Heike Stockner

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

BACKGROUND Patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinsons disease. In patients with Parkinsons 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 [corrected] 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 Parkinsons 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 Parkinsons 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.

Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome

In patients with Parkinsons disease, hyperechogenicity of the substantia nigra using transcranial ultrasound has been related to increased tissue concentrations of iron. Recently, deficient iron transport mechanisms in substantia nigra neurons have been described in postmortem tissue of patients with restless legs syndrome (RLS). This study was performed to study substantia nigra echogenicity in RLS patients compared with normal control subjects and Parkinsons disease patients. RLS patients had significantly reduced midbrain areas of hyperechogenicity compared with control subjects, and even more markedly reduced hyperechogenicity compared with Parkinsons disease patients. These findings lend further support to nigral iron deficiency as a pathogenetic factor in RLS. Ann Neurol 2005

Enlarged Substantia Nigra Hyperechogenicity and Risk for Parkinson Disease: A 37-Month 3-Center Study of 1847 Older Persons

OBJECTIVE To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Midbrain sonography in patients with essential tremor

Several studies have reported an increased risk to develop Parkinsons disease (PD) in essential tremor (ET) populations. Hyperechogenicity of the substantia nigra (SN) is a common transcranial sonography (TCS) finding in PD and has been suggested as a PD risk‐marker in nonparkinsonian subjects. This study compared SN areas of 44 ET patients with 100 controls and 100 PD patients. Sixteen percent of ET patients had SN hyperechogenicity as compared with 3% of controls and 75% of PD patients. These findings might correspond to an increased risk of ET patients to develop PD. Long‐term follow‐up will show if those with hyperechogenic SN develop PD, while these without will not.

Midbrain Hyperechogenicity in Idiopathic REM Sleep Behavior Disorder

Recent studies have reported an increased risk to develop Parkinsons disease (PD) in patients with idiopathic RBD (iRBD). Midbrain hyperechogenicity is a common transcranial sonography (TCS) finding in PD and has been suggested as a PD risk‐marker in nonparkinsonian subjects. The objective of this study is to assess midbrain echogenicity by TCS in patients with iRBD and compare the findings with the healthy controls. TCS was performed in 55 iRBD patients and in 165 age and sex‐matched controls. The area of echogenicity in the SN region in the iRBD group was significantly increased compared with the control group (P < 0.001). About 19 (37.3%) of patients with iRBD were found to have SN hyperechogenicity when compared with 16 (10.7%) of the controls (P < 0.001). This is the first case‐control study assessing midbrain echogenicity in a large iRBD cohort compared to age‐ and sex‐matched healthy individuals. The finding of an increased prevalence of hyperechogenicity in a subgroup of individuals with a priori increased risk for PD supports the potential role of hyperechogenicity as a risk marker for PD. The prospective follow‐up of this iRBD cohort is needed to establish if those with midbrain hyperechogenicity will go on to develop clinically defined PD or not.

Enlarged hyperechogenic substantia nigra as a risk marker for Parkinson's disease

SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinsons disease (PD). Recently, we reported a 17.4‐fold increased risk for PD in individuals with SN+ older than 50 years within 3 years.

Burden of atherosclerosis and risk of venous thromboembolism in patients with migraine.

Background: Previous studies have yielded evidence of an enhanced risk of cardiovascular disease, especially stroke, among patients with migraine. Our understanding of the underlying mechanisms is far from complete. The aims of the present study were to investigate the potential association between migraine and atherosclerosis and to assess the risk of venous thromboembolism as a clinical surrogate for a procoagulant state in patients with migraine. Methods: The examination was part of the population-based Bruneck Study. During the 2005 evaluation, 574 participants aged 55–94 years underwent neurologic and laboratory examinations involving a standardized headache interview and scanning of the carotid and femoral arteries to evaluate presence, severity, and progression (2000–2005) of atherosclerosis. Results: A large number of well-founded and putative cardiovascular risk factors have emerged as being unrelated to migraine status. Prevalence, severity, and 5-year progression of carotid and femoral atherosclerosis did not differ significantly between migraineurs with and without aura and nonmigraineurs. In fact, there was even a tendency for atherosclerosis to be less pronounced among patients with migraine, and for the intima-media thickness to be lower (p = 0.029). As a novel finding migraineurs faced a significantly enhanced risk of venous thromboembolism (18.9% vs 7.6% in nonmigraineurs, age/sex-adjusted p = 0.031). Conclusion: This study is the first to compare the burden of atherosclerosis as quantified by high-resolution duplex ultrasound between migraineurs and nonmigraineurs in the general community, and provides solid evidence against the view that migraine predisposes to atherosclerosis. The higher risk for venous thromboembolism among migraineurs (prothrombotic state) awaits confirmation and elaboration in future research. GLOSSARY: CCA = common carotid arteries; CVD = cardiovascular disease; ICA = internal carotid arteries; IMT = intima-media thickness; MMSE = Mini-Mental State Examination; VTE = venous thromboembolism.

Probable RBD and association with neurodegenerative disease markers: A population‐based study

The prevalence of rapid eye movement sleep behavior disorder (RBD) and its association with markers of neurodegeneration in the general population are poorly defined.

Prevalence of primary headaches and cranial neuralgias in men and women aged 55–94 years (Bruneck Study)

The aim of the current study was to estimate the prevalence of all primary headaches and cranial neuralgias in the general community. As part of the population-based Bruneck Study, 574 men and women aged 55–94 years underwent extensive neurological and laboratory examinations involving a standardized headache interview. In the Bruneck Study population the lifetime prevalence of all primary headaches combined and of cranial neuralgias was 51.7 and 1.6%, respectively. Tension-type headache (40.9%) and migraine (19.3%) emerged as the most common types of headache. In men and women aged 55–94 years the 1-year prevalence of primary headaches was high at 40.5%. In this age range headaches caused significant impairment of health-related quality of life. The Bruneck Study has confirmed the high lifetime prevalence of primary headaches and cranial neuralgias in the general population and provided first valid prevalence data for all primary headaches based on International Classification of Headache Disorders, 2nd edition criteria.

Five‐year follow‐up of substantia nigra echogenicity in idiopathic REM sleep behavior disorder

Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinsons disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow‐up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty‐one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20 ± 0.09 cm2 vs. 0.19 ± 0.07 cm2; P = 0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P = 0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow‐up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains stable over time.