Publications by authors named "Stefanie Schreiber"

71 Publications

Detection of Cerebral Microbleeds With Venous Connection at 7 Tesla MRI.

Neurology 2021 Mar 2. Epub 2021 Mar 2.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

Objective: Cerebral microbleeds (MBs) are a common finding in cerebral small vessel disease (CSVD) and Alzheimer's disease patients as well as in healthy elderly people, but their pathophysiology remains unclear. To investigate a possible role of veins in the development of MBs, we performed an exploratory study, assessing in vivo presence of MBs with a direct connection to a vein.

Methods: 7 Tesla (7 T) MRI was conducted and MBs were counted on Quantitative Susceptibility Mapping (QSM). A submillimeter resolution QSM-based venogram allowed identification of MBs with a direct spatial connection to a vein.

Results: 51 subjects (mean age [SD] 70.5[8.6] years, 37% females) participated in the study: 20 were patients with CSVD (cerebral amyloid angiopathy (CAA) with strictly lobar MBs (n=8), hypertensive arteriopathy (HA) with strictly deep MBs (n=5), and mixed lobar and deep MBs (n=7), 72.4 [6.1] years, 30% females) and 31 were healthy controls (69.4 [9.9] years, 42% females). In our cohort, we counted a total of 96 MBs with a venous connection, representing 14% of all detected MBs on 7T QSM. Most venous MBs (86%, n = 83) were observed in lobar locations and all of these were cortical. CAA subjects showed the highest ratio of venous to total MBs (19%) (HA=9%, mixed=18%, controls=5%) CONCLUSIONS: Our findings establish a link between cerebral MBs and the venous vasculature, pointing towards a possible contribution of veins to CSVD in general and to CAA in particular. Pathological studies are needed to confirm our observations.
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http://dx.doi.org/10.1212/WNL.0000000000011790DOI Listing
March 2021

High-Resolution Nerve Ultrasound Abnormalities in POEMS Syndrome-A Comparative Study.

Diagnostics (Basel) 2021 Feb 9;11(2). Epub 2021 Feb 9.

Center for Neurology, Tuebingen University Hospital and Hertie-Institute for Clinical Brain Research, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.

Background: High-resolution nerve ultrasound (HRUS) has been proven to be a valuable tool in the diagnosis of immune-mediated neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is an important differential diagnosis of CIDP. Until now, there have been no studies that could identify specific HRUS abnormalities in POEMS syndrome patients. Thus, the aim of this study was to assess possible changes and compare findings with CIDP patients.

Methods: We retrospectively analyzed HRUS findings in three POEMS syndrome and ten CIDP patients by evaluating cross-sectional nerve area (CSA), echogenicity and additionally calculating ultrasound pattern scores (UPSA, UPSB, UPSC and UPSS) and homogeneity scores (HS).

Results: CIDP patients showed greater CSA enlargement and higher UPSS (median 14 vs. 11), UPSA (median 11.5 vs. 8) and HS (median 5 vs. 3) compared with POEMS syndrome patients. However, every POEMS syndrome patient illustrated enlarged nerves exceeding reference values, which were not restricted to entrapment sites. In CIDP and POEMS syndrome, heterogeneous enlargement patterns could be identified, such as inhomogeneous, homogeneous and regional nerve enlargement. HRUS in CIDP patients visualized both increased and decreased echointensity, while POEMS syndrome patients pictured hypoechoic nerves with hyperechoic intraneural connective tissue. This is the first study to demonstrate HRUS abnormalities in POEMS syndrome outside of common entrapment sites. Although nerve enlargement was more prominent in CIDP, POEMS syndrome patients revealed distinct echogenicity patterns, which might aid in its differentiation from CIDP. Future studies should consider HRUS and its possible role in determining diagnosis, prognosis and treatment response in POEMS syndrome.
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http://dx.doi.org/10.3390/diagnostics11020264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915164PMC
February 2021

From many, one: A call for meta-cohorts in neuromuscular ultrasound.

Eur J Neurol 2021 May 23;28(5):1435-1436. Epub 2021 Feb 23.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

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http://dx.doi.org/10.1111/ene.14767DOI Listing
May 2021

DimLift: Interactive Hierarchical Data Exploration through Dimensional Bundling.

IEEE Trans Vis Comput Graph 2021 Feb 5;PP. Epub 2021 Feb 5.

The identification of interesting patterns and relationships is essential to exploratory data analysis. This becomes increasingly difficult in high dimensional datasets. While dimensionality reduction techniques can be utilized to reduce the analysis space, these may unintentionally bury key dimensions within a larger grouping and obfuscate meaningful patterns. With this work we introduce DimLift, a novel visual analysis method for creating and interacting with dimensional bundles. Generated through an iterative dimensionality reduction or user-driven approach, dimensional bundles are expressive groups of dimensions that contribute similarly to the variance of a dataset. Interactive exploration and reconstruction methods via a layered parallel coordinates plot allow users to lift interesting and subtle relationships to the surface, even in complex scenarios of missing and mixed data types. We exemplify the power of this technique in an expert case study on clinical cohort data alongside two additional case examples from nutrition and ecology.
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http://dx.doi.org/10.1109/TVCG.2021.3057519DOI Listing
February 2021

Integrated Dual Analysis of Quantitative and Qualitative High-Dimensional Data.

IEEE Trans Vis Comput Graph 2021 Feb 3;PP. Epub 2021 Feb 3.

The Dual Analysis framework is a powerful enabling technology for the exploration of high dimensional quantitative data by treating data dimensions as first-class objects that can be explored in tandem with data values. In this work, we extend the Dual Analysis framework through the treatment of quantitative (numerical) and qualitative (categorical) dimensions. Computing common measures for all dimensions allows us to visualize both quantitative and qualitative dimensions in the same view. This enables a natural treatment of mixed data during interactive visual exploration and analysis. Several measures of variation for nominal qualitative data can also be applied to ordinal qualitative and quantitative data. For example, instead of measuring variability from a mean or median, other measures assess inter-data variation or average variation from a mode. In this work, we demonstrate how these measures can be integrated into the Dual Analysis framework to explore and generate hypotheses about high-dimensional mixed data. A medical case study using clinical routine data of patients suffering from Cerebral Small Vessel Disease (CSVD), conducted with a senior neurologist and a medical student, shows that a joint Dual Analysis approach for quantitative and qualitative data can rapidly lead to new insights based on which new hypotheses may be generated.
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http://dx.doi.org/10.1109/TVCG.2021.3056424DOI Listing
February 2021

Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers.

Exp Neurol 2021 May 23;339:113620. Epub 2021 Jan 23.

Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.
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http://dx.doi.org/10.1016/j.expneurol.2021.113620DOI Listing
May 2021

Longitudinal clinical and neuroanatomical correlates of memory impairment in motor neuron disease.

Neuroimage Clin 2021 25;29:102545. Epub 2020 Dec 25.

Department of Neurology, Otto-von-Guericke University Magdeburg, Germany; Leibniz Institute for Neurobiology, Magdeburg, Germany; Kliniken Schmieder, Heidelberg, Germany.

Memory impairment in motor neuron disease (MND) is still an underrecognized feature and has traditionally been attributed to executive dysfunction. Here, we investigate the rate of memory impairment in a longitudinal cohort of MND patients, its relationship to other cognitive functions and the underlying neuroanatomical correlates. 142 patients with MND and 99 healthy controls (HC) underwent comprehensive neuropsychological testing and structural MRI at 3T up to four times over a period of 18 months. Linear-mixed effects models were fitted to identify changes at baseline and over time in episodic memory function (learning, immediate and delayed recall, recognition), composed cognitive scores (memory, verbal fluency, executive function), and memory-related structural brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus). Associations between episodic memory performance and volumetric or cortical thickness changes of these regions were computed using Pearson's r. Learning, immediate and delayed recall, as well as recognition performance were significantly reduced in MND when compared to controls at baseline. Performances in these subtests improved over time although MND showed less improvement than controls. This relationship did not change when only "classical" ALS patients were considered. Patients with MND showed thinning of the right parahippocampal gyrus (PhG) in comparison to controls that was progressing over time. Bilateral hippocampal atrophy was observed in MND patients with memory impairment after splitting the group according to their overall episodic memory performance, with the right hippocampus shrinking over time. In MND patients, the bilateral hippocampal atrophy was associated with impairment in learning, recall, and recognition at baseline. In contrast, left PhG thinning was associated with a poorer learning performance. These results show that episodic memory impairment in MND is a frequent cognitive dysfunction. Since deficits are not clearly declining with disease course, an early involvement of this cognitive domain in the disease seems probable. The memory performance-dependent atrophy of the hippocampus and PhG provide evidence for a widespread involvement of these non-motor cortical areas in disease pathology.
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http://dx.doi.org/10.1016/j.nicl.2020.102545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786131PMC
December 2020

Topographical layer imaging as a tool to track neurodegenerative disease spread in M1.

Nat Rev Neurosci 2021 01;22(1):68-69

Institute for Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

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http://dx.doi.org/10.1038/s41583-020-00404-wDOI Listing
January 2021

MRI phenotyping of underlying cerebral small vessel disease in mixed hemorrhage patients.

J Neurol Sci 2020 Dec 9;419:117173. Epub 2020 Oct 9.

Department of Neurology, Otto-von-Guericke University, Leipziger Straße 44, 39120 Magdeburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120 Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Universitätsplatz 2, 39106 Magdeburg, Germany. Electronic address:

Objective: To investigate underlying cerebral small vessel disease (CSVD) in patients with mixed cerebral hemorrhages patterns and phenotype them according to the contribution of the two most common sporadic CSVD subtypes: cerebral amyloid angiopathy (CAA) vs. hypertensive arteriopathy (HA).

Methods: Brain MRIs of patients with intracerebral hemorrhages (ICHs) and/or cerebral microbleeds (CMBs) were assessed for the full spectrum of CSVD markers using validated scales: ICHs, CMBs, cortical superficial siderosis (cSS), white matter hyperintensities, MRI-visible perivascular spaces (PVS). PVS predominance pattern was grouped as centrum-semiovale (CSO)-PVS predominance, basal-ganglia (BG)-PVS predominance, CSO-PVS and BG-PVS equality. Patients with mixed cerebral hemorrhages were classified into mixed CAA-pattern or mixed HA-pattern according to the existence of cSS and/or a CSO-PVS predominance pattern and comparisons were performed.

Results: We included 110 patients with CAA (strictly lobar ICHs/CMBs), 33 with HA (strictly deep ICHs/CMBs) and 97 with mixed lobar/deep ICHs/CMBs. Mixed patients were more similar to HA with respect to their MRI-CSVD markers, vascular risk profile and cerebrospinal fluid (CSF) measures. In the mixed patients, 33 (34%) had cSS, a CSO-PVS predominance pattern, or both, and were defined as mixed CAA-pattern cases. The mixed CAA-pattern patients were more alike CAA patients regarding their MRI-CSVD markers, CSF and genetic profile.

Conclusion: Our findings suggest that the heterogeneous group of patients with mixed cerebral hemorrhages distribution can be further phenotyped according to the predominant underlying CSVD. cSS presence and a CSO-PVS predominance pattern could serve as strongly suggestive markers of a contribution from CAA among patients with mixed hemorrhages.
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http://dx.doi.org/10.1016/j.jns.2020.117173DOI Listing
December 2020

Textural markers of ultrasonographic nerve alterations in amyotrophic lateral sclerosis.

Muscle Nerve 2020 11 7;62(5):601-610. Epub 2020 Sep 7.

Department of Neurology, Otto von Guericke University, Magdeburg, Germany.

Ultrasound has revealed cross-sectional nerve area (CSA) reduction in amyotrophic lateral sclerosis (ALS), but little is known about the sonographic nerve texture beyond CSA alterations. In a large cohort of 177 ALS patients and 57 control subjects, we investigated the covariance and disease-specific signature of several sonographic texture features of the median and ulnar nerves and their relationship to the patients' clinical characteristics. ALS patients showed atrophic nerves, a loss of the intranerve structures' echoic contrast, elevated coarseness, and a trend toward lower cluster shading compared with controls. A reduction in intranerve echoic contrast was related to longer disease duration and poorer functional status in ALS. Sonographic texture markers point toward a significant reorganization of the deep nerve microstructure in ALS. Future studies will be needed to further substantiate the markers' potential to assess peripheral nerve alterations in ALS.
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http://dx.doi.org/10.1002/mus.27043DOI Listing
November 2020

Modification of In-Hospital Recommendation and Prescription of Anticoagulants for Secondary Prevention of Stroke after Launch of Direct Oral Anticoagulants and Change of National Guidelines.

Cerebrovasc Dis 2020 5;49(4):412-418. Epub 2020 Aug 5.

Department of Neurology, Magdeburg University Vascular and Stroke Center, Magdeburg, Germany.

Introduction: Approximately 1 out of 4 stroke patients suffers ischemic stroke secondary to atrial fibrillation (AF). Although indicated, withholding of anticoagulants for secondary prevention is a widespread phenomenon.

Objective: We examined the longitudinal change of recommendation and prescription of secondary preventive anticoagulation in AF patients in an acute stroke center setting focusing on the impact of the introduction of direct oral anticoagulants (DOACs) and the change of national stroke prevention guidelines.

Methods: Consecutive patients admitted with an acute cerebrovascular ischemic event underwent regular diagnostic work-up. Pseudonymized clinical data were entered into the institution's stroke registry. In those patients with AF, discharge letters were collected and evaluated for temporal trends and affecting factors of recommended and prescribed antithrombotic secondary medication at the time of discharge from hospital.

Results: Of 7,175 patients admitted between January 2009 and December 2018, 1,812 (25.3%) suffered stroke caused by AF. Frequency of patients with recommended anticoagulation increased within the observation period from 66.7 to 95.8% (per year; adjusted odds ratio [OR], 1.309; confidence interval [CI], 1.153-1.486). Independently from this time trend, DOAC approval (adjusted OR, 4.026; CI 1.962-8.265) and guideline change (adjusted OR, 2.184; CI, 1.006-4.743) were associated with an increasing frequency of recommendation for anticoagulation. The rate of patients already receiving recommended anticoagulation for secondary prevention at discharge increased from 42.1 to 62.5%. Introduction of DOACs was not associated with this trend, and guideline change was even associated with decreasing frequency of anticoagulated patients at hospital discharge (adjusted OR, 0.641; CI, 0.414-0.991). Fear of early intracerebral bleeding was the most common reason for withholding anticoagulation (37%) at hospital discharge and stayed stable during the observation period.

Conclusions: Changing national guidelines with discard of contraindications for anticoagulation and the introduction of DOACs led to a broader recommendation of oral anticoagulation. However, both, new guidelines and DOACs, were not found to be associated with an increasing percentage of patients discharged from our hospital already on recommended anticoagulant prevention. This might be explained by the decreasing length of hospital stay during the study period and a missing evidence of early bleeding risk of DOACs in patients with acute brain infarction. Evidence-based data to close this therapeutic gap are needed.
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http://dx.doi.org/10.1159/000509416DOI Listing
November 2020

Peripheral Nerve Imaging Aids in the Diagnosis of Immune-Mediated Neuropathies-A Case Series.

Diagnostics (Basel) 2020 Jul 30;10(8). Epub 2020 Jul 30.

Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany.

Background: Diagnosis of immune-mediated neuropathies and their differentiation from amyotrophic lateral sclerosis (ALS) can be challenging, especially at early disease stages. Accurate diagnosis is, however, important due to the different prognosis and available treatment options. We present one patient with a left-sided dorsal flexor paresis and initial suspicion of ALS and another with multifocal sensory deficits. In both, peripheral nerve imaging was the key for diagnosis.

Methods: We performed high-resolution nerve ultrasound (HRUS) and 7T or 3T magnetic resonance neurography (MRN).

Results: In both patients, HRUS revealed mild to severe, segmental or inhomogeneous, nerve enlargement at multiple sites, as well as an area increase of isolated fascicles. MRN depicted T2 hyperintense nerves with additional contrast-enhancement.

Discussion: Peripheral nerve imaging was compatible with the respective diagnosis of an immune-mediated neuropathy, i.e., multifocal motor neuropathy (MMN) in patient 1 and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) in patient 2. Peripheral nerve imaging, especially HRUS, should play an important role in the diagnostic work-up for immune-mediated neuropathies and their differentiation from ALS.
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http://dx.doi.org/10.3390/diagnostics10080535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459443PMC
July 2020

Retinal Vascular Pathology in a Rat Model of Cerebral Small Vessel Disease.

Front Neurol 2020 30;11:533. Epub 2020 Jun 30.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

The initial disease stages of hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), the two main forms of sporadic human cerebral small vessel diseases (CSVD), are too subtle to be detectable on clinical routine imaging. Small vessel disease (SVD) is a systemic condition, affecting not only the brain, but also other organs. The retina appears as an ideal marker for the early detection of incipient CSVD. We therefore investigated the retinal microvasculature of the spontaneously hypertensive stroke-prone rat (SHRSP), an animal model of sporadic CSVD. The brains and retinas of 26 male SHRSP (18-44 weeks) were examined histologically and immunohistochemically for the presence of HA phenomena (erythrocyte thrombi, small perivascular bleeds) and amyloid angiopathy (AA). CAA and AA in the retina showed a significant correlation with age (CAA: rho = 0.55, = 0.005; AA: rho = 0.89, < 0.001). The number of erythrocyte thrombi in the brain correlated with the severity of retinal erythrocyte thrombi (rho = 0.46, = 0.023), while the occurrence of CAA correlated with the appearance of AA in the retina (rho = 0.51, = 0.012). Retinal SVD markers predicted CSVD markers with good sensitivity. These results indicate that SVD also occurs in the retinal microvasculature of SHRSP and the prediction of cerebral erythrocyte thrombi and CAA might be possible using retinal biomarkers. This underlines the important role of the investigation of the retina in the early diagnosis of CSVD.
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http://dx.doi.org/10.3389/fneur.2020.00533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338761PMC
June 2020

Impaired occipital cerebrovascular reactivity as a biomarker for vascular β-amyloid.

Neurology 2020 09 8;95(10):415-416. Epub 2020 Jul 8.

From the Department of Neurology (S.S.), Otto-von-Guericke University; German Center for Neurodegenerative Diseases (S.S.) within the Helmholtz Association; Center for Behavioral Brain Sciences (S.S.), Magdeburg, Germany; and Department of Neurology (J.C.D.), ASST San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000010207DOI Listing
September 2020

[Peripheral Nerve Imaging - from a Neurological Perspective for Surgeons].

Zentralbl Chir 2020 Dec 2;145(6):541-548. Epub 2020 Jul 2.

Klinik für Neurologie, Städtisches Klinikum Dessau, Deutschland.

Nerve ultrasound is a fairly new non-invasive method to visualise peripheral nerves and to detect peripheral nerve lesions. This technique can depict nerve compression syndromes and their aetiologies as well as fascicular torsions. It is also suitable for sonographically guided nerve interventions and for intraoperative navigation. The main advantage of nerve ultrasound is its capability for early diagnosis of severe traumatic nerve lesions that require immediate surgery. Neurologists further use this method to aid the diagnosis of different kinds of polyneuropathies. Within this review we introduce nerve ultrasound to surgeons from a neurological perspective. We focus on different peripheral nerve disorders that might need surgical interventions. Nerve ultrasound will lay the grounds to bring together different expertise in medicine and thus to establish interdisciplinary excellence centres for the understanding, diagnosis and treatment of diseases of the peripheral nervous system.
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http://dx.doi.org/10.1055/a-1189-3627DOI Listing
December 2020

Interplay between perivascular and perineuronal extracellular matrix remodelling in neurological and psychiatric diseases.

Eur J Neurosci 2020 Jun 28. Epub 2020 Jun 28.

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.

Vascular damage, central nervous system (CNS) injury, seizure or even psychological stress may trigger activation of microglia and infiltration of other immune cells, accompanied by high levels of expression and activity of extracellular proteases, such as matrix metalloproteinases (MMPs), and degradation/remodelling of the perivascular and perineuronal extracellular matrix (ECM). This acute response is followed by the recovery/chronic phase, during which the activation of astrocytes leads to the upregulated synthesis of ECM molecules, which, in combination with elevated expression of tissue inhibitor of metalloproteinases (TIMP) proteins, increases the aggregation of ECM molecules. This biphasic dysregulation of local balance between extracellular proteases and the ECM activates multiple temporally overlapping signalling cascades, involving receptor-type protein tyrosine phosphatases, integrins, Toll-like receptors, cell adhesion molecules, and ion channels, resulting in impaired synaptic plasticity and cognition. An additional level of complexity is related to the leakage of blood plasma proteins, such as fibrinogen, and the diffusion of perivascularly overproduced MMPs, TIMPs and ECM molecules into the CNS parenchyma, leading to diverse effects on neurons and incorporation of these molecules into the interstitial neural ECM. This review aims to outline these complex common mechanisms in stroke, CNS injury, depression, epilepsy, multiple sclerosis and cerebral small vessel disease and to discuss translational strategies to advance the development of new therapies for these neurological and psychiatric diseases.
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http://dx.doi.org/10.1111/ejn.14887DOI Listing
June 2020

Reply: Heterogeneity of the circle of Willis and its implication in hippocampal perfusion.

Brain 2020 07;143(7):e59

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

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http://dx.doi.org/10.1093/brain/awaa170DOI Listing
July 2020

AANEM - IFCN glossary of terms in neuromuscular electrodiagnostic medicine and ultrasound.

Clin Neurophysiol 2020 Jul 27;131(7):1662-1663. Epub 2020 Apr 27.

Department of Neurology, Indiana University, 362 W 15th St, Suite 3200, Indianapolis, IN 46202, USA. Electronic address:

Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide.
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http://dx.doi.org/10.1016/j.clinph.2020.03.014DOI Listing
July 2020

Peripheral nerve imaging in amyotrophic lateral sclerosis.

Clin Neurophysiol 2020 Sep 13;131(9):2315-2326. Epub 2020 Apr 13.

Department of Neurology, Wake Forest School of Medicine, NC, USA.

We systematically identified and reviewed 29 studies of peripheral nerve ultrasound or magnetic resonance imaging (MRN) in amyotrophic lateral sclerosis (ALS). The majority of the ultrasound studies reported smaller nerves and nerve roots in ALS compared to healthy controls, but there was a large overlap of the cross-sectional nerve area between ALS and controls. Most of the MRN studies confirmed nerve abnormalities demonstrating slight T2 hyperintensities and, sometimes, mild enlargement of more proximal nerve segments (plexus, roots) in ALS. The size of the proximal nerve segments, i.e. nerve roots, is thus somewhat incongruent between nerve ultrasound and MRN in ALS. Peripheral nerve ultrasound has the potential to differentiate between ALS and multifocal motor neuropathy (MMN) in that patients with MMN have significantly larger nerves. Conversely, there is an overlap of MRN abnormalities in ALS and MMN, restricting the techniques' utility in the clinical setting. A subgroup of patients with ALS seems to reveal a sonographic nerve pattern suggesting peripheral nerve inflammation. In the future, combined imaging with nerve ultrasound and MRN assessing parameters such as blood flow or textural markers may aid in the understanding of the deep nerve microstructure down to the fascicle level, and thus, in the classification of the nerve state as more degenerative or more inflammatory in ALS. This systematic review provides evidence that nerve imaging abnormalities are common in ALS.
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http://dx.doi.org/10.1016/j.clinph.2020.03.026DOI Listing
September 2020

AANEM - IFCN Glossary of Terms in Neuromuscular Electrodiagnostic Medicine and Ultrasound.

Muscle Nerve 2020 07 26;62(1):10-12. Epub 2020 Apr 26.

author for the AANEM.

Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide. HIGHLIGHTS: Optimal terminology in neuromuscular electrodiagnosis and ultrasound has been revisited. A team of international experts have revised and expanded a standardized glossary. This list of terms serves as standard reference for clinical practice, education and research.
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http://dx.doi.org/10.1002/mus.26868DOI Listing
July 2020

Sonographic and 3T-MRI-based evaluation of the tongue in ALS.

Neuroimage Clin 2020 2;26:102233. Epub 2020 Mar 2.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany; German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, Magdeburg, Germany; Center for behavioral brain sciences (CBBS), Magdeburg, Germany. Electronic address:

A few systematic imaging studies employing ultrasound (HRUS) and magnetic resonance imaging (MRI) have suggested tongue measures to aid in diagnosis of amyotrophic lateral sclerosis (ALS). The relationship between structural tongue alterations and the ALS patients' bulbar and overall motor function has not yet been elucidated. We here thus aimed to understand how in-vivo tongue alterations relate to motor function and motor function evolution over time in ALS. Our study included 206 ALS patients and 104 age- and sex-matched controls that underwent HRUS and 3T MRI of the tongue at baseline. Sonographic measures comprised coronal tongue echointensity, area, height, width and height/width ratio, while MRI measures comprised sagittal T1 intensity, tongue area, position and shape. Imaging-derived markers were related to baseline and longitudinal bulbar and overall motor function. Baseline T1 intensity was lower in ALS patients with more severe bulbar involvement at baseline. Smaller baseline coronal (HRUS) and sagittal (MRI) tongue area, smaller coronal height (HRUS) and width (HRUS) as well as more rounded sagittal tongue shape predicated more rapid functional impairment - not only of bulbar, but also of overall motor function - in ALS. Our results suggest that in-vivo sonography und MRI tongue measures could aid as biomarkers to reflect bulbar and motor function impairment.
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http://dx.doi.org/10.1016/j.nicl.2020.102233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068685PMC
February 2021

Dyspnea as a Fatigue-Promoting Factor in ALS and the Role of Objective Indicators of Respiratory Impairment.

J Pain Symptom Manage 2020 08 5;60(2):430-438.e1. Epub 2020 Mar 5.

Department of Anesthesiology and Intensive Care, Otto-von-Guericke University, Magdeburg, Germany.

Context: There is no evidence-based treatment for fatigue in amyotrophic lateral sclerosis (ALS), and identification of treatable causes determines management strategies. Although dyspnea is a key symptom of ALS and effectively treatable, it has not been sufficiently investigated whether dyspnea may be a fatigue-promoting factor.

Objectives: To determine the level of fatigue in dyspneic ALS patients and whether fatigue is promoted by dyspnea. We further evaluated the correlation of fatigue with respiratory function tests.

Methods: About 101 dyspneic patients and 20 matched controls completed the ALS Functional Rating Scale-Extension and the Fatigue Severity Scale. Dyspneic patients additionally completed the Dyspnea-ALS Scale and the ALS Assessment Questionnaire and underwent respiratory function tests (forced vital capacity, sniff nasal inspiratory pressure, mean inspiratory and expiratory pressure with respective relaxation rates, and blood gases). Multiple regression and correlation analyses were conducted.

Results: Dyspneic patients had significantly higher fatigue scores than nondyspneic patients, and their fatigue significantly affected quality of life. Dyspnea alone explained up to 24% of the variance in fatigue. No associations were observed between fatigue and respiratory function tests. Patients with noninvasive ventilation reported significantly more dyspnea and fatigue.

Conclusion: Fatigue is a frequent and bothersome symptom in dyspneic ALS patients. Dyspnea-related distress is, in contrast to objective indicators of respiratory impairment, a determining factor of experienced fatigue. There is an urgent need for further symptom relief beyond noninvasive ventilation. Adequate treatment of dyspnea has the potential for synergies in symptom management arising from the association between fatigue and dyspnea.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.02.021DOI Listing
August 2020

The upper cervical spinal cord in ALS assessed by cross-sectional and longitudinal 3T MRI.

Sci Rep 2020 02 4;10(1):1783. Epub 2020 Feb 4.

Department of Neurology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

The upper cervical spinal cord is measured in a large longitudinal amyotrophic lateral sclerosis (ALS) cohort to evaluate its role as a biomarker. Specifically, the cervical spinal cord´s cross-sectional area (CSA) in plane of the segments C1-C3 was measured semi-automatically with T1-weighted 3T MRI sequences in 158 ALS patients and 86 controls. Six-month longitudinal follow-up MRI scans were analyzed in 103 patients. Compared to controls, in ALS there was a significant mean spinal cord atrophy (63.8 mm² vs. 60.8 mm², p = 0.001) which showed a trend towards worsening over time (mean spinal cord CSA decrease from 61.4 mm² to 60.6 mm² after 6 months, p = 0.06). Findings were most pronounced in the caudal segments of the upper cervical spinal cord and in limb-onset ALS. Baseline CSA was related to the revised ALS functional rating scale, disease duration, precentral gyrus thickness and total brain gray matter volume. In conclusion, spinal cord atrophy as assessed in brain MRIs in ALS patients mirrors the extent of overall neurodegeneration and parallels disease severity.
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http://dx.doi.org/10.1038/s41598-020-58687-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000761PMC
February 2020

Hippocampal vascular reserve associated with cognitive performance and hippocampal volume.

Brain 2020 02;143(2):622-634

Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke-University, Magdeburg, Germany.

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.
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http://dx.doi.org/10.1093/brain/awz383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009470PMC
February 2020

7T MR neurography-ultrasound fusion for peripheral nerve imaging.

Muscle Nerve 2020 04 22;61(4):521-526. Epub 2020 Jan 22.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

Background: We present one patient with an initial diagnosis of Guillain-Barré syndrome (GBS) and one with Charcot-Marie-Tooth disease (CMT) type 1A.

Methods: Both patients underwent ankle tibial nerve fusion-imaging of high-resolution ultrasound (HRUS) with 7T MR neurography (MRN).

Results: In GBS, the nerve was enlarged, T2-hyperintense, and showed increased vascularization 21 months after symptom onset. In CMT1A, the enlarged nerve was T2-isointense with normal endoneurial blood flow.

Conclusions: We demonstrate the utility of 7T-MRN-HRUS-fusion-imaging. In GBS, there was evidence of ongoing inflammation resulting in a changed diagnosis to acute-onset chronic demyelinating polyradiculoneuropathy and maintenance of immunotherapy. By MRN-HRUS-fusion, patients with presumed peripheral axonal degeneration could be shown to display imaging markers associated with peripheral nervous system inflammation. Thus, more accurate identification of a treatable inflammatory component may become possible.
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http://dx.doi.org/10.1002/mus.26800DOI Listing
April 2020

Acute symptomatic extracranial internal carotid occlusion - natural course and clinical impact.

Vasa 2020 Jan 17;49(1):31-38. Epub 2019 Oct 17.

Vascular and Stroke Center, Magdeburg University Hospital, Magdeburg, Germany.

To assess the vascular and clinical course of acute symptomatic extracranial internal carotid artery (ICA) occlusion. Patients with an acute ischemic event in the anterior circulation and corresponding extracranial ICA occlusion at CT angiography and/or color-coded duplex sonography underwent recurrent duplex follow-up for detection of spontaneous recanalization. Stroke recurrence and functional outcome 4.5 months after the ischemic index event assessed by modified Rankin scale served as secondary outcome parameters. 133 patients (91 men, mean age 62.3 years, SD 10.8) demonstrated symptomatic occlusion of the extracranial ICA with open intracranial ICA and open middle cerebral artery and were followed-up for spontaneous recanalization. Twenty-eight recanalized spontaneously, 25 to high-grade focal stenosis within 12 days, revealing an early cumulative recanalization rate of 23 %. Detection of recanalization was independently associated with de novo dual anti-platelet therapy (adjusted odds ratio [OR], 3.24; 95 % confidence interval [CI], 1.34 to 7.80). Ischemic recurrence occurred in 16 patients, of which 10 deemed to be embolic and 5 hemodynamic. Spontaneous ICA recanalization and an exhausted cerebrovascular reserve in the hemisphere distal to the occluded ICA were both independently associated with the occurrence of a recurrent ischemic event at Cox regression. An increasing NIHSS score at admission, a decreasing middle cerebral artery flow velocity and an ischemic recurrence independently predicted poor outcome (modified Rankin scale 3 to 6) in multivariate analysis. Acute symptomatic extracranial ICA occlusion is an unstable condition with frequent spontaneous recanalization to severe stenosis and early embolic stroke recurrence, demanding appropriate prevention especially in those patients with only mild deficit.
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http://dx.doi.org/10.1024/0301-1526/a000826DOI Listing
January 2020

Advancing diagnostic criteria for sporadic cerebral amyloid angiopathy: Study protocol for a multicenter MRI-pathology validation of Boston criteria v2.0.

Int J Stroke 2019 12 12;14(9):956-971. Epub 2019 Sep 12.

Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Rationale: The Boston criteria are used worldwide for the in vivo diagnosis of cerebral amyloid angiopathy and are the basis for clinical decision-making and research in the field. Given substantial advances in cerebral amyloid angiopathy's clinical aspects and MRI biomarkers, we designed a multicenter study within the International cerebral amyloid angiopathy Association aimed at further validating the diagnostic accuracy of the Boston and potentially improving and updating them.

Aim: We aim to derive and validate an updated "version 2.0" of the Boston criteria across the spectrum of cerebral amyloid angiopathy-related presentations and MRI biomarkers.

Sample Size Estimates: Participating centers with suitable available data (see Methods) were identified from existing collaborations and an open invitation to the International Cerebral Amyloid Angiopathy Association emailing list. Our study sample will include: (1) a derivation cohort - Massachusetts General Hospital (MGH), Boston cases from inception to 2012 (∼150 patients); (2) temporal external validation cohort - MGH, Boston cases from 2012 to 2018 (∼100 patients); and (3) geographical external validation cohort - non-Boston cases (∼85 patients).

Methods And Design: Multicenter collaborative study. We will collect and analyze data from patients' age ≥ 50 with any potential sporadic cerebral amyloid angiopathy-related clinical presentations (spontaneous intracerebral hemorrhage, transient focal neurological episodes and cognitive impairment), available brain MRI ("index test"), and histopathologic assessment for cerebral amyloid angiopathy ("reference standard" for diagnosis). Trained raters will assess MRI for all prespecified hemorrhagic and non-hemorrhagic small vessel disease markers of interest, according to validated criteria and a prespecified protocol, masked to clinical and histopathologic features. Brain tissue samples will be rated for cerebral amyloid angiopathy, defined as Vonsattel grade ≥2 for whole brain autopsies and ≥1 for cortical biopsies or hematoma evacuation. Based on our estimated available sample size, we will undertake pre-specified cohort splitting as above. We will: (a) pre-specify variables and statistical cut-offs; (b) examine univariable and multivariable associations; and (c) then assess classification measures (sensitivity, specificity etc.) for each MRI biomarker individually, in relation to the cerebral amyloid angiopathy diagnosis reference standard on neuropathology in a derivation cohort. The MRI biomarkers strongly associated with cerebral amyloid angiopathy diagnosis will be selected for inclusion in provisional (probable and possible cerebral amyloid angiopathy) Boston criteria v2.0 and validated using appropriate metrics and models.

Study Outcomes: Boston criteria v2.0 for clinical cerebral amyloid angiopathy diagnosis.

Discussion: This work aims to potentially update and improve the diagnostic test accuracy of the Boston criteria for cerebral amyloid angiopathy and to provide wider validation of the criteria in a large sample. We envision that this work will meet the needs of clinicians and investigators and help accelerate progress towards better treatment of cerebral amyloid angiopathy.
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http://dx.doi.org/10.1177/1747493019855888DOI Listing
December 2019

The Dyspnea-ALS-Scale (DALS-15) optimizes individual treatment in patients with amyotrophic lateral sclerosis (ALS) suffering from dyspnea.

Health Qual Life Outcomes 2019 Jun 3;17(1):95. Epub 2019 Jun 3.

Department of Neurology, Otto-von-Guericke University, Leipziger Str. 44, D-39120, Magdeburg, Germany.

Background: Dyspnea is frequent in amyotrophic lateral sclerosis (ALS) and one of the most bothersome symptoms. The recently developed Dyspnea-ALS-Scale (DALS-15) is a disease-specific patient-reported outcome to detect and quantify dyspnea.

Objectives: To analyze in a case-based approach the diagnostic and clinical implications and the benefit of the DALS-15 for individual patients in daily clinical routine.

Methods: Dyspnea was assessed by the 15-item comprising DALS-15 in two patients with ALS. Spirometry was performed and blood gases were analyzed. Results were evaluated in the clinical context of the respective patients.

Results: In one patient the presence of dyspnea detected by the DALS-15 indicated noninvasive ventilation (NIV) although forced vital capacity (FVC) and blood gas analysis were well preserved. After NIV implementation, the DALS-15 was helpful to determine the patient's need for medication, the timing of NIV titration and the adaptation of NIV sessions. In another patient, who was anarthric and no longer able to perform spirometry due to severe bulbar impairment, the DALS-15 allowed a standardized assessment of dyspnea-related distress independently of bulbar dysfunction.

Conclusion: The DALS-15 provides a deeper insight into the respiratory status of individual patients. It helps to diagnose respiratory impairment in patients in whom NIV should be considered although FVC and blood gas results do not reveal indication for NIV. It is also valuable for the guidance of patients in later stages of respiratory impairment when NIV is already implemented, and in patients with severe bulbar dysfunction. The DALS-15 can improve specific symptom management and coordination of care and therefore has the potential to optimize individual treatment in ALS patients with dyspnea.
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http://dx.doi.org/10.1186/s12955-019-1167-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547457PMC
June 2019

Toward in vivo determination of peripheral nervous system immune activity in amyotrophic lateral sclerosis.

Muscle Nerve 2019 05 8;59(5):567-576. Epub 2019 Mar 8.

Department of Neurology, Otto-von-Guericke University, Leipziger Straße 44, 39120 Magdeburg, Germany.

Introduction: We sought to identify patients with amyotrophic lateral sclerosis (ALS) who displayed suspected peripheral nervous system (PNS) inflammation to compare them to those with suspected PNS degeneration.

Methods: We measured sonographic median and ulnar nerve cross-sectional area (CSA) and cerebrospinal fluid albumin/serum albumin ratio (Q ) in patients with ALS to classify them as having suspected PNS degeneration (small CSA/low Q ) or inflammation (larger CSA/high Q ).

Results: Fifty-seven percent of patients had suspected PNS degeneration, 21% had suspected PNS inflammation, and 21% displayed suspected "normal PNS state." Suspected PNS degeneration was related to classic ALS, shorter disease duration, and a smaller hypoechoic nerve area. Suspected PNS inflammation was associated with men, longer disease duration, and a larger hypoechoic nerve area and was the dominant finding in superoxide dismutase 1 mutation carriers.

Discussion: Our simple approach might aid in the in vivo differentiation of supposed ALS subtypes, those with suspected PNS degeneration vs. inflammation, for stratification in clinical trials. Muscle Nerve 59:567-567, 2019.
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http://dx.doi.org/10.1002/mus.26444DOI Listing
May 2019

CSF Neurofilament Light Chain Levels in Primary Progressive MS: Signs of Axonal Neurodegeneration.

Front Neurol 2018 14;9:1037. Epub 2018 Dec 14.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

Elevated neurofilament light chain (NFL) levels within the cerebrospinal fluid (CSF) are a biomarker representing axonal neurodegeneration in rapid progressive neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). It is unclear to what extent the levels of NFL increase in the CSF (CSF-NFL) in a chronic neuroinflammatory process with axonal neurodegeneration, as found in primary progressive multiple sclerosis (PPMS). We used a multicenter approach to statistically compare CSF-NFL levels between PPMS patients ( = 50), ALS patients ( = 50), and healthy controls ( = 50). Clinical findings, including disease duration, expanded disability status scale (EDSS), electrophysiological recordings such as visual evoked potentials or spinal and cerebral MRI, and previously administered treatment were selected as experimental parameters retrospectively. Median [range] CSF-NFL concentrations in PPMS patients were significantly higher than in the controls [1724 (799-4275) pg/ml vs. 1202 (612-2934) pg/ml, = 0.015], and significantly lower compared to ALS patients [1724 (799-4275) pg/ml vs. 10238 (2610-35138) pg/ml, < 0.001]. There was no correlation between CSF-NFL and disease duration ( = 0.5), EDSS ( = 0.2) or treatment ( = 0.3). We conclude that CSF-NFL may mirror the proposed slow axonal degeneration in PPMS, but does not reflect the disease severity.
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http://dx.doi.org/10.3389/fneur.2018.01037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315185PMC
December 2018