Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study

Summary

Background

Patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinson's disease. In patients with Parkinson's disease, ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) SPECT detects striatal dopamine dysfunction resulting from nigral pathology whereas transcranial sonography (TCS) shows increased substantia nigra echogenic size, even before parkinsonism is clinically evident. We postulated that these neuroimaging changes could occur in a proportion of IRBD individuals who might then be at increased risk for development of a neurodegenerative disorder associated with substantia nigra dysfunction.

Methods

In our prospective study, we identified patients with IRBD from individuals referred to our sleep disorders centre in Barcelona, Spain. At baseline, we assessed dopamine transporter uptake by use of ¹²³I-FP-CIT SPECT, and estimated echogenicity of the substantia nigra by use of TCS. After a follow-up of 2·5 years, participants were clinically assessed to establish whether they had developed neurodegenerative syndromes. Data were compared with those of matched healthy controls.

Findings

43 individuals with IRBD agreed to participate in the study. We found reduced ¹²³I-FP-CIT binding in the striatum (p=0·045) in 17 (40%) of 43 participants compared with 18 controls, and substantia nigra hyperechogenicity in 14 (36%) of 39 participants with IRBD, compared with 16 (11%) of 149 controls (p=0·0002). Tracer uptake reduction was more pronounced in the putamen than it was in the caudate nucleus. 27 (63%) participants had reduced ¹²³I-FP-CIT binding or substantia nigra hyperechogenicity at baseline. Eight (30%) of these participants developed a neurodegenerative disorder (five Parkinson's disease, two dementia with Lewy bodies, and one multiple system atrophy). Individuals with normal neuroimaging results remained disease-free. Sensitivity of combined ¹²³I-FP-CIT SPECT and TCS to predict conversion to synucleinopathy after 2·5 years was 100% and specificity was 55%.

Interpretation

In patients with IRBD, ¹²³I-FP-CIT SPECT and TCS can detect subclinical changes much the same as those typically seen in patients with early Parkinson's disease. Decreased striatal ¹²³I-FP-CIT binding and substantia nigra hyperechogenicity might be useful markers to identify individuals at increased risk for development of synucleinopathies.

Funding

None.

Introduction

Neurodegenerative disorders such as Parkinson's disease have latent periods during which neuropathological features develop in the nervous system but do not reach the threshold for clinical symptoms to emerge or diagnosis to be established. Neuroprotective or disease-modifying therapies might be most successful when given in this preclinical disease phase. Thus, identification of individuals in the preclinical phase of a neurodegenerative disorder such as Parkinson's disease is a clinical and research priority.¹ Studies of these individuals would improve knowledge of disease progression at very early stages and allow testing of drugs with potential disease-modifying effects before motor and cognitive symptoms have emerged.1, 2, 3 Furthermore, close follow-up of individuals with preclinical disease would allow early diagnosis of symptom onset and treatment that might improve their health status.⁴

Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is characterised by dream-enacting behaviours, which are linked to REM sleep without atonia.⁵ Patients with idiopathic RBD (IRBD) can develop synucleinopathies associated with substantia nigra dysfunction such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy.6, 7, 8 Presently, identification of which patients with IRBD will develop these disorders is not known. The interval between onset of RBD and development of parkinsonism or dementia is variable, and can be up to 50 years.⁹ Factors that lead to an increased short-term risk for development of synucleinopathy in IRBD are not known. Hence, the identification of markers for early development of synucleinopathies in patients with IRBD would aid research in the preclinical phase.

Dopamine transporter (DAT) imaging and transcranial sonography (TCS) are two neuroimaging methods that might be useful in the early diagnosis of patients with Parkinson's disease. In patients with Parkinson's disease, DAT imaging shows decreased striatal DAT uptake, indicating substantia nigra dopaminergic dysfunction that is more marked in the putamen than in the caudate nucleus;10, 11, 12, 13 whereas TCS shows midbrain hyperechogenicity, a finding thought to reflect increased iron content in the substantia nigra;14, 15, 16, 17, 18, 19 and in patients with early disease striatal ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) uptake is not correlated with substantia nigra echogenic size suggesting that they are independent from each other.20, 21 We postulated that these neuroimaging findings typical of early Parkinson's disease might also occur in some patients with IRBD, who might then be at increased risk for development of a neurological syndrome associated with substantia nigra impairment, such as Parkinson's disease. In this study, 43 patients with IRBD had both DAT imaging and TCS at baseline in October, 2007, and 2·5 years later we assessed how many patients developed a neurodegenerative syndrome and its nature, and compared their neuroimaging results with those from the patients who remained disease-free.