Publications by authors named "Klaus Seppi"

259 Publications

Pragmatic Approach on Neuroimaging Techniques for the Differential Diagnosis of Parkinsonisms.

Mov Disord Clin Pract 2022 Jan 15;9(1):6-19. Epub 2021 Nov 15.

Institut du Cerveau-ICM, Team "Movement Investigations and Therapeutics," Centre de NeuroImagerie de Recherche-CENIR, Neuroradiology Department Paris France.

Background: Rapid advances in neuroimaging technologies in the exploration of the living human brain also apply to movement disorders. However, the accurate diagnosis of Parkinson's disease (PD) and atypical parkinsonian disorders (APDs) still remains a challenge in daily practice.

Methods: We review the literature and our own experience as the Movement Disorder Society-Neuroimaging Study Group in Movement Disorders with the aim of providing a practical approach to the use of imaging technologies in the clinical setting.

Results: The enormous amount of articles published so far and our increasing recognition of imaging technologies contrast with a lack of imaging protocols and updated algorithms for differential diagnosis. The distinctive pathological involvement in different brain structures and the correlation with imaging findings obtained with magnetic resonance, positron emission tomography, or single-photon emission computed tomography illustrate what qualitative and quantitative measures may be useful in the clinical setting.

Conclusion: We delineate a pragmatic approach to discuss imaging technologies, updated imaging algorithms, and their implications for differential diagnoses in PD and APDs.
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http://dx.doi.org/10.1002/mdc3.13354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721825PMC
January 2022

Association of Essential Tremor With Novel Risk Loci: A Genome-Wide Association Study and Meta-analysis.

JAMA Neurol 2022 Jan 4. Epub 2022 Jan 4.

Parkinson's and Movement Disorders Center, Department of Neurology, Virginia Commonwealth University, Richmond.

Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified.

Objective: To identify common genetic factors associated with risk of ET.

Design, Setting, And Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used.

Main Outcomes And Measures: Genotypes of common variants associated with risk of ET.

Results: Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum.

Conclusions And Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.
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http://dx.doi.org/10.1001/jamaneurol.2021.4781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728658PMC
January 2022

Associations of Gait Disorders and Recurrent Falls in Older People: A Prospective Population-Based Study.

Gerontology 2021 Dec 28:1-6. Epub 2021 Dec 28.

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

Background: Recurrent falls represent a major source of serious adverse health outcomes in the general older population. Gait impairment has been linked to recurrent falls, but there are only limited long-term data on this association.

Objectives: The objective of the study was to investigate the association of gait disorders (GDs) and gait tests with future falls in an existing longitudinal population-based cohort.

Method: The study was performed in participants of the Bruneck Study cohort 2010 aged 60-97 years, with prospective 5-year follow-up. At baseline, participants underwent a clinical gait assessment (to determine neurological and non-neurological GDs according to an established classification) and were also evaluated by quantitative and semiquantitative gait tests (Hauser Index, Tinetti balance and gait test, and gait speed). Logistic regression analysis adjusted for age and sex was used to determine the relationship of baseline variables with incident recurrent falls at 5-year follow-up.

Results: Of 328 included participants, 22 (6.7%) reported recurrent falls at follow-up. Baseline presence of GDs was associated with recurrent falls at follow-up (odds ratio [OR] 4.2; 95% confidence interval [CI] 1.6-11.1; p = 0.004), and this effect was largely driven by neurological GDs (OR 5.5; 95% CI 1.7-17.4; p = 0.004). All 3 simple gait tests were predictive for incident falls (Hauser Index, p = 0.002; Tinetti test, p = 0.006; and gait speed, p < 0.001).

Conclusions: Clinical assessment of GDs and gait tests both had independent significant predictive value for recurrent falls over a 5-year follow-up period. This highlights the potential of such assessments for early fall risk screening and timely implementation of fall-preventive measures.
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http://dx.doi.org/10.1159/000520959DOI Listing
December 2021

Factors associated with augmentation in patients with restless legs syndrome.

Eur J Neurol 2021 Dec 18. Epub 2021 Dec 18.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background And Purpose: Augmentation is a paradoxical reaction mainly to dopaminergic medication in patients with restless legs syndrome (RLS), but the exact pathomechanism remains unclear. The aim of this study was to identify factors associated with augmentation in RLS patients.

Methods: RLS patients with and without current or previous augmentation were recruited. Demographic characteristics, history of smoking, questionnaires for depression, alexithymia, and impulsivity, and RLS severity were obtained.

Results: We included 122 patients, of whom half had a history of augmentation. Patients with augmentation had a longer disease duration (p = 0.001), had higher RLS severity scores (p = 0.013), had higher levodopa equivalent doses (p < 0.001), had higher scores for alexithymia (p = 0.028), had higher prevalence of impulse control disorders (p < 0.001), more often had a history of smoking (p = 0.039), were more often currently smoking (p = 0.015), and had more average pack-years (p = 0.016).

Conclusions: Here, we describe several factors commonly associated with augmentation in RLS. These may help clinicians to screen and treat patients carefully to avoid the challenging side effect of augmentation.
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http://dx.doi.org/10.1111/ene.15221DOI Listing
December 2021

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

Mov Disord 2022 Jan 29;37(1):25-35. Epub 2021 Nov 29.

Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments.

Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers.

Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention.

Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments.

Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28855DOI Listing
January 2022

Tit for tat: costly punishment in manifest Huntington's disease.

Neurodegener Dis 2021 Oct 27. Epub 2021 Oct 27.

Objective: We aimed to investigate costly punishment in patients with HD.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with motor, cognitive, and psychiatric symptoms. As neuropsychiatric abnormalities often precede motor symptoms, we wanted to assess whether costly punishment is part of the neuropsychological profile of patients with HD.

Methods: A total of 40 non demented subjects were prospectively enrolled in this study with a between-subject design comparing manifest HD patients (n=18) to healthy controls (HC; n=22). All participants performed eight rounds of a costly punishment task, in which money was shared unevenly in 5 rounds or in a fair manner in the remaining three rounds. Participants then had to decide whether they wanted to punish the trustee. Furthermore, all participants underwent neuropsychological background tasks.

Results: HD patients performed worse in the neuropsychological background tests compared to HC (all p-values<0.05). Moreover, HD patients punished more often in fair (Wald x2=5.03, p=0.025) but not in unfair rounds (Wald x2=1.63, p=0.202).

Conclusions: Our results demonstrate increased costly punishment during fair conditions in HD patients. Whether this behaviour is due to a lack of recognition of social norms, an impairment in top-down inhibition, or an effect of anti-dopaminergic medication remains unclear.
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http://dx.doi.org/10.1159/000520303DOI Listing
October 2021

Urodynamic Evaluation in Multiple System Atrophy: A Retrospective Cohort Study.

Mov Disord Clin Pract 2021 Oct 21;8(7):1052-1060. Epub 2021 Jul 21.

Department of Neurology Medical University of Innsbruck Innsbruck Austria.

Background: Urological dysfunction in patients with multiple system atrophy (MSA) is one of the main manifestations of autonomic failure. Urodynamic examination is clinically relevant since underlying pathophysiology of lower urinary tract (LUT) dysfunction can be variable.

Objective: Evaluation of the pathophysiology of urological symptoms and exploration of differences in urodynamic patterns of LUT dysfunction between MSA-P and MSA-C.

Methods: Retrospective study of patients with possible and probable MSA who were referred for urodynamic studies between 2004 and 2019. Demographic data, medical history, physical examination and urodynamic studies assessing storage and voiding dysfunction were obtained.

Results: Seventy-four patients were included in this study (MSA-P 64.9% n = 48; median age 62.5 (IQR 56.8-70) years). Detrusor overactivity during filling phase was noted in 58.1% (n = 43) of the patients. In the voiding phase, detrusor sphincter dyssynergia and detrusor underactivity were observed in 24.6% (n = 17) and in 62.1% (n = 41) of the patients, respectively. A postmicturition residual volume of over 100 ml was present in 71.4% (n = 50) of the patients. Comparison of MSA subtypes showed weaker detrusor contractility in MSA-P compared to MSA-C [pdetQmax 26.2 vs. 34.4 cmH20,  = 0.04]. In 56.2% (n = 41) of patients pathophysiology of LUT dysfunction was deemed to be neurogenic and consistent with the diagnosis of MSA. In 35.6% (n = 26) urodynamic pattern suggested other urological co-morbidities.

Conclusion: Urodynamic evaluation is an important tool to analyze the pattern of LUT dysfunction in MSA. Impaired detrusor contractility was seen more in MSA-P which needs to be investigated in further studies.
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http://dx.doi.org/10.1002/mdc3.13307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485589PMC
October 2021

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [ C]PBR28 and Machine Learning Analysis.

Mov Disord 2022 Jan 5;37(1):119-129. Epub 2021 Oct 5.

Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.

Background: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA.

Objective: In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.

Methods: We analyzed [ C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA.

Results: We observed a conspicuous pattern of elevated regional [ C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns.

Conclusions: We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28814DOI Listing
January 2022

Factors associated with impaired quality of life three months after being diagnosed with COVID-19.

Qual Life Res 2021 Sep 28. Epub 2021 Sep 28.

Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Purpose: To assess patient characteristics associated with health-related quality of life (HR-QoL) and its mental and physical subcategories 3 months after diagnosis with COVID-19.

Methods: In this prospective multicentre cohort study, HR-QoL was assessed in 90 patients using the SF-36 questionnaire (36-item Short Form Health Survey), which consists of 8 health domains that can be divided into a mental and physical health component. Mental health symptoms including anxiety, depression, and post-traumatic stress disorders were evaluated using the Hospital Anxiety and Depression Scale (HADS) and Post-traumatic Stress Disorder Checklist-5 (PCL-5) 3 months after COVID-19. Using descriptive statistics and multivariable regression analysis, we identified factors associated with impaired HR-QoL 3 months after COVID-19 diagnosis.

Results: Patients were 55 years of age (IQR, 49-63; 39% women) and were classified as severe (23%), moderate (57%), or mild (20%) according to acute disease severity. HR-QoL was impaired in 28/90 patients (31%). Younger age [per year, adjOR (95%CI) 0.94 (0.88-1.00), p = 0.049], longer hospitalization [per day, adjOR (95%CI) 1.07 (1.01-1.13), p = 0.015], impaired sleep [adjOR (95%CI) 5.54 (1.2-25.61), p = 0.028], and anxiety [adjOR (95%CI) 15.67 (3.03-80.99), p = 0.001) were independently associated with impaired HR-QoL. Twenty-nine percent (n = 26) scored below the normal range on the mental health component of the SF-36 and independent associations emerged for anxiety, depression, and self-reported numbness. Impairments in the physical health component of the SF-36 were reported by 12 (13%) patients and linked to hypogeusia and fatigue.

Conclusion: Every third patient reported a reduction in HR-QoL 3 months after COVID-19 diagnosis and impairments were more prominent in mental than physical well-being.
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http://dx.doi.org/10.1007/s11136-021-02998-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476326PMC
September 2021

Extending the Spectrum of Nonmotor Symptoms with Olfaction in Premotor Huntington's Disease: A Pilot Study.

Neurodegener Dis 2020 9;20(5-6):207-211. Epub 2021 Jul 9.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Objective: The aim of this pilot study was to investigate change of olfactory functions in Huntington's disease (HD).

Background: HD is a neurodegenerative disease characterized by motor, cognitive, and behavioral abnormalities. There are several studies reporting olfactory dysfunction in manifest and some studies in premanifest HD carriers, and a recent neuropathological study demonstrated HD-specific protein aggregation in the anterior olfactory nucleus in HD patients. In this study, we wanted to assess olfactory functions as a possible early nonmotor symptom of HD mutation carriers without disease-specific motor symptoms and HD patients.

Methods: All participants had genetic confirmed HD and were prospectively recruited during their routine control in a specialized outpatient clinic of the Medical University of Innsbruck, Department of Neurology, Austria. Healthy controls (HCs) were caregivers from patients. They were only included if they were younger than 70 years, scored more than 24/30 points on the Mini Mental State Examination, and had no other disease compromising olfactory function. Furthermore, all participants were tested on the Sniffin' sticks 16-items identification test.

Results: We included 23 patients with manifest HD, 13 HD mutation carriers, and 19 HCs. Mutation carriers showed significant impaired odor identification compared to HCs (p < 0.001), as well as Huntington's patients compared with both mutation carriers (p = 0.003) and HCs (p < 0.001).

Conclusions: The results of this pilot study suggest that olfactory dysfunction may be an early nonmotor symptom of HD and could be a potential marker to assess disease progression.
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http://dx.doi.org/10.1159/000518136DOI Listing
July 2021

Automated segmentation of deep brain nuclei using convolutional neural networks and susceptibility weighted imaging.

Hum Brain Mapp 2021 Oct 29;42(15):4809-4822. Epub 2021 Jul 29.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

The advent of susceptibility-sensitive MRI techniques, such as susceptibility weighted imaging (SWI), has enabled accurate in vivo visualization and quantification of iron deposition within the human brain. Although previous approaches have been introduced to segment iron-rich brain regions, such as the substantia nigra, subthalamic nucleus, red nucleus, and dentate nucleus, these methods are largely unavailable and manual annotation remains the most used approach to label these regions. Furthermore, given their recent success in outperforming other segmentation approaches, convolutional neural networks (CNN) promise better performances. The aim of this study was thus to evaluate state-of-the-art CNN architectures for the labeling of deep brain nuclei from SW images. We implemented five CNN architectures and considered ensembles of these models. Furthermore, a multi-atlas segmentation model was included to provide a comparison not based on CNN. We evaluated two prediction strategies: individual prediction, where a model is trained independently for each region, and combined prediction, which simultaneously predicts multiple closely located regions. In the training dataset, all models performed with high accuracy with Dice coefficients ranging from 0.80 to 0.95. The regional SWI intensities and volumes from the models' labels were strongly correlated with those obtained from manual labels. Performances were reduced on the external dataset, but were higher or comparable to the intrarater reliability and most models achieved significantly better results compared to multi-atlas segmentation. CNNs can accurately capture the individual variability of deep brain nuclei and represent a highly useful tool for their segmentation from SW images.
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http://dx.doi.org/10.1002/hbm.25604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449109PMC
October 2021

The Parkinson disease connectome - insights from new imaging studies.

Nat Rev Neurol 2021 09;17(9):527-528

Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1038/s41582-021-00543-3DOI Listing
September 2021

Differentiating PSP from MSA using MR planimetric measurements: a systematic review and meta-analysis.

J Neural Transm (Vienna) 2021 10 8;128(10):1497-1505. Epub 2021 Jun 8.

Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Differential diagnosis of parkinsonian syndromes is considered one of the most challenging in neurology. Quantitative MR planimetric measurements were reported to discriminate between progressive supranuclear palsy (PSP) and non-PSP-parkinsonism. Several studies have used midbrain to pons ratio (M/P) and the Magnetic Resonance Parkinsonism Index (MRPI) in distinguishing PSP patients from those with Parkinson's disease. The current meta-analysis aimed to compare the performance of these measures in discriminating PSP from multiple system atrophy (MSA). A systematic MEDLINE review identified 59 out of 2984 studies allowing a calculation of sensitivity and specificity using the MRPI or M/P. Meta-analyses of results were carried out using random effects modelling. To assess study quality and risk of bias, the QUADAS-2 tool was used. Eight studies were suitable for analysis. The meta-analysis showed a pooled sensitivity and specificity for the MRPI of PSP versus MSA of 79.2% (95% CI 72.7-84.4%) and 91.2% (95% CI 79.5-96.5%), and 84.1% (95% CI 77.2-89.2%) and 89.2% (95% CI 81.8-93.8%), respectively, for the M/P. The QUADAS-2 toolbox revealed a high risk of bias regarding the methodological quality of patient selection and index test, as all patients were seen in a specialized outpatient department without avoiding case control design and no predefined threshold was given regarding MRPI or M/P cut-offs. Planimetric brainstem measurements, in special the MRPI and M/P, yield high diagnostic accuracy for the discrimination of PSP from MSA. However, there is an urgent need for well-designed, prospective validation studies to ameliorate the concerns regarding the risk of bias.
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http://dx.doi.org/10.1007/s00702-021-02362-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528799PMC
October 2021

Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson's Disease: A Randomized, Placebo-Controlled, Phase 1 Study.

J Parkinsons Dis 2021 ;11(3):1079-1089

AFFiRiS AG, Vienna, Austria.

Background: Immunotherapies targeting α-synuclein aim to limit its extracellular spread in the brain and prevent progression of pathology in Parkinson's disease (PD). PD03A is a specific active immunotherapy (SAIT) involving immunization with a short peptide formulation.

Objective: This phase 1 study characterized the safety and tolerability of PD03A in patients with early PD. A key secondary objective was to evaluate immunological activity following immunization.

Methods: This was a phase 1 study of two different doses of PD03A versus placebo in PD patients. Patients were randomized (1:1:1) to receive four priming plus one booster vaccination of PD03A 15μg, PD03A 75μg or placebo and were followed for 52 weeks.

Results: Overall, 36 patients were randomized, of which 35 received five immunizations and completed the study. All patients experienced at least one adverse event. Transient local injection site reactions affected all but two patients; otherwise most AEs were considered unrelated to study treatment. A substantial IgG antibody response against PD03 was observed with a maximum titer achieved at Week-12. Differences in titers between both active groups versus placebo were statistically significant from the second immunization at Week-8 until Week-52.

Conclusion: The safety profile and positive antibody response of PD03A supports the further development of active immunotherapeutic approaches for the treatment of PD.
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http://dx.doi.org/10.3233/JPD-212594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461711PMC
January 2022

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

Ann Neurol 2021 07 7;90(1):62-75. Epub 2021 May 7.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Objective: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD).

Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.

Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.

Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.
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http://dx.doi.org/10.1002/ana.26085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252762PMC
July 2021

Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder.

Brain 2021 05;144(4):1118-1126

Department of Neurosciences, Biomedicine and Movement Sciences University of Verona, Verona, Italy.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.
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http://dx.doi.org/10.1093/brain/awab005DOI Listing
May 2021

Laboratory-Supported Multiple System Atrophy beyond Autonomic Function Testing and Imaging: A Systematic Review by the MoDiMSA Study Group.

Mov Disord Clin Pract 2021 Apr 10;8(3):322-340. Epub 2021 Mar 10.

Department of Neurology Medical University of Innsbruck Innsbruck Austria.

Background: Neuroimaging has been used to support a diagnosis of possible multiple system atrophy (MSA). Only blood pressure changes upon standing are included in the second consensus criteria but other autonomic function tests (AFT) are also useful to diagnose widespread and progressive autonomic failure typical of MSA. Additional diagnostic tools are of interest to improve accuracy of MSA diagnosis.

Objectives: To assess the utility of diagnostic tools beyond brain imaging and AFT in enhancing a laboratory-supported diagnosis of MSA to support the upcoming revision of the consensus criteria.

Methods: The International Parkinson and Movement Disorders Society MSA Study Group (MoDiMSA) performed a systematic review of original papers on biomarkers, sleep studies, genetic, neuroendocrine, neurophysiological, neuropsychological and other tests including olfactory testing and acute levodopa challenge test published before August 2019.

Results: Evaluation of history of levodopa responsiveness and olfaction is useful in patients in whom MSA-parkinsonian subtype is suspected. Neuropsychological testing is useful to exclude dementia at time of diagnosis. Applicability of sphincter EMG is limited. When MSA-cerebellar subtype is suspected, a screening for the common causes of adult-onset progressive ataxia is useful, including spinocerebellar ataxias in selected patients. Diagnosing stridor and REM sleep behavior disorder is useful in both MSA subtypes. However, none of these tools are validated in large longitudinal cohorts of postmortem confirmed MSA cases.

Conclusions: Despite limited evidence, additional laboratory work-up of patients with possible MSA beyond imaging and AFT should be considered to optimize the clinical diagnostic accuracy.
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http://dx.doi.org/10.1002/mdc3.13158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015918PMC
April 2021

Birds of a Feather Flock Together: Disadvantageous Decision Making in Augmented Restless Legs Syndrome Patients with and without Impulse Control Disorders.

Brain Sci 2021 Mar 17;11(3). Epub 2021 Mar 17.

Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Background: Augmentation (AUG) in patients with restless legs syndrome (RLS) can be associated with impulse control disorder (ICD) symptoms, such as compulsive sexual behavior, gambling disorder or compulsive shopping. In this study, we wanted to assess whether RLS patients with AUG differ in decision making from those patients who have augmentation and in addition ICD symptoms (AUG + ICD) in a post hoc analysis of a patient cohort assessed in a previous study.

Methods: In total, 40 RLS patients with augmentation (19 AUG + ICD, 21 AUG without ICDs) were included. RLS diagnosis, severity, and diagnosis of augmentation were made by sleep disorder specialists. ICD symptoms were assessed using semi-structured interviews. All patients performed the beads task, which is an information sampling task where participants must decide from which of the two cups colored beads were drawn. Results were compared to 21 healthy controls (HC).

Results: There was no difference in information sampling or irrational decision making between AUG and AUG + ICD patients ( = 0.67 and = 1.00, respectively). Both patient groups drew less beads and made more irrational decisions than HC (all -values < 0.03, respectively).

Conclusions: Our results suggest that augmentation itself is associated with poorer decision making even in the absence of ICD symptoms. Further studies are necessary to explore whether rapid and hasty decision making are a harbinger of augmentation in RLS.
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http://dx.doi.org/10.3390/brainsci11030383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002414PMC
March 2021

Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia are more frequent in advanced versus early Parkinson's disease.

Sleep 2021 09;44(9)

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

Study Objectives: To evaluate macro sleep architecture and characterize rapid eye movement (REM) sleep without atonia (RWA) by using the SINBAR excessive electromyographic (EMG) montage including mentalis and upper extremity muscles in early and advanced Parkinson's disease (PD).

Methods: We recruited 30 patients with early- and advanced-stage of PD according to Movement Disorder Society (MDS) Clinical Diagnostic Criteria. Participants were classified as early-stage PD if they were treatment-naïve or had no motor complications and had been diagnosed with PD within the previous 6 years. Advanced PD was defined as a disease duration equal to or >6 years with or without motor complications.

Results: There was significantly shorter REM sleep latency in early as compared to the advanced stage of PD. We found that the sleep Innsbruck Barcelona (SINBAR) EMG index and tonic EMG activity of the mentalis muscle in advanced-stage PD were significantly higher than in early-stage PD with a trend in phasic EMG activity of the flexor digitorum superficialis muscles. The SINBAR EMG index, tonic and any EMG activity of the mentalis muscle, and phasic EMG activity of flexor digitorum superficialis muscles significantly correlated with disease duration.

Conclusions: This study analyzed RWA using the SINBAR EMG montage in early- and advanced-stage of PD and showed higher RWA in mentalis and flexor digitorum superficialis muscles and SINBAR EMG index in advanced-PD patients compared to patients in the early stage. Also, polysomnography-confirmed REM sleep behavior disorder was more common in advanced versus early-stage patients. Our findings suggest that RWA worsens or is more intense or more frequent with disease progression.
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http://dx.doi.org/10.1093/sleep/zsab067DOI Listing
September 2021

Characterization and diagnostic potential of diffusion tractography in multiple system atrophy.

Parkinsonism Relat Disord 2021 04 3;85:30-36. Epub 2021 Mar 3.

Medical University of Innsbruck, Department of Neurology, Anichstrasse 35, 6020, Innsbruck, Austria; Medical University of Innsbruck, Neuroimaging Research Core Facility, Anichstrasse 35, 6020, Innsbruck, Austria. Electronic address:

Introduction: Microstructural integrity of the middle cerebellar peduncle (MCP) and the putamen captured by diffusion-tensor imaging (DTI) is differentially affected in the parkinsonian and cerebellar variants of multiple system atrophy (MSA-P, MSA-C) compared to Parkinson's disease (PD). The current study applied DTI and tractography in order to 1) characterize the distribution of DTI metrics along the tracts of the MCP and from the putamen in MSA variants, and 2) evaluate the usefulness of combining these measures for the differential diagnosis of MSA-P against PD in the clinical setting.

Methods: Twenty-nine MSA patients (MSA-C, n = 10; MSA-P, n = 19), with a mean disease duration of 2.8 ± 1.7 years, 19 PD patients, and 27 healthy controls (HC) were included in the study. Automatized tractography with a masking procedure was employed to isolate the MCP tracts. DTI measures along the tracts of the MCP and within the putamen were acquired and jointly used to classify MSA vs. PD, and MSA-P vs. PD. Putamen volume was additionally tested as classification feature in post hoc analyses.

Results: DTI measures within the MCP and putamen showed significant alterations in MSA variants compared to HC and PD. Classification accuracy for MSA vs. PD and MSA-P vs PD using diffusion measures was 91.7% and 89.5%, respectively. When replacing the putaminal DTI measure by a normalized measure of putamen volume classification accuracy improved to 95.8% and 94.7%, respectively.

Conclusion: Multimodal information from MCP tractography and putamen volume yields excellent diagnostic accuracy to discriminate between early-to-moderately advanced patients with MSA and PD.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.027DOI Listing
April 2021

Neurological outcome and quality of life 3 months after COVID-19: A prospective observational cohort study.

Eur J Neurol 2021 Oct 3;28(10):3348-3359. Epub 2021 May 3.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background And Purpose: To assess neurological manifestations and health-related quality of life (QoL) 3 months after COVID-19.

Methods: In this prospective, multicenter, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16-item Sniffin Sticks test), cognitive deficits (Montreal Cognitive Assessment), QoL (36-item Short Form), and mental health (Hospital Anxiety and Depression Scale, Posttraumatic Stress Disorder Checklist-5) 3 months after disease onset.

Results: Of 135 consecutive COVID-19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3-month follow-up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID-19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain-Barré syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3-month follow-up. Self-reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p < 0.001). At follow-up, cognitive deficits were apparent in 23%, and QoL was impaired in 31%. Assessment of mental health revealed symptoms of depression, anxiety, and posttraumatic stress disorders in 11%, 25%, and 11%, respectively.

Conclusions: Despite recovery from the acute infection, neurological symptoms were prevalent at the 3-month follow-up. Above all, smelling disorders were persistent in a large proportion of patients.
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http://dx.doi.org/10.1111/ene.14803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250725PMC
October 2021

Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement.

Clin Auton Res 2021 04 7;31(2):157-164. Epub 2021 Feb 7.

Department of Neurology, Dysautonomia Center, New York University School of Medicine, 530 First Av, Suite 9Q, New York, NY, 10016, USA.

Purpose: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA.

Methods: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations.

Results: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others.

Conclusions: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.
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http://dx.doi.org/10.1007/s10286-021-00782-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868077PMC
April 2021

A Modified Progressive Supranuclear Palsy Rating Scale.

Mov Disord 2021 05 29;36(5):1203-1215. Epub 2021 Jan 29.

Department of Neurology, Technische Universität München, Munich, Germany.

Background: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status.

Objective: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones.

Methods: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy.

Results: The modified scale retained 14 items (yielding 0-2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months).

Conclusions: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28470DOI Listing
May 2021

Towards subgroup-specific risk estimates: A meta-analysis of longitudinal studies on olfactory dysfunction and risk of Parkinson's disease.

Parkinsonism Relat Disord 2021 03 12;84:155-163. Epub 2021 Jan 12.

Radboud University Medical Centre; Donders Institute for Brain, Cognition and Behaviour; Department of Neurology; Center of Expertise for Parkinson & Movement Disorders; Nijmegen, the Netherlands; Department of Epidemiology; Erasmus MC University Medical Centre; the Netherlands. Electronic address:

Background: Interest has risen in identifying individuals at high risk of incident Parkinson's disease (PD) to facilitate inclusion in neuroprotective treatment trials. Current risk estimates of prodromal markers are based on aggregated data of an entire population, but this approach disregards differences in risk estimates by subgroups of a population. In this proof of concept, we determine subgroup-specific risk estimates of olfactory dysfunction for incident PD.

Methods: PubMed, EMBASE and Cochrane were searched for prospective studies investigating the association between olfactory dysfunction and incident PD. Random-effects meta-analysis, subgroup analyses and meta-regression were performed to investigate general and subgroup risk estimates.

Results: Individuals with odor identification dysfunction seemed to be at greater risk of incident PD compared to controls without olfactory dysfunction (OR = 4.18; 95%CI [2.47-7.07]). Risk estimates were higher in studies that included higher percentages of women (regression slope β = 0.053 increase in log odds ratio per 1% increase 1%, p = 0.0006), increased with mean study age (β = 0.21 per one year increase; p = 0.005) and in REM-sleep behavior disorder cohorts (β = 1.95; p = 0.03). Furthermore, the association between olfactory dysfunction and incident PD was most distinct in studies with shorter follow-up duration (ß = -0.56; p = 0.0047).

Conclusion: The presence of olfactory dysfunction conveys a considerably elevated risk of incident PD, likely more in studies with a higher proportion of women, older individuals or short follow-up duration. Individual patient data are warranted to confirm these findings and to yield subgroup-specific risk estimates of other common markers to refine prodromal PD criteria.
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http://dx.doi.org/10.1016/j.parkreldis.2021.01.005DOI Listing
March 2021

Impaired Inhibitory Control of Saccadic Eye Movements in Cervical Dystonia: An Eye-Tracking Study.

Mov Disord 2021 05 8;36(5):1246-1250. Epub 2021 Jan 8.

Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

Background: The pathophysiology of cervical dystonia is still unclear. Recent evidence points toward a network disorder affecting several brain areas. The objective of this study was to assess the saccadic inhibition as a marker of corticostriatal function in cervical dystonia.

Methods: We recruited 31 cervical dystonia patients and 17 matched healthy controls. Subjects performed an overlap prosaccade, an antisaccade, and a countermanding task on an eye tracker to assess automatic visual response and response inhibition.

Results: Cervical dystonia patients made more premature saccades (P = 0.041) in the overlap prosaccade task and more directional errors in the antisaccade task (P = 0.011) and had a higher rate of failed inhibition in the countermanding task (P = 0.001).

Conclusions: The results suggest altered saccadic inhibition in cervical dystonia, possibly as a consequence of dysfunctional corticostriatal networks. Further studies are warranted to confirm whether these abnormalities are affected by the available therapies and whether this type of impairment is found in other focal dystonias. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247854PMC
May 2021

Characterization of gait variability in multiple system atrophy and Parkinson's disease.

J Neurol 2021 May 31;268(5):1770-1779. Epub 2020 Dec 31.

Department of Molecular Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander University, Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.

Background: Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls.

Objectives: We compared gait variability at different walking velocities between and within groups of patients with Parkinson-variant multiple system atrophy, idiopathic Parkinson's disease, and a control group of older adults.

Methods: Gait metrics were recorded in 11 multiple system atrophy, 12 Parkinson's disease patients, and 18 controls using sensor-based gait analysis. Gait variability was analyzed for stride, swing and stance time, stride length and gait velocity. Values were compared between and within the groups at self-paced comfortable, fast and slow walking speed.

Results: Multiple system atrophy patients displayed higher gait variability except for stride time at all velocities compared with controls, while Parkinson's patients did not. Compared with Parkinson's disease, multiple system atrophy patients displayed higher variability of swing time, stride length and gait velocity at comfortable speed and at slow speed for swing and stance time, stride length and gait velocity (all P < 0.05). Stride time variability was significantly higher in slow compared to comfortable walking in patients with multiple system atrophy (P = 0.014). Variability parameters significantly correlated with the postural instability/gait difficulty subscore in both disease groups. Conversely, significant correlations between variability parameters and MDS-UPDRS III score was observed only for multiple system atrophy patients.

Conclusion: This analysis suggests that gait variability parameters reflect the major axial impairment and postural instability displayed by multiple system atrophy patients compared with Parkinson's disease patients and controls.
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http://dx.doi.org/10.1007/s00415-020-10355-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068710PMC
May 2021

Diagnostic accuracy of MR planimetry in clinically unclassifiable parkinsonism.

Parkinsonism Relat Disord 2021 01 24;82:87-91. Epub 2020 Nov 24.

Department of Neurology, Medical University of Innsbruck, Austria; Neuroimaging Core Facility, Medical University Innsbruck, Innsbruck, Austria. Electronic address:

Introduction: Quantitative MR planimetric measurements were reported to discriminate between progressive supranuclear palsy (PSP) and non-PSP parkinsonism, yet few data exist on the usefulness of these markers in early disease stages.

Methods: The pons-to-midbrain area ratio (P/M) and the Magnetic Resonance Parkinsonism Index (MRPI) as well as new indices, termed P/M2.0 and MRPI2.0, multiplying the former by a ratio of the third ventricle (3rdV) width/frontal horns (FH) width, were calculated on T1-weighted images in 84 patients with clinically unclassifiable neurodegenerative parkinsonism (CUP) at the time of imaging. Areas under the curve (AUCs) of these markers for predicting future PSP was determined. The final clinical diagnosis was made after at least 24 months of follow-up.

Results: Final diagnosis was Parkinson's disease in 55 patients, multiple system atrophy in 12 cases, and PSP in 17. At baseline imaging, patients with a final PSP diagnosis had significantly higher MRPI, P/M, MRPI2.0 and P/M2.0 values compared to the other groups. AUCs in discriminating between future PSP and non-PSP parkinsonism were 0.91 for both the P/M and the MRPI and 0.98 for the P/M2.0 and the MRPI2.0.

Conclusions: Brainstem-derived MR planimetric measures yield high diagnostic accuracy for separating PSP from non-PSP parkinsonism in early disease stages when clinical criteria are not yet fully met. Consistent with the underlying pathology in PSP, our study suggests that inclusion of 3V width makes P/M2.0 and MRPI2.0 more accurate in diagnosing early stage PSP patients than the P/M and MRPI.
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http://dx.doi.org/10.1016/j.parkreldis.2020.11.019DOI Listing
January 2021
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