Article

A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson's disease.

William S. Middleton Memorial Veterans Hospital, Madison, WI 53792, USA.
Brain Imaging and Behavior (Impact Factor: 2.67). 05/2011; 5(3):203-11. DOI: 10.1007/s11682-011-9124-5
Source: PubMed

ABSTRACT Although [(18)F]fluoro-L: -dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.

0 Bookmarks
 · 
134 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review article is focused upon the most recent biomarker studies of Parkinson's disease. It provides an update on promising areas of biomarker research in a rapidly expanding field, and discusses future directions that might lead to successful development of Parkinson's disease biomarkers. Studies of molecular-genetic and biochemical biomarkers of Parkinson's disease have not only targeted hypothesis-driven measures of specific substrates involved in processes such as protein misprocessing, but also have made use of sophisticated analyses such as transcriptomic, proteomic, and metabolomic approaches. Whereas none of these are yet established as Parkinson's disease biomarkers, brain imaging using the 123I-ioflupane ligand with single-photon emission computed tomography was recently approved in the United States to aid in Parkinson's disease diagnosis, and research on other imaging modalities is ongoing. Neurophysiological tests are also being adapted for biomarker research, and we review recent promising data. The search for effective biomarkers for diagnosis and surveillance of Parkinson's disease continues. A battery of biomarkers comprising different modalities might be required to address clinical needs in this complex disorder. Critically, collaborative efforts including centralized tissue repository and clinical research infrastructure that are being organized will advance this field further.
    Current opinion in neurology 08/2012; 25(4):460-5. · 5.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The diverse and independently-varying signs of Parkinson's disease (PD) are often attributed to one simple mechanism: degeneration of the dopaminergic innervation of the posterolateral striatum. However, growing recognition of the dopamine (DA) loss and other pathology in extra-striatal brain regions has led to uncertainty whether loss of DA in the striatum is sufficient to cause parkinsonian signs. We tested this hypothesis by infusing cis-flupenthixol (cis-flu; a broad-spectrum D1/D2 receptor antagonist) into different regions of the macaque putamen (3 hemispheres of 2 monkeys) while the animal performed a visually-cued choice reaction time task in which visual cues indicated the arm to reach with and the peripheral target to contact to obtain food reward. Following reward delivery, the animal was required to self-initiate release of the peripheral target and return of the chosen hand to its home position (i.e., without the benefit of external sensory cues or immediate rewards). Infusions of cis-flu at 15 of 26 sites induced prolongations of reaction time (9 of 15 cases), movement duration (6 cases), and/or dwell time of the hand at the peripheral target (8 cases). Dwell times were affected more severely (+95%) than visually-triggered reaction times or movement durations (+25% and +15%, respectively). Specifically, the animal's hand often 'froze' at the peripheral target for up to 25-s, similar to the akinetic freezing episodes observed in PD patients. Across injections, slowing of self-initiation did not correlate in severity with prolongations of visually-triggered reaction time or movement duration, although the latter two were correlated with each other. Episodes of slowed self-initiation appeared primarily in the arm contralateral to the injected hemisphere and were not associated with increased muscle co-contraction or global alterations in behavioral state (i.e., inattention or reduced motivation), consistent with the idea that these episodes reflected a fundamental impairment of movement initiation. We found no evidence for an anatomic topography within the putamen for the effects elicited. We conclude that acute focal blockade of DA transmission in the putamen is sufficient to induce marked akinesia-like impairments. Furthermore, different classes of impairments can be induced independently, suggesting that specific parkinsonian signs have unique pathophysiologic substrates.
    Neurobiology of Disease 03/2012; 47(1):114-25. · 5.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Striatal dopamine is an important modulator of current behavior, as seen in the rapid and dramatic effects of dopamine replacement therapy in Parkinson disease (PD). Yet there is also extensive evidence that dopamine acts as a learning signal, modulating synaptic plasticity within striatum to affect future behavior. Disentangling these “performance” and “learning” functions is important for designing effective, long-term PD treatments. We conducted a series of unilateral drug manipulations and dopamine terminal lesions in the dorsolateral striatum of rats highly trained to perform brief instructed head/neck movements (two-alternative forced choice task). Reaction times and accuracy were measured longitudinally to determine if task behavior changed immediately, progressed over time, and/or persisted after drug withdrawal. Enhanced dopamine signaling with amphetamine caused an immediate, nonprogressive, and bilateral decrease in reaction times (RT). The altered RT distributions were consistent with reduced distance to threshold in the linear approach to threshold with ergodic rate (LATER) model of decision-making. Conversely, the dopamine antagonist flupenthixol caused experience-dependent, persistent changes in RT and accuracy indicative of a “learning” effect. These RT distributions were consistent with a slowed rate of approach to decision threshold. Our results show that dopaminergic signaling makes dissociable contributions to current and future behavior even within a single striatal subregion, and provide important clues for both models of normal decision-making and the design of novel drug therapies in PD.
    Basal Ganglia. 01/2013;

Full-text (2 Sources)

View
23 Downloads
Available from
May 30, 2014