Mirthe M. Ponsen

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.

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 Parkinsons 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.

Diagnosing premotor Parkinson's disease using a two-step approach combining olfactory testing and DAT SPECT imaging

Extranigral neuropathological changes may precede the degeneration of nigrostriatal dopaminergic neurones in Parkinsons 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.

The Dopamine Stabilizer (−)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [ 11 C]Raclopride PET Study in Healthy Human Subjects

(−)-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 [11C]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 [11C]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 [11C]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.

Reply: Olfaction and early detection of Parkinson's disease

The article by Ponsen and colleagues and the accompanying editorial by Stern point out the importance of preclinical detection of risk for subsequent development of Parkinson’s disease. The interesting work by Ponsen and colleagues would suggest that tests of olfactory function, alone or in combination with other tests, may play a role in developing prognosticating tests. We developed such a test that, when applied prospectively to 212 subjects with symptoms suggestive but not diagnostic of Parkinson’s disease, was able to detect 40 of the 59 subjects subsequently diagnosed with Parkinson’s disease over a 2-year period. Also, the test battery, using tests of olfaction, motor speed, and depression, was able to predict 37 of 40 subjects in whom Parkinson’s disease subsequently was clinically excluded. The test battery was 92% specific and 68% sensitive with an area of the receiver operator characteristics curve of 0.88. Olfactory testing alone had a sensitivity of 82% and a specificity of 81%. Developing any diagnostic or prognostic test is complicated. In addition to specificity and sensitivity, prior probabilities (prevalence of those at risk) are a major factor. For example, the prevalence of persons at risk for Parkinson’s disease in a population of concern (such as first-degree relatives or those with specific environmental exposures) would have to be nearly 18% for olfactory testing to have a 50% positive and negative predictive value. Even at this, there would be as many false-positives and false-negatives as true-positives and true-negatives. Often little attention is given to the anticipated prevalence rates of those at risk when discussing potential diagnostic or predictive tests. Combining multiple tests into a diagnostic or prognostic battery to improve specificity and sensitivity is problematic. Ultimately, the choice of diagnostic or predictive test is social, that is, what are the social, economic, political, moral, and ethical consequences of failing to treat someone at risk versus treating someone not at risk. If an effective neuroprotective therapy is developed, who would be treated? What would happen if an effective neuroprotective treatment cost

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

10,000 per year and had to be taken continuously? Could or would our society be willing to pay such a cost? Could or would we say that only those who could afford neuroprotection are entitled to it? Perhaps it would be wise to devote efforts to resolve these questions at the same time we are developing neuroprotective therapies.