Jana Godau

Transcranial sonography in movement disorders

Over the past 15 years the use of transcranial B-mode sonography to assess brainstem and subcortical brain structures has become an important tool for the diagnosis and differential diagnosis of various movement disorders. The most widely recognised finding for movement disorders has been an increase in echogenicity of the substantia nigra, an area of the midbrain that is affected in idiopathic Parkinsons disease (PD). This finding has enabled the reliable diagnosis of PD with high predictive values. Other sonographic features, such as hypoechogenicity of the brainstem midline and hyperechogenicity of the lentiform nucleus, might help the differential diagnosis of PD and other movement disorders. This Review provides detailed information about the advantages and limitations of this novel neuroimaging method, including guidelines for the scanning procedure and considerations on the origin of ultrasound abnormalities. We discuss the use of transcranial sonography for early and preclinical diagnosis and for differential diagnosis of PD and other movement disorders, and we compare this method with other functional neuroimaging strategies. Transcranial B-mode sonography is a reliable, non-invasive, commonly available, easily applicable, and inexpensive method, which provides new information about the morphology of the brain to help the diagnosis of various movement disorders. Thus, this neuroimaging method could be recommended for general application in the diagnosis and differential diagnosis of PD.

The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study

BACKGROUND Increased echogenicity of the substantia nigra (SN), as determined by transcranial sonography (TCS), is characteristic of idiopathic Parkinsons disease (iPD). The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes (aPS); however, these early studies were done in patients with later disease stages and known clinical diagnosis. We aimed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes, when the clinical symptoms often do not enable a definite diagnosis to be made. METHODS 60 patients who presented with the first, but still unclear, clinical symptoms of parkinsonism had TCS in this prospective blinded study. Investigators were blinded to the results of the clinical investigations, the ultrasound findings, and the diagnosis at time of investigation. The patients were followed-up every 3 months for 1 year to assess and re-evaluate the clinical symptoms. The patients in whom a clinical diagnosis could not be made with certainty were investigated with raclopride PET or dopamine transporter single-photon emission computed tomography (SPECT), or both. FINDINGS A clinical diagnosis of parkinsonism could not be established at baseline in 38 patients. At 12 months, 39 patients were clinically categorised as having iPD. Compared with endpoint diagnosis, the sensitivity of TCS at baseline was 90%7% and the specificity was 82.4%; the positive predictive value of TCS for iPD was 92.9% and the classification accuracy was 88.3%. INTERPRETATION TCS is an easy to implement, non-invasive, and inexpensive technique that could help in the early differential diagnosis of parkinsonian syndromes. The routine use of TCS in the clinic could enable disease-specific therapy to be started earlier. FUNDING Michael J Fox Foundation for Parkinsons Research.

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.

Substantia nigra hypoechogenicity: Definition and findings in restless legs syndrome

Pathological studies demonstrate a decreased iron content in the substantia nigra (SN) contributing to the pathophysiology of restless legs syndrome (RLS). SN echogenicity as measured by transcranial sonography (TCS) correlates with the SN iron content. The objective of this study was to determine a critical value to define SN hypoechogenicity as a potential marker for RLS. There were 49 RLS patients (39 idiopathic, 10 secondary) and 49 age‐ and sex‐matched controls who underwent TCS by 2 independent and blinded examiners to determine the area of SN echogenicity. We found that SN echogenicity is significantly decreased in RLS patients compared to healthy controls (P < 0.001). SN hypoechogenicity (sum area of SN echogenicity of both sides < 0.2 cm2) is more common in idiopathic than in secondary RLS patients. The area under curve for idiopathic RLS versus controls (receiver operating characteristics) is 0.91, specificity is 0.90, and sensitivity is 0.82. TCS provides an interesting additional instrument in the diagnosis of RLS. Therefore, SN hypoechogenicity (SN sum area < 0.2 cm2), which is supposed to indicate a decreased SN iron content, is a marker for RLS. Further studies are needed to investigate its significance for the pathophysiology of this frequent movement disorder and possible clinical applications.

Multiregional brain iron deficiency in restless legs syndrome

Evidence for tissue iron deficiency in restless legs syndrome (RLS) is limited to the substantia nigra (SN). Using MRI, we assessed T2 values of various brain regions in 6 RLS patients and 19 controls and correlated them with sonographically assessed SN echogenicity. Both neuroimaging features are supposed to correlate with tissue iron content. Mean T2 values of all regions were higher in patients (2.9–7.8%), though significantly increased only in four regions; the mean T2 over all voxels was higher in patients (5.1%, P < 0.001) and correlated inversely with SN echogenicity (r = −0.61, P < 0.001). This indicates multiregional (global) brain iron deficiency in RLS and proposes SN echogenicity as a potential morphological marker for brain iron status.

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.

Prodromal features for Parkinson's disease – baseline data from the TREND study

A number of non‐motor features are known to precede motor manifestations of Parkinsons disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD.

Poor Trail Making Test Performance Is Directly Associated with Altered Dual Task Prioritization in the Elderly – Baseline Results from the TREND Study

Background Deterioration of executive functions in the elderly has been associated with impairments in walking performance. This may be caused by limited cognitive flexibility and working memory, but could also be caused by altered prioritization of simultaneously performed tasks. To disentangle these options we investigated the associations between Trail Making Test performance—which specifically measures cognitive flexibility and working memory—and dual task costs, a measure of prioritization. Methodology and Principal Findings Out of the TREND study (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders), 686 neurodegeneratively healthy, non-demented elderly aged 50 to 80 years were classified according to their Trail Making Test performance (delta TMT; TMT-B minus TMT-A). The subjects performed 20 m walks with habitual and maximum speed. Dual tasking performance was tested with walking at maximum speed, in combination with checking boxes on a clipboard, and subtracting serial 7 s at maximum speeds. As expected, the poor TMT group performed worse when subtracting serial 7 s under single and dual task conditions, and they walked more slowly when simultaneously subtracting serial 7 s, compared to the good TMT performers. In the walking when subtracting serial 7 s condition but not in the other 3 conditions, dual task costs were higher in the poor TMT performers (median 20%; range −6 to 58%) compared to the good performers (17%; −16 to 43%; p<0.001). To the contrary, the proportion of the poor TMT performance group that made calculation errors under the dual tasking situation was lower than under the single task situation, but higher in the good TMT performance group (poor performers, −1.6%; good performers, +3%; p = 0.035). Conclusion Under most challenging conditions, the elderly with poor TMT performance prioritize the cognitive task at the expense of walking velocity. This indicates that poor cognitive flexibility and working memory are directly associated with altered prioritization.

Autoantibodies Against Amyloid and Glial-Derived Antigens are Increased in Serum and Cerebrospinal Fluid of Lewy Body-Associated Dementias

There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinsons disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimers disease (AD), 11 frontotemporal dementia (FTD), 11 vascular dementia patients (VaD), and 31 healthy controls). Autoantibody levels against α-synuclein, amyloid-β₄₂ (Aβ₄₂), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against α-synuclein, Aβ₄₂, MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte-derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural-derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated.

Cross-sectional study discloses a positive family history for Parkinson’s disease and male gender as epidemiological risk factors for substantia nigra hyperechogenicity

SummaryHyperechogenicity of the substantia nigra (SN) has been proposed to be a typical finding in Parkinson’s disease (PD) and a marker of vulnerability to nigrostriatal dysfunction in healthy subjects. This large cross-sectional study including 1120 subjects older than 50 years without any signs of PD was performed to evaluate the association of SN hyperechogenicity and other proposed epidemiological risk factors for PD. Among all variables assessed only family history of PD and male gender proved to be significantly associated with SN hyperechogenicity, indicating a genetic predisposition for the ultrasound marker.