Diagnosis Of Atypical Parkinsonian Syndromes Research Articles

Magnetic resonance imaging modalities aid in the differential diagnosis of atypical parkinsonian syndromes.

Accurate and timely diagnosis of atypical parkinsonian syndromes (APS) remains a challenge. Especially early in the disease course, the clinical manifestations of the APS overlap with each other and with those of idiopathic Parkinson's disease (PD). Recent advances in magnetic resonance imaging (MRI) technology have introduced promising imaging modalities to aid in the diagnosis of APS. Some of these MRI modalities are also included in the updated diagnostic criteria of APS. Importantly, MRI is safe for repeated use and more affordable and accessible compared to nuclear imaging. These advantages make MRI tools more appealing for diagnostic purposes. As the MRI field continues to advance, the diagnostic use of these techniques in APS, alone or in combination, are expected to become commonplace in clinical practice.

Parkinson's disease fluid biomarkers for differential diagnosis of atypical parkinsonian syndromes

AbstractThe scope of the present review is to synthesize existing literature data on fluid biomarkers for Parkinson's disease (PD) and atypical parkinsonian syndromes (APS). Parkinsonian syndromes encompass a body of heterogeneous neurodegenerative diseases marked by characteristic movement dysfunction, among which PD is the most prevalent form. In addition to the stereotypical presentation of PD, patients may also manifest atypical symptoms that raise the suspicion of APS, such as PD with dementia, progressive supranuclear palsy, multiple system atrophy, dementia with Lewy body, and corticobasal degeneration.Clinical diagnosis of PD and APS depends heavily on patients’ presenting symptoms without reliable objective tests or imaging studies. Fluid biomarkers are powerful tools that facilitate diagnosing and monitoring various parkinsonian syndromes. Therefore, establishing parkinsonian biomarkers is a necessary step in the scope of basic science research and clinical practice. This review will discuss some of the past decade's most promising cerebrospinal fluid and other fluid biomarkers. We highlighted the shortcomings of alpha‐synuclein (α‐syn), Aβ42, and tau as differences in the expression of these proteins are moderate at best. Protein misfolding cyclic amplification and real‐time quaking‐induced conversion are novel techniques with remarkable discriminatory capacity for PD and APS. Autoantibodies have also introduced a marker for possible early diagnosis and staging for PD. Neurofilament light chain and microRNAs are promising fluid biomarkers that may be more suitable as biomarkers compared to α‐syn, Aβ42, and tau. At its current stage, fluid‐based biomarkers have improved significantly in diagnosing PD from healthy controls and differentiating between PD and APS, but insufficient for clinical usage due to a lack of validation and limitation in discriminatory power.

Diagnostic Performance for Differential Diagnosis of Atypical Parkinsonian Syndromes from Parkinson's Disease Using Quantitative Indices of 18F-FP-CIT PET/CT.

We are aimed to evaluate the diagnostic performances of quantitative indices obtained from dual-phase 18F-FP-CIT PET/CT for differential diagnosis of atypical parkinsonian syndromes (APS) from Parkinson’s disease (PD). We analyzed 172 subjects, including 105 non-Parkinsonism, 26 PD, 8 PSP, 1 CBD, 8 MSA-P, 9 MSA-C, and 15 DLB retrospectively. Two sequential PET/CT scans were acquired at 5 min and 3 h. We compared subregional binding potentials, putamen-to-caudate nucleus ratio of the binding potential, asymmetry index, and degree of washout. To differentiate APS, all BPs in both early and late phases (except late BPbrainstem) and all factors of the percent change except for putamen in APS significantly differed from PD. When a cut-off for early BPcerebellum was set as 0.79, the sensitivity, specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy for differentiating APS 73.2%, 91.7%, 93.8%, 66.7%, and 80.0%. The early BPcerebellum showed significantly greater SP and PPV than the late quantitative indices. Combined criteria regarding both early and late indices exhibited only greater NPV. The quantitative indices showed high diagnostic performances in differentiating APS from PD. Our findings provide the dual-phase 18F-FP-CIT PET/CT would be useful for differentiating APS from PD.

Radiomics on routine T1-weighted MRI can delineate Parkinson's disease from multiple system atrophy and progressive supranuclear palsy.

This study aimed to explore the feasibility of radiomics features extracted from T1-weighted MRI images to differentiate Parkinson's disease (PD) from atypical parkinsonian syndromes (APS). Radiomics features were computed from T1 images of 65 patients with PD, 61 patients with APS (31: progressive supranuclear palsy and 30: multiple system atrophy), and 75 healthy controls (HC). These features were extracted from 19 regions of interest primarily from subcortical structures, cerebellum, and brainstem. Separate random forest classifiers were applied to classify different groups based on a reduced set of most important radiomics features for each classification as determined by the random forest-based recursive feature elimination by cross-validation method. The PD vs HC classifier illustrated an accuracy of 70%, while the PD vs APS classifier demonstrated a superior test accuracy of 92%. Moreover, a 3-way PD/MSA/PSP classifier performed with 96% accuracy. While first-order and texture-based differences like Gray Level Co-occurrence Matrix (GLCM) and Gray Level Difference Matrix for the substantia nigra pars compacta and thalamus were highly discriminative for PD vs HC, textural features mainly GLCM of the ventral diencephalon were highlighted for APS vs HC, and features extracted from the ventral diencephalon and nucleus accumbens were highlighted for the classification of PD and APS. This study establishes the utility of radiomics to differentiate PD from APS using routine T1-weighted images. This may aid in the clinical diagnosis of PD and APS which may often be indistinguishable in early stages of disease. • Radiomics features were extracted from T1-weighted MRI images. • Parkinson's disease and atypical parkinsonian syndromes were classified at an accuracy of 92%. • This study establishes the utility of radiomics to differentiate Parkinson's disease and atypical parkinsonian syndromes using routine T1-weighted images.

Atypical parkinsonian syndromes: a general neurologist's perspective.

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non-fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson-plus syndromes in the past, they are now classified as FTD-related disorders, reflecting that they pathologically differ from α-synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.

18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment.

Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. In addition, with the development of invasive therapies and novel disease-specific therapies, strategies for patient enrichment in trial populations are of growing importance. Imaging disease-specific patterns of regional glucose metabolism with PET and 18F-FDG allows for a highly accurate distinction between Parkinson disease (PD) and atypical parkinsonian syndromes, including multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. On the basis of a preliminary metaanalysis of currently available studies with inclusion of multiple disease groups, we estimated that the diagnostic sensitivity and specificity for visual PET readings supported by voxel-based statistical analyses for diagnosis of atypical parkinsonian syndromes are 91.4% and 90.6%, respectively. The diagnostic specificity of 18F-FDG PET for diagnosing multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration was consistently shown to be high (>90%), whereas sensitivity was more variable (>75%). It is increasingly acknowledged that cognitive impairment represents a major challenge in PD, with mild cognitive impairment being a prodromal stage of PD with dementia (PDD). In line with clinical and neuropsychologic studies, recent PET studies demonstrated that posterior cortical dysfunction in nondemented PD patients precedes cognitive decline and the development of PDD by several years. Taken together, the current literature underscores the utility of 18F-FDG PET for diagnostic evaluation of parkinsonism and the promising role of 18F-FDG PET for assessment and risk stratification of cognitive impairment in PD.

Patterns of gray matter atrophy in atypical parkinsonism syndromes: a VBM meta-analysis.

Background and PurposeAccurate diagnosis of Atypical Parkinsonian Syndromes (APS) is important due to differences in prognosis and management, but remains a challenge in the clinical setting. The purpose of our meta-analysis was to identify characteristic patterns of gray matter atrophy in Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Multisystem-Atrophy Parkinsonian type (MSA-P), and Idiopathic Parkinson's Disease (IPD).Materials and MethodsWhole-brain meta-analysis was performed on 39 published voxel-based morphometry (VBM) articles (consisting of 404 IPD, 87 MSA-P, 165 CBD, and 176 PSP subjects) using the modified Anatomic Likelihood Estimation method. Based on these results, contrast analyses were then utilized to determine areas of atrophy shared by as well as unique to each disorder.ResultsCBD was characterized by asymmetric gray matter atrophy in multiple cortical regions, while the thalamus-midbrain and insula were predominantly involved in PSP. The striatum and superior cerebellum were affected in MSA-P, while IPD demonstrated an anterior cerebral pattern. Although there was a mild overlap among PSP, CBD, and MSA-P, significant regions of atrophy unique to each disorder were identified, including (1) the superior parietal lobule in CBD (2) putamen in MSA-P (3) insula and medial dorsal nucleus in PSP.ConclusionOur results suggest that there are characteristic patterns of atrophy in APS. Guided by these findings, future studies on the individual subject level may lead to the development of robust imaging biomarkers.

A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes

BackgroundPatients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system...

Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson's disease

The aim of this study was to investigate whether visual assessment of (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan ((123)I-FP-CIT) single photon emission computed tomography (SPECT) in addition to quantitative analyses can help to differentiate idiopathic Parkinson's disease (PD) from atypical parkinsonian syndromes (APS). From a consecutive series of patients examined with (123)I-FP-CIT SPECT (n = 190) over a three-year period we identified 165 patients with a clinical diagnosis of PD (n = 120) or APS (n = 45). (123)I-FP-CIT SPECT results were analysed visually and quantitatively and compared for PD and APS and for the subgroup of patients with early PD and APS (disease duration <5 years). According to predefined visual patterns of dopaminergic degeneration the results were graded as normal (grade 5) or abnormal (grade 1-4), distinguishing a posterior-anterior degeneration pattern ("egg shape") from a global and severe degeneration pattern ("burst striatum"). Visual assessment of (123)I-FP-CIT SPECT showed significant different dopaminergic degeneration patterns for PD and APS patients. A grade 1 ("burst striatum") degeneration pattern was predominantly associated with APS patients. In contrast to that, a grade 2 (egg shape) degeneration pattern was the characteristic finding in PD patients. In a subgroup of patients with early disease, visual assessment with identification of the burst striatum degeneration pattern provided 90% positive predictive value and 99% specificity for the diagnosis of APS. Quantitative analysis of striatal binding ratios failed to depict these different degeneration patterns in PD and APS patients. Visual assessment of the pattern of dopaminergic loss in (123)I-FP-CIT SPECT shows different patterns of dopaminergic degeneration for PD and APS patients. Therefore, it could provide valuable information to distinguish APS from PD patients, especially in early stages of disease. Within the first 5 years of disease, the occurrence of a burst striatum degeneration pattern has a high positive predictive value of APS.

Anal sphincter EMG in the diagnosis of parkinsonian syndromes

The role of electromyography (EMG) recorded from the external anal sphincter (EAS) in the diagnosis of atypical parkinsonian syndromes is a matter for continuous debate. Most studies addressing this issue are retrospective. In this study, we prospectively investigated six patients with Parkinson's Disease (IPD), 14 patients with multiple system atrophy (MSA) and eight with progressive supranuclear palsy (PSP) using EMG of the EAS, motor-evoked potential (MEP) to the EAS and EMG of m. gastrocnemius and nerve conduction velocity measured at the sural nerve. Patients were followed up for 2 years to secure correct diagnosis. The mean duration of motor unit potentials (MUPs) recorded from the EAS was significantly longer in patients with MSA and PSP compared with MUPs recorded from patients with PD (P < 0.005 for both). There were no signs of diffuse loss of motor neurons or peripheral neuropathy. MEP revealed signs of supranuclear affection in patients with MSA, whereas in patients with PSP the mechanism is a focal loss of motor neurons in Onuf's nucleus. Abnormal EMG of the EAS is strongly suggestive of atypical parkinsonism and the pathophysiology may be different in patients with MSA and PSP.

Neurofilament heavy‐chain NfHSMI35 in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfH(SMI35) in the laboratory-supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinson's disease (PD; n = 22), multiple-system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age-matched controls (n = 45) were included. CSF levels of NfH(SMI35) were measured using ELISA. Levels of CSF NfH(SMI35) were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfH(SMI35) differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfH(SMI35) is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfH(SMI35) may therefore be of some value for the laboratory-supported differential diagnosis of atypical parkinsonian syndromes.

The dopamine D2 receptor ligand 18F-desmethoxyfallypride: an appropriate fluorinated PET tracer for the differential diagnosis of parkinsonism

For therapeutic and prognostic reasons it is important to differentiate between idiopathic parkinsonian syndrome (IPS, Parkinson's disease) and atypical parkinsonian syndromes (APS) like multiple system atrophy or progressive supranuclear palsy. Whereas IPS patients usually show a normal or upregulated postsynaptic dopamine D2 receptor profile, APS patients present decreased postsynaptic tracer binding. The aim of this prospective study was to evaluate the D2 receptor antagonist fluorine-18 desmethoxyfallypride (18F-DMFP), a recently developed positron emission tomography (PET) tracer with better clinical availability than carbon-11 raclopride, for the differential diagnosis of IPS versus APS. The study included 16 healthy control subjects and 35 patients with clinically diagnosed parkinsonism (16 IPS patients, 19 APS patients). All patients underwent PET imaging after injection of 180-200 MBq 18F-DMFP. Receiver operating characteristic (ROC) analyses were performed in order to assess the diagnostic performance of 18F-DMFP PET. We found the striatal 18F-DMFP uptake ratio to be significantly (P<0.01) reduced in the APS patients (2.44+/-0.42) compared with the healthy control subjects (3.61+/-0.43) and the IPS patients (3.21+/-0.78), whereas the uptake ratios of the IPS patients and the control subjects did not differ significantly. For the differential diagnosis of APS versus IPS, the ROC analysis of caudate 18F-DMFP binding showed a specificity, sensitivity and accuracy of 100%, 74% and 86%, respectively, as well as positive and negative predictive values of 100% and 76%, respectively. Based on these first clinical results, we consider 18F-DMFP to be an appropriate PET tracer for the differential diagnosis of parkinsonian syndromes, with the advantage of better clinical availability than 11C-labelled D2 radioligands.