require too many DAT SPECT scans in healthy individuals. Therefore, future studies in larger populations are necessary to further characterize premotor PD and identify additional genetic and/or clinical susceptibility markers to be used in conjunction with olfactory testing as additional screening steps toward diagnosing PD in its earliest stages.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of neurology, neurosurgery, and psychiatry 12/2009; 81(4):396-9. DOI:10.1136/jnnp.2009.183715 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to compare different kinetic and semi-quantitative methods for analysing human [18F]FP-beta-CIT studies: plasma input models, simplified (SRTM) and full (FRTM) reference tissue models, standard uptake values (SUV) and SUV ratios (SUVr). Both simulations and clinical evaluations were performed to determine the effects of noise, scan duration and blood volume on Akaike model selection, and on precision and accuracy of estimated parameters. For typical noise levels (COV approximately 2.5%) and scan durations (<90 mins), simulations provided poor fits (Akaike criterion) in case of reversible plasma input models showing a relatively high number of outliers compared with the two-tissue irreversible model. Reference tissue models provided more reliable fits, which were nearly independent of noise and scan duration. For clinical data, two tissue irreversible and reversible plasma input models fitted striatum curves equally well (Akaike criterion). BP with plasma input models were less precise and contained more outliers than BP obtained with SRTM or FRTM. Among all methods tested, SRTM showed the highest contrast between patients and controls. When differentiating between patients and controls, SUVr performed almost equally well as SRTM, although contrast between striatum and background was lower. In conclusion, SRTM provided BP estimates with the highest precision and accuracy. Moreover, SRTM provided good contrast between patients and controls, and between striatum and background. SRTM is therefore the method of choice for quantitative [18F]FP-beta-CIT studies. SUVr might be an alternative for larger clinical trials.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: The association of Parkinson's disease (PD) with an impaired sense of smell was first reported about thirty years ago. Since then, it has become quite firmly established that olfactory dysfunction is one of the first and most prevalent clinical manifestations of this disorder. Recent data from an ongoing prospective study indicate that otherwise unexplained hyposmia in first degree relatives of patients with sporadic PD is associated with an increased risk of developing clinical PD of at least 13%. In particular, a combination of impaired olfactory function and reduced striatal [123I]beta-CIT binding on a baseline SPECT scan appears to be a strong predictor of a subsequent diagnosis of PD. Pathological studies support these observations by demonstrating that the anterior olfactory structures may be one of the induction sites of PD pathology. Considering that there is a doubling rather than a loss of dopaminergic neurons in the olfactory bulb in PD patients, the pathophysiology of olfactory dysfunction in PD is far from being elucidated. Studying prodromal manifestations of PD, such as olfactory dysfunction, and their underlying pathophysiology may greatly contribute to the development of treatment strategies that focus on preclinical detection and slowing down disease progression.
Journal of neural transmission. Supplementum 02/2006; · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association of Parkinson’s disease (PD) with an impaired sense of smell was first reported about thirty years ago. Since
then, it has become quite firmly established that olfactory dysfunction is one of the first and most prevalent clinical manifestations
of this disorder. Recent data from an ongoing prospective study indicate that otherwise unexplained hyposmia in first degree
relatives of patients with sporadic PD is associated with an increased risk of developing clinical PD of at least 13%. In
particular, a combination of impaired olfactory function and reduced striatal [123I]β-CIT binding on a baseline SPECT scan appears to be a strong predictor of a subsequent diagnosis of PD. Pathological studies
support these observations by demonstrating that the anterior olfactory structures may be one of the induction sites of PD
pathology. Considering that there is a doubling rather than a loss of dopaminergic neurons in the olfactory bulb in PD patients,
the pathophysiology of olfactory dysfunction in PD is far from being elucidated. Studying prodromal manifestations of PD,
such as olfactory dysfunction, and their underlying pathophysiology may greatly contribute to the development of treatment
strategies that focus on preclinical detection and slowing down disease progression.
Parkinson’s Disease and Related Disorders, 12/2005: pages 321-325;
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is characterized by a progressive degeneration of mesencephalic dopaminergic neurons. More than half of these neurons are lost in a presymptomatic phase of an estimated 4-6 years duration. It is obvious that any type of treatment aimed at slowing down the disease process should preferably be applied in this presymptomatic phase. Presymptomatic detection of PD has therefore become an important goal. In a recent study in a population of 361 asymptomatic first degree relatives of PD patients, we were able to demonstrate that presymptomatic detection is possible by means of a combination of three olfactory processing tasks and [123l] beta-CIT single photon emission computed tomography (SPECT) scanning of the nigrostriatal dopaminergic system. These results are a first step towards the development of a screening strategy that may be applied in the general population. Impairments of olfactory function, however, are not specific to PD but are also associated with other neurodegenerative disorders (e.g. Alzheimer's disease) and certain lifestyle characteristics (e.g. smoking). In the next few years our research efforts will focus on two different approaches to develop a more specific screening strategy. First, olfactory processing tasks will be combined with tasks aimed at detecting subtle (visuo)motor disturbances and early cognitive impairments. In parallel, an effort will be made to define disease-specific patterns of olfactory dysfunction in neurodegenerative disorders.
Tijdschrift voor gerontologie en geriatrie 05/2002; 33(2):70-7.