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

Summary

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.

Introduction

Degeneration of the nigrostriatal dopaminergic system has traditionally been considered the pathological hallmark of Parkinson's disease (PD). Recent neuropathological work, however, revealed that PD specific brain pathology extends far beyond the nigrostriatal dopaminergic system and affects widespread brain areas, including the olfactory system, autonomic and gain setting brainstem nuclei, and the cerebral cortex [1]. In parallel, there has been a revival of interest in the non-motor features of PD [2]. PD is now considered as a multisystem neurodegenerative disorder, manifesting itself by a combination of motor deficits and a wide range of non-motor disturbances. The broadening of the clinical and pathological concept of PD has already provided new insight into its pathogenesis as well as novel potential targets to try and slow down disease progression [3, 4, 5]. A true disease-modifying treatment is much wanted, as current symptomatic treatment can only delay functional impairments for a limited period of time and is associated with the development of disabling dyskinesias and motor response fluctuations. Moreover, with disease progression levodopa-resistant motor symptoms emerge and non-motor symptoms start to dominate the clinical picture. To successfully counter the neurodegenerative process, we need to increase our knowledge of the initial stages of the disease process. This can only be done by identifying and studying patients in the premotor phase of the disease.