Clinical utility of visualisation of nigrosome-1 in patients with Parkinson's disease.

OBJECTIVE: To determine the diagnostic characteristics of poor visualisation of nigrosome-1 as a neuroimaging biomarker in Parkinson's disease (PD) and to explore the relationship of poor visualisation of nigrosome-1 and clinical asymmetry. METHODS: High-resolution gradient-echo sequences of 67 patients with PD and 63 healthy controls were reviewed by two radiologists blinded to the clinical details. A three-tier classification system was used to categorise the scans based on the visualisation of nigrosome-1, and inter-rater reliability was calculated at each level of classification. Other diagnostic properties such as sensitivity, specificity and predictive values were calculated. The relationship between poor visualisation of nigrosome-1 and clinical asymmetry was also assessed. RESULTS: Poor visualisation of nigrosome-1 had high sensitivity (98.5%), specificity (93.6%), positive-predictive value (94.3%), negative-predictive value (98.3%), accuracy (96%) and inter-rater reliability (k = 0.75-0.92). Poorly visualised nigrosome-1 was significantly associated with higher motor asymmetry in the contralateral side in 64.8% of subjects (p = 0.004). CONCLUSIONS: Poor visualisation of nigrosome-1 in PD had good diagnostic properties as a neuroimaging biomarker in PD. There was also a significant agreement on clinical asymmetry and poor visualisation of nigrosome-1. KEY POINTS: • Nigrosome-1 represents the largest collection of dopaminergic neurons in dorso-lateral substantia nigra. • Loss of nigrosome-1 is being studied as a biomarker in Parkinson's disease. • Visualisation of nigrosome-1 had good diagnostic properties as a biomarker. • There was a contralateral relationship between nigrosome-1 lateralisation and clinical asymmetry. • We also highlight the potential limitations of nigrosome-1 visualisation as a biomarker.

Ultra high-field SWI of the substantia nigra at 7T: reliability and consistency of the swallow-tail sign.

BACKGROUND: The loss of the swallow-tail sign of the substantia nigra has been proposed for diagnosis of Parkinson's disease. Aim was to evaluate, if the sign occurs consistently in healthy subjects and if it can be reliably detected with high-resolution 7T susceptibility weighted imaging (SWI). METHODS: Thirteen healthy adults received SWI at 7T. 3 neuroradiologists, who were blinded to patients' diagnosis, independently classified subjects regarding the swallow-tail sign to be present or absent. Accuracy, positive and negative predictive values (PPV and NPV) as well as inter- and intra-rater reliability and internal consistency were analyzed. RESULTS: The sign could be detected in 81% of the cases in consensus reading. Accuracy to detect the sign compared to the consensus was 100, 77 and 96% for the three readers with PPV reader 1/2/3 = 1/0.45/0.83 and NPV = 1/1/1. Inter-rater reliability was excellent (inter-class correlation coefficient = 0.844, alpha = 0.871). Intra-rater reliability was good to excellent (reader 1 R/L = 0.625/0.786; reader 2 = 0.7/0.64; reader 3 = 0.9/1). CONCLUSION: The swallow-tail sign can be reliably detected. However, our data suggest its occurrence is not consistent in healthy subjects. It may be possible that one reason is an individually variable molecular organization of nigrosome 1 so that it does not return a uniform signal in SWI.

Loss of the "swallow tail sign" on susceptibility-weighted imaging in the diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis.

INTRODUCTION: Loss of dorsolateral nigral hyperintensity (DNH) on iron-sensitive brain MRI is useful for Parkinson's disease detection. DNH loss could also be of diagnostic value in dementia with Lewy bodies (DLB), an a-synuclein-related pathology. We aim to quantitatively synthesize evidence, investigating the role of MRI, a first-line imaging modality, in early DLB detection and differentiation from other dementias. METHODS: Our study was conducted according to the PRISMA statement. MEDLINE, Scopus, Web of Science, and Cochrane Library were searched using the terms like "dementia with Lewy bodies", "dorsolateral nigral hyperintensity", and "MRI". Only English-written peer-reviewed diagnostic accuracy studies were included. We used QUADAS-2 for quality assessment. RESULTS: Our search yielded 363 search results. Three studies were eligible, all with satisfying, high quality. The total population of 227 patients included 63 with DLB and 164 with other diseases (Alzheimer disease, frontotemporal dementia, mild cognitive impairment). Using a univariate random-effects logistic regression model, our meta-analysis resulted in pooled sensitivity, specificity and DOR of 0.82 [0.62; 0.92], 0.79 [0.70; 0.86] and 16.26 ([3.3276; 79.4702], p = 0.0006), respectively, for scans with mixed field strength (1.5 and 3 T). Subgroup analysis of 3 T scans showed pooled sensitivity, specificity and DOR of 0.82 [0.61; 0.93], 0.82 [0.72; 0.89] and 18.36 ([4.24; 79.46], p < 0.0001), respectively. DISCUSSION: DNH loss on iron-sensitive MRI might comprise a supportive biomarker for DLB detection, that could augment the value of the DLB diagnostic criteria. Further evaluation using standardized protocols is needed, as well as direct comparison to other supportive and indicative biomarkers.

Free water and iron content in the substantia nigra at different stages of Parkinson's disease.

PURPOSE: Abnormalities in free water (FW) and susceptibility values exist in the substantia nigra (SN) of patients with Parkinson's disease (PD), but their role in characterizing the disease processes remains uncertain. This study investigated these values at various SN locations and stages of PD, and their relationship with clinical symptoms. METHOD: FW and quantitative susceptibility mapping (QSM) values were evaluated in the anterior and posterior SN, along with swallow-tail-sign (STS) ratings, in patients with PD (early-stage: n = 39; middle-to-advanced-stage: n = 97) and healthy controls (n = 82). The correlation between these indices and motor and non-motor symptoms, and their capability to distinguish PD from healthy controls, were also examined. RESULTS: Increased FW in the anterior and posterior SN and increased QSM values in the posterior SN were observed in both early-stage and middle-to-advanced-stage PD patients (p < 0.05). However, there was no significant difference in FW, QSM values, or STS ratings among patients at different stages. FW and QSM values correlated with motor symptoms in middle-to-advanced-stage patients (p < 0.05), while STS ratings were associated with non-motor symptoms (p < 0.05). Additionally, combining FW and QSM values in the posterior SN with STS ratings in logistic regression showed better performance in distinguishing PD (area under curve = 0.931) compared to using STS ratings alone (area under curve = 0.880). CONCLUSIONS: Findings suggest elevated FW and iron content in PD at different stages, with dissociation in SN location between the two indices. Elevated signals are related to the motor symptom severity in middle-to-advanced-stage patients, and may have the potential for PD diagnosis and symptom assessment.

The Swallow Tail Sign of Substantia Nigra: A Case-Control Study to Establish Its Role in Diagnosis of Parkinson Disease on 3T MRI.

Background and Objectives The loss of swallow tail sign (STS) has been studied for the diagnosis of Parkinson's disease (PD). The study aims to establish the role of STS on high-resolution 3D susceptibility-weighted images (SWI) on 3T MRI in clinically diagnosed cases of PD and compare with control population. Methods and Materials Forty-five patients with clinically diagnosed PD and Parkinson plus syndrome (PPS) formed the study group and were compared with 45 controls without any neurological disease and normal brain magnetic resonance imaging (MRI). Presence or absence of STS was studied on 1-mm thick axial 3D SWI images in bilateral substantia nigra by two radiologists independently, followed by consensus reading. Bilateral absent, unilateral absent, and faintly present STS were considered as absent STS and predicted PD or PPS, and bilateral presence was considered as a positive STS, and was assessed keeping the clinical diagnosis as the gold standard. Results The sensitivity of the absent STS was 75.55%, specificity 97.77%, positive predictive value 97.14%, negative predictive value 80% and accuracy 86.66%, in the diagnosis of PD or PPS, with odd ratio of 132 (confidence interval 15.97-1098.75). Kappa coefficient was 0.80 ( p < 0.001) for both inter- and intrarater agreement, suggesting high reproducibility for the detection of STS. Conclusions Absence of the STS is a good predictor of degeneration of the nigrosome 1 in the substantia nigra in the PD or PPS patients; hence, it can act as a useful marker of these diseases.

Evaluation of the Swallow-Tail Sign and Correlations of Neuromelanin Signal with Susceptibility and Relaxations.

The presence of a swallow-tail sign in the nigrosome-1 with hyperintense signal shown on the susceptibility-weighted imaging (SWI) has been shown to be sensitive in detecting the abnormal iron deposits in this area. A systematic evaluation in healthy subjects is required before this tool can be recommended in a widespread application. We evaluated a simple and practical SWI approach using a multiecho gradient-echo sequence with an improved contrast-to-noise ratio (CNR). We also evaluated the association of the neuromelanin imaging contrast behavior with the susceptibility and relaxation measurements. Twenty-five older and 23 young healthy adults were evaluated. The CNRs of the nigrosome-1 were compared along with method and group. Correlations of the nigrosome-1 neuromelanin signal in the neuromelanin-sensitive imaging with CNRs in the susceptibility, T1 and T2 mappings were examined. Two different coils were used to confirm the reproducibility. Compared with the single-echo, multiecho SWI can improve the CNR of the swallow-tail sign. We found significant correlations between neuromelanin signal and CNRs in the susceptibility and T2 mappings, and T1 value. The older subjects exhibited increased CNRs compared with the young adults. No significant difference was observed in the measurements between 20 and 64 channels. The multiecho technique allows the high-quality nigrosome-1 images in SWI and allows for a joint analysis of T2* and quantitative-susceptibility mapping at high spatial resolution. The correlations of neuromelanin-sensitive imaging with susceptibility and T2 imply that the iron content in the nigrosome-1 may have significant influences on the hyperintensity of neuromelanin in the magnetization transfer-related contrast.

The evaluation of the swallow tail sign in patients with parkinsonism and gait disorders.

BACKGROUND: Swallow tail sign (STS), which represents nigrosome-1 in the substantia nigra on 3 Tesla (T) susceptibility-weighted imaging (SWI), has attracted attention as a promising magnetic resonance imaging (MRI) biomarker for idiopathic Parkinson's disease (iPD). Some reports have shown high sensitivity and specificity-both above 94%-for distinguishing iPD from healthy controls. However, abnormal STS has been observed in many neurodegenerative parkinsonisms and even in multiple sclerosis. METHODS: All patients with parkinsonism who had 3 T MRI were included in a retrospective chart review from a single movement disorders clinic. All subjects were evaluated by a single movement disorder specialist, using Movement Disorders Society diagnostic criteria and American Academy of Neurology consensus guidelines for diagnoses. All MRIs were interpreted by a single neuroradiologist who was blinded to the diagnosis. RESULTS: Twenty patients were included in the study. Twelve had abnormal STS: iPD (n = 2), probable multiple system atrophy (n = 3), vascular parkinsonism (n = 1), psychogenic gait disorder (n = 1), neuroleptic parkinsonism (n = 2), cervical dystonia (n = 1), static encephalopathy (n = 1) and gait disorder of unknown etiology (n = 1). Eight had normal STS: iPD (n = 1), probable progressive supranuclear palsy (n = 1), vascular parkinsonism (n = 2), transient parkinsonism of unknown etiology (n = 2), valproic acid induced parkinsonism (n = 1), and essential tremor with parkinsonism (n = 1). 123I-Ioflupane SPECT dopamine transporter (DaT) scan results were available on seven subjects; four subjects had incongruency between DaT and MRI. CONCLUSION: Our results suggest that the abnormal STS is not, in isolation, a reliable biomarker of idiopathic Parkinson's disease.

Clinical MR imaging in Parkinson's disease: How useful is the swallow tail sign?

BACKGROUND: With conventional MRI, no Parkinson's disease (PD)-specific abnormalities can be detected. However, there is a critical need for accompanying neuroimaging markers to guide the diagnosis. With high-resolution susceptibility-weighted MRI (SWI) sequences, the imaging of nigrosome-1 (N1) is possible. The so-called swallow tail sign (STS) has been proposed as a suitable neuroimaging marker for the diagnosis of PD. OBJECTIVES: To investigate whether the absence of the STS can be applied for distinguishing PD patients from healthy controls (HCs). METHODS: SWI images of 44 PD patients and 50 age- and gender-matched HCs were investigated using a 3T MRI scanner. Two trained neuroradiologists blind-rated the images and evaluated whether the STS was absent (1) on one side or (2) both sides of the participant's midbrain. RESULTS: Our results confirmed good interrater reliability comparable to previously published studies. However, we did not identify any group differences between PD patients and HCs. Measures of diagnostic values revealed overall poor diagnostic performance. CONCLUSIONS: Even though previously stated, our study does not confirm the potential use of the STS as a supportive neuroimaging marker for PD in a clinical setting. In conclusion, there is a critical need for improvements in N1-targeted MRI sequences and the development of advanced segmentation algorithms.

Susceptibility-Weighted 3T MRI of the Swallow Tail Sign in Multiple Sclerosis: A Case Control Study.

BACKGROUND AND PURPOSE: The swallow tail sign describes the physiological appearance of nigrosome-1 within the substantia nigra on high-resolution transverse susceptibility-weighted imaging (SWI). Previous studies demonstrated its absence in Parkinson's disease due to increasing iron content. In multiple sclerosis (MS), increased iron accumulation can be found in the brain tissue including the substantia nigra. METHODS: We investigated the swallow tail sign on high-resolution SWI MRI in 46 MS and 23 age- and sex-matched controls. RESULTS: MS patients demonstrated significantly more often an abnormal swallow tail sign (28/46; 60%) compared to controls (4/23; 17%; P = .001). In MS patients, we found no correlation between an abnormal swallow tail sign and age, disease duration or Expanded Disability Status Scale scores. CONCLUSION: The finding of an abnormal swallow tail sign in MS patients may provide an additional imaging marker even in early MS development.

PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases.

BACKGROUND: An improved understanding of the genetic determinants of Parkinson's disease (PD) in underrepresented populations, and better characterization of genotype-phenotype correlations in monogenic PD, are needed. Scarce literature exists regarding the genetic aetiology of PD in Malays, who comprise 200 million individuals in South-East Asia. Phenotypic data regarding PARK-PINK1 are also limited. METHODS: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry. RESULTS: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9% among Malays with PD onset ≤50 years (2.7% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and "loss of the swallow tail" sign, were documented. CONCLUSIONS: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant.

Loss of Swallow Tail Sign on Susceptibility-Weighted Imaging in Dementia with Lewy Bodies.

We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer's disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p < 0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53%) but specificity increased (82-100%). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis.

Microvessels may Confound the "Swallow Tail Sign" in Normal Aged Midbrains: A Postmortem 7 T SW-MRI Study.

BACKGROUND AND PURPOSE: Susceptibility weighted imaging (SWI) plays a role in the differential diagnosis of Parkinson's disease, but lacks widespread acceptance in clinical routine. In a descriptive pilot study, we assessed hypointense microstructures of the normal substantia nigra pars compacta at ultrahigh-field strength for interpretation of the "swallow tail sign." METHODS: Magnetic resonance imaging at 7 Tesla was performed in five postmortem samples obtained from subjects not affected by Parkinson's disease. Susceptibility weighted images, including minimum intensity projections, were created followed by consensus assessment for microvascular confound. Histological workup in this case-control study included iron and myelin staining. Seven Tesla SWI images from the reference cohort of nine living subjects, all of which showed a positive "swallow tail sign" in their midbrains, were assessed visually. RESULTS: All specimens showed microvessels running through the dorsal pars compacta and along the caudolateral circumference of the red nucleus. Hypointense imaging patterns in the medial part of the "swallow tail" were due to susceptibility effects of iron deposits and microvessels. In eight out of nine control subjects, one or more microvessels were detected medial to the dorsolateral nigral hyperintensity or at least unilaterally in the medial part of the "swallow tail." One microvessel crossing nigrosome 1 was found in two in-vivo cases. CONCLUSION: Both iron deposits and microvessels contribute to the hyposignal surrounding nigrosome 1 in susceptibility weighted imaging of normal aged midbrains at ultrahigh-field strength. When assessing the substantia nigra for the presence or absence of the "swallow tail sign," intrinsic vessels may be a sporadic confounder.

Can loss of the swallow tail sign help distinguish between Parkinson Disease and the Parkinson-Plus syndromes?

PURPOSE: To determine if loss of the swallow tail sign (STS) can distinguish Parkinson Disease (PD) from the Parkinson-Plus syndromes. METHODS: Twenty-five patients with PD, 21 with Parkinson-Plus syndromes, and 14 control patients were included. Presence of the STS was assessed. RESULTS: The STS was present in 79% of controls, statistically greater than the PD/Parkinson-Plus patients. There was no difference in the presence of the STS between the PD/Parkinson-Plus subgroups or when scanning at 1.5 T or 3 T. CONCLUSIONS: Loss of the STS could not distinguish between PD and Parkinson-Plus patients. The STS can be identified at both 1.5 T and 3 T.