The preclinical detection of Parkinson's disease: Ready for prime time?

Stern, Matthew B.

doi:10.1002/ana.20180

Cited by 29 publications

(24 citation statements)

References 20 publications

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“…We may also be nearing a stage where we might be able to test new interventions in patients who are in the earliest stages of the disease, or are defined as being "at risk" based on their clinical profile, neuroimaging studies, or genetic screening. 54,55 Indeed, it may be that patients who have disease sufficient to permit conventional diagnosis might be too far along in the course of their neurodegenerative disease process to be able to respond to a disease-modifying therapy.…”

Section: Future Directionsmentioning

confidence: 99%

Why have we failed to achieve neuroprotection in Parkinson's disease?

2009

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The development of a neuroprotective therapy that slows, stops, or reverses neurodegeneration in Parkinson's disease (PD) is the single most important unresolved issue in the management of this disorder. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but disease progression is associated with the development of "nondopaminergic" features such as postural instability, falling, and dementia that are not adequately controlled with existing medications. There are many promising candidate neuroprotective agents based on pathological and laboratory studies, but to date, it has not been possible to determine that any drug has a disease-modifying effect in PD. Obstacles to the development of a neuroprotective therapy in PD include: (1) uncertainty as to the precise cause of cell death in PD and what to target; (2) the lack of an animal model of PD that precisely reflects the etiopathogenesis of the disease, the pattern of dopaminergic and nondopaminergic pathology, and its chronic, progressive nature; (3) determination of the correct dose to use in clinical trials; and (4) delineation of a clinical end point that is an accurate measure of the underlying disease and is not confounded by potential symptomatic effects of a study intervention. New developments in understanding the cause of the disease, in the development of animal models of PD, and in clinical trial methodology will hopefully hasten the resolution of these problems.

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Section: Future Directionsmentioning

confidence: 99%

Why have we failed to achieve neuroprotection in Parkinson's disease?

2009

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“…The combination of smell loss or RBD with DAT imaging has already been successfully used to identify groups of individuals with increased risk of developing PD (Ponsen et al, 2004;Stiasny-Kolster et al, 2005). These observations have led to the development of an extensive clinical effort called the PARS to generate a strategy that could help detect parkinsonism in a cohort of 30 000 first-degree relatives of PD patients using combined changes in olfaction and DAT imaging as biomarkers (Stern, 2004;Siderowf and Stern, 2006;Blekher et al, 2009;Marek and Jennings, 2009). Longitudinal clinical and imaging evaluations will help assess the progression of deficits and the state of DAT imaging in these individuals, and determine if these changes predict the eventual development of PD signs in a subset of patients.…”

Section: Neuroimagingmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…Imaging offers the best opportunity to accurately push back the diagnosis to the presymptomatic period (24). Although imaging is unlikely to be used as a primary screen for PD because of cost, coupling of DAT imaging with more widely available PD biomarkers may effectively identify subjects who might be presymptomatic (25). As DAT imaging is used in increasing numbers of subjects and imaging sites, OSA would provide both a reliable and a practical method to ensure accurate quantitation of imaging outcomes.…”

Section: Discussionmentioning

confidence: 99%

Optimized, Automated Striatal Uptake Analysis Applied to SPECT Brain Scans of Parkinson's Disease Patients

Zubal¹,

Early²,

Yuan³

et al. 2007

Journal of Nuclear Medicine

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Reliable quantitative dopamine transporter imaging is critical for early and accurate diagnosis of Parkinson's disease (PD). Image quantitation is made difficult by the variability introduced by manual interventions during the quantitative processing steps. A fully automated objective striatal analysis (OSA) program was applied to dopamine transporter images acquired from PD subjects with early symptoms of suspected parkinsonism and compared with manual analysis by a trained image-processing technologist. Methods: A total of 101 123 I-b-CIT SPECT scans were obtained of subjects recruited to participate in the Query-PD Study. Data were reconstructed and then analyzed according to a package of scripts (OSA) that reorients the SPECT brain volume to the standard geometry of an average scan, automatically locates the striata and occipital structures, locates the caudate and putamen, and calculates the background-subtracted striatal uptake ratio (V3$). The striatal uptake ratio calculated by OSA was compared with manual analysis by a trained image-processing technologist. Several parameters were varied in the automated analysis, including the number of summed transverse slices and the size and separation of the regions of interest applied to the caudate and putamen to determine the optimum OSA analysis. The parameters giving V3$ with the closest correlation to the manual analysis were accepted as optimal. Results: The optimal comparison between the V3$ obtained by the human analyst and that obtained by the automated OSA analysis yielded a correlation coefficient of 0.96. Conclusion: Our optimized OSA delivers V3$ evaluations that closely correlate with a similar evaluation manually applied by a highly trained image-processing technologist.

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The preclinical detection of Parkinson's disease: Ready for prime time?

Cited by 29 publications

References 20 publications

Why have we failed to achieve neuroprotection in Parkinson's disease?

Why have we failed to achieve neuroprotection in Parkinson's disease?

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Optimized, Automated Striatal Uptake Analysis Applied to SPECT Brain Scans of Parkinson's Disease Patients

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