Publications by authors named "Nathan P Staff"

71 Publications

Alterations of mesenchymal stromal cells in cerebrospinal fluid: insights from transcriptomics and an ALS clinical trial.

Stem Cell Res Ther 2021 Mar 18;12(1):187. Epub 2021 Mar 18.

Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Background: Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases.

Methods: In this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS).

Results: Our results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs.

Conclusions: Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.
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http://dx.doi.org/10.1186/s13287-021-02241-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977179PMC
March 2021

Academic physician specialists' views toward the unproven stem cell intervention industry: areas of common ground and divergence.

Cytotherapy 2021 Apr 6;23(4):348-356. Epub 2021 Feb 6.

Biomedical Ethics Research Program and Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Background And Aims: Premature commercialization of unproven stem cell interventions (SCIs) has received significant attention within the regenerative medicine community. Patients considering SCIs may encounter misinformation and seek out guidance from their physicians who are trusted brokers of health information. However, little is known about the perspectives of academic physician specialists toward the SCI industry. The purpose of this study was to capture the attitudes of physician specialists with experience addressing patient questions about unproven SCIs.

Methods: The authors undertook 25 semi-structured interviews with academic physicians in cardiology, ophthalmology, orthopedics, pulmonology and neurology primarily from one academic center.

Results: The authors identified two major themes: concerns and mediators of appropriateness of offering SCIs as therapies to patients. Specialists were generally aware of the industry and reported scientific and commercial concerns, including the scientific uncertainty of SCIs, medical harms to patients, misleading marketing and its impact on patient informed consent and economic harms due to large out-of-pocket costs for patients. All specialists outside of orthopedics voiced that it was inappropriate to be offering SCIs to patients today. These views were informed by previously expressed concerns surrounding safety and properly informing patients, levels of evidence needed prior to offering SCIs therapeutically and desired qualifications for clinicians. Among the specialties, orthopedists reported that under certain conditions, SCIs may be appropriate for patients with limited clinical options but only when safety is adequate, expectations are managed and patients are well informed about the risks and chances of benefit. Most participants expressed a desire for phase 3 studies and Food and Drug Administration approval prior to marketing SCIs, but some also shared the challenges associated with upholding these thresholds of evidence, especially when caring for out-of-option patients.

Conclusions: The authors' results suggest that medical specialists are aware of the industry and express several concerns surrounding SCIs but differ in their views on the appropriateness and clinical evidence necessary for offering SCIs currently to patients. Additional educational tools may help physicians with patient engagement and expectation management surrounding SCIs.
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http://dx.doi.org/10.1016/j.jcyt.2020.12.011DOI Listing
April 2021

Nelarabine-Induced Myelotoxicity.

Neurology 2021 01 11;96(4):175-176. Epub 2020 Dec 11.

From the Departments of Radiology (A.A.M., C.M.C.), Hematology and Oncology (H.A.), and Neurology (N.P.S., E.N.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000011343DOI Listing
January 2021

Proteomic analysis of human iPSC-derived sensory neurons implicates cell stress and microtubule dynamics dysfunction in bortezomib-induced peripheral neurotoxicity.

Exp Neurol 2021 01 29;335:113520. Epub 2020 Oct 29.

Department of Neurology, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

The neurotoxic effects of the chemotherapeutic agent bortezomib on dorsal root ganglia sensory neurons are well documented, yet the mechanistic underpinnings that govern these cellular processes remain incompletely understood. In this study, system-wide proteomic changes were identified in human induced pluripotent stem cell-derived sensory neurons (iSNs) exposed to a clinically relevant dose of bortezomib. Label-free mass spectrometry facilitated the identification of approximately 2800 iSN proteins that exhibited differential levels in the setting of bortezomib. A significant proportion of these proteins affect the cellular processes of microtubule dynamics, cytoskeletal and cytoplasmic organization, and molecular transport, and pathway analysis revealed an enrichment of proteins in signaling pathways attributable to the unfolded protein response and the integrated stress response. Alterations in microtubule-associated proteins suggest a multifaceted relationship exists between bortezomib-induced proteotoxicity and microtubule cytoskeletal architecture, and MAP2 was prioritized as a topmost influential candidate. We observed a significant reduction in the overall levels of MAP2c in somata without discernable changes in neurites. As MAP2 is known to affect cellular processes including axonogenesis, neurite extension and branching, and neurite morphology, its altered levels are suggestive of a prominent role in bortezomib-induced neurotoxicity.
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http://dx.doi.org/10.1016/j.expneurol.2020.113520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750199PMC
January 2021

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.

Sci Transl Med 2020 10;12(566)

Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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http://dx.doi.org/10.1126/scitranslmed.abb7086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927160PMC
October 2020

Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and Medications.

Authors:
Nathan P Staff

Continuum (Minneap Minn) 2020 10;26(5):1280-1298

Purpose Of Review: Vitamin and mineral deficiencies, neurotoxins, and, particularly, prescription medications, are some of the most common causes of peripheral neuropathy. Recognition and prompt treatment of these neuropathies require a high index of suspicion and an accompanied detailed history. This article provides a comprehensive approach and list of items that must be considered in the setting of new-onset neuropathy.

Recent Findings: Although many of the neuropathies described in this article have decreased in prevalence in developed countries because of public health interventions and occupational/environmental regulations, new causes for this class of neuropathy continue to be uncovered.

Summary: The peripheral nervous system is susceptible to a broad array of metabolic and toxic abnormalities, which most often lead to a length-dependent sensory-predominant axonal peripheral neuropathy. A careful history accompanied by recognition of multisystem clues can increase recognition of these neuropathies, which is important as many have specific treatments that may either improve the neuropathy or halt its progression.
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http://dx.doi.org/10.1212/CON.0000000000000908DOI Listing
October 2020

Expanded neuromuscular morbidity in Hodgkin lymphoma after radiotherapy.

Brain Commun 2020 25;2(1):fcaa050. Epub 2020 Apr 25.

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.

Our study aims to quantitate neuromuscular morbidity from radiotherapy in Hodgkin lymphoma including: (i) frequency and (ii) time of onsets for neurological localizations; (iii) degree of disabilities and (iv) number of clinical visits compared to cardiopulmonary Hodgkin lymphoma-radiation complications. Medical records from Mayo Health systems were retrieved; identifying neuromuscular radiation treated Hodgkin lymphoma-complications from 1 January 1994 to 31 December 2016. Of an estimated 4100 post-radiotherapy Hodgkin lymphoma patients, 4.6% (189) were identified with complications. Mean latency to physician visit for symptoms was 23.7 years (range: 1-50). Most commonly identified complications included: head drop 10% (19) with or without myopathy, myopathy 39% (73), plexopathy 29% (54), myelopathy 27% (51) and polyradiculopathy 13% (24). Other findings included benign and malignant nerve sheath tumours 5% (9), phrenic and long thoracic mononeuropathies 7% (14) and compressive spinal meningioma 2% (4). Patients frequently had multiple coexisting complications (single = 76% [144], double = 17% [33], triple = 4% [8], quadruple = 2% [4]). Cardiac 28% (53) and pulmonary 15% (29) complications were also seen in these patients. History of Hodgkin lymphoma was initially overlooked by neurologists (14.3%, 48/336 clinical notes). Hospital and outpatient visits for complications were frequent: neuromuscular 19% (77/411) versus cardiopulmonary 30% (125/411). Testing was largely exclusionary, except when imaging identified secondary malignancy. Modified Rankin score at diagnosis varied: 0-1 (55.8%), 2-3 (5.8%) and 4-5 (38.3%). Neuromuscular complications among post-radiation Hodgkin lymphoma are diverse, occurring in ∼1 of 20 having markedly delayed onsets often eluding diagnosis. Frequent care visits and major morbidity are common. Survivorship recommendations should recognize the diverse neurological complications.
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http://dx.doi.org/10.1093/braincomms/fcaa050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425393PMC
April 2020

The NEALS primary lateral sclerosis registry.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 11;21(sup1):74-81. Epub 2020 Sep 11.

Henry Ford Health System, Detroit, MI, USA.

Background And Objective: Primary lateral sclerosis (PLS) is a neurodegenerative disease characterized by progressive upper motor neuron dysfunction. Because PLS patients represent only 1 to 4% of patients with adult motor neuron diseases, there is limited information about the disease's natural history. The objective of this study was to establish a large multicenter retrospective longitudinal registry of PLS patients seen at Northeast ALS Consortium (NEALS) sites to better characterize the natural progression of PLS. Clinical characteristics, electrophysiological findings, laboratory values, disease-related symptoms, and medications for symptom management were collected from PLS patients seen between 2000 and 2015. The NEALS registry included data from 250 PLS patients. Median follow-up time was 3 years. The mean rate of functional decline measured by ALSFRS-R total score was -1.6 points/year (SE:0.24,  = 124); the mean annual decline in vital capacity was -3%/year (SE:0.55,  = 126). During the observational period, 18 patients died, 17 patients had a feeding tube placed and 7 required permanent assistive ventilation. The NEALS PLS Registry represents the largest available aggregation of longitudinal clinical data from PLS patients and provides a description of expected natural disease progression. Data from the registry will be available to the PLS community and can be leveraged to plan future clinical trials in this rare disease.
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http://dx.doi.org/10.1080/21678421.2020.1804591DOI Listing
November 2020

The current state of electrocorticography-based brain-computer interfaces.

Neurosurg Focus 2020 07;49(1):E2

3Neurology, Mayo Clinic, Rochester, Minnesota.

Brain-computer interfaces (BCIs) provide a way for the brain to interface directly with a computer. Many different brain signals can be used to control a device, varying in ease of recording, reliability, stability, temporal and spatial resolution, and noise. Electrocorticography (ECoG) electrodes provide a highly reliable signal from the human brain surface, and these signals have been used to decode movements, vision, and speech. ECoG-based BCIs are being developed to provide increased options for treatment and assistive devices for patients who have functional limitations. Decoding ECoG signals in real time provides direct feedback to the patient and can be used to control a cursor on a computer or an exoskeleton. In this review, the authors describe the current state of ECoG-based BCIs that are approaching clinical viability for restoring lost communication and motor function in patients with amyotrophic lateral sclerosis or tetraplegia. These studies provide a proof of principle and the possibility that ECoG-based BCI technology may also be useful in the future for assisting in the cortical rehabilitation of patients who have suffered a stroke.
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http://dx.doi.org/10.3171/2020.4.FOCUS20185DOI Listing
July 2020

Postsurgical Neuropathy: A Descriptive Review.

Mayo Clin Proc 2020 02;95(2):355-369

Department of Neurology, Mayo Clinic, Rochester, MN.

Postsurgical neuropathies represent an infrequent but potentially devastating complication of surgery that may result in significant morbidity with medicolegal implications. Elucidation of this phenomenon has evolved over the past few decades, with emerging evidence for not only iatrogenic factors contributing to this process but also inflammatory causes. This distinction can be important; for instance, cases in which inflammatory etiologies are suspected may benefit from further investigations including nerve biopsy and may benefit from treatment in the form of immunotherapy. In contrast, postsurgical neuropathies due to perioperative causes including anesthesia, traction, compression, and transection will not benefit in the same manner. This article summarizes early and current literature surrounding the frequency of new neurologic deficits after various surgical types, potential causes including anatomical and inflammatory considerations, and roles for treatment. To capture the scope of the issue, a literature review was conducted for human studies in English via MEDLINE and EMBASE from January 1, 1988 to March 31, 2018. Search terms included anesthesia and/or surgical procedures, operative, peripheral nervous system diseases, trauma, mononeuropathy, polyneuropathy, peripheral nervous system, nerve compression, neuropathy, plexopathy, postoperative, postsurgical, perioperative, complication. We excluded case series with less than 10 patients and review papers. We then narrowed the studies to those presented highlighting key concepts in postsurgical neuropathy.
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http://dx.doi.org/10.1016/j.mayocp.2019.05.038DOI Listing
February 2020

Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS.

Muscle Nerve 2020 08 22;62(2):156-166. Epub 2020 Jan 22.

Healey Center at Massachusetts General Hospital, Boston, Massachusetts.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.
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http://dx.doi.org/10.1002/mus.26801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496557PMC
August 2020

Association between ALS and retroviruses: evidence from bioinformatics analysis.

BMC Bioinformatics 2019 Dec 20;20(Suppl 24):680. Epub 2019 Dec 20.

Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Background: Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Specifically, activation of ancient viral genes embedded in the human genome is theorized to lead to motor neuron degeneration. We explore whether connections exist between ALS and retroviruses through protein interaction networks (PIN) and pathway analysis, and consider the potential roles in drug target discovery. Protein database and pathway/network analytical software including Ingenuity Pathway BioProfiler, STRING, and CytoScape were utilized to identify overlapping protein interaction networks and extract core cluster (s) of retroviruses and ALS.

Results: Topological and statistical analysis of the ALS-PIN and retrovirus-PIN identified a shared, essential protein network and a core cluster with significant connections with both networks. The identified core cluster has three interleukin molecules IL10, Il-6 and IL-1B, a central apoptosis regulator TP53, and several major transcription regulators including MAPK1, ANXA5, SQSTM1, SREBF2, and FADD. Pathway enrichment analysis showed that this core cluster is associated with the glucocorticoid receptor singling and neuroinflammation signaling pathways. For confirmation purposes, we applied the same methodology to the West Nile and Polio virus, which demonstrated trivial connectivity with ALS, supporting the unique connection between ALS and retroviruses.

Conclusions: Bioinformatics analysis provides evidence to support pathological links between ALS and retroviral activation. The neuroinflammation and apoptotic regulation pathways are specifically implicated. The continuation and further analysis of large scale genome studies may prove useful in exploring genes important in retroviral activation and ALS, which may help discover new drug targets.
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http://dx.doi.org/10.1186/s12859-019-3249-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923964PMC
December 2019

Modeling chemotherapy induced peripheral neuropathy (CIPN) in vitro: Prospects and limitations.

Exp Neurol 2020 04 5;326:113140. Epub 2019 Dec 5.

Department of Neurology, Johns Hopkins Medical School, Baltimore, USA. Electronic address:

Neuronal cell cultures have been used as an essential tool for studying pathomechanisms of toxicity of chemotherapeutic drugs and to develop neuroprotective approaches. They offer the opportunity to dissect disease mechanisms and molecular pathways while allowing precise control of a variety of confounding factors of the physio-chemical environment. As such, a growing number of in vitro studies are published each year to decipher mechanisms of neurotoxicity of taxanes, vinca alcaloids, proteasome inhibitors and platin derivatives and/or to test neuroprotective strategies. Here, we provide a review of cell culture techniques and outcome measures that have been used in the past or are currently employed to model chemotherapy induced neuropathy in vitro. Furthermore, we discuss their advantages as well as their limitations and ways to enhance efficiency and reproducibility of cell culture studies in the field of toxic neuropathy.
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http://dx.doi.org/10.1016/j.expneurol.2019.113140DOI Listing
April 2020

Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems.

Exp Neurol 2020 02 21;324:113121. Epub 2019 Nov 21.

Department of Biology, University of Miami, Coral Gables, FL 33146, USA. Electronic address:

Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.
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http://dx.doi.org/10.1016/j.expneurol.2019.113121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993945PMC
February 2020

NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results.

Neurology 2019 12 18;93(24):e2294-e2305. Epub 2019 Nov 18.

From Massachusetts General Hospital Neurological Clinical Research Institute and Harvard Medical School (J.D.B., M.E.C., K.N.), Boston; Mayo Clinic (A.J.W., N.P.S.), Rochester, MN; University of Massachusetts (M.O., D.M.-Y., R.H.B.), Worcester; Brainstorm Cell Therapeutics (Y.S.L., N.A., H.K., R.A., Y.G.), Petach Tikva, Israel; and Tigermed USA (M.M.), Somerset, NJ.

Objective: To determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial.

Methods: The study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months. CSF was collected before and 2 weeks after transplantation.

Results: The study met its primary safety endpoint. The rate of disease progression (Revised ALS Functional Rating Scale [ALSFRS-R] slope change) in the overall study population was similar in treated and placebo participants. In a prespecified rapid progressor subgroup (n = 21), rate of disease progression was improved at early time points ( < 0.05). To address heterogeneity, a responder analysis showed that a higher proportion of treated participants experienced ≥1.5 points/month ALSFRS-R slope improvement compared to placebo at all time points, and was significant in rapid progressors at 4 and 12 weeks ( = 0.004 and 0.046, respectively). CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants ( < 0.05) post-transplantation. CSF monocyte chemoattractant protein-1 levels correlated with ALSFRS-R slope improvement up to 24 weeks ( < 0.05).

Conclusion: A single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS.

Classification Of Evidence: This phase II study provides Class I evidence.
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http://dx.doi.org/10.1212/WNL.0000000000008620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937497PMC
December 2019

Chemotherapy-induced peripheral neurotoxicity: A multifaceted, still unsolved issue.

J Peripher Nerv Syst 2019 10;24 Suppl 2:S6-S12

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

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a potentially dose-limiting side effect of several commonly used cytotoxic chemotherapy agents. The main pharmacological classes that may cause CIPN include classical anticancer drugs, as well as the recently introduced immune checkpoint inhibitors and antibody drug conjugates. The absence of a complete knowledge of CIPN pathophysiology is only one of the several unsolved issues related to CIPN. Among some of the most relevant aspects of CIPN deserving further attention include the real number of patients exposed to the risk of CIPN, the long-term impact on cancer survivors' quality of life due to incomplete recovery from CIPN, the economic burden related to acute and chronic CIPN, and the different perspective and education of the healthcare specialists in charge of managing patients with CIPN. Overall, CIPN remains a very challenging area of research as there are still several unresolved issues to be addressed in the future. In this special issue, the multifaceted profile of CIPN will be presented, with particular emphasis on bolstering the need to develop more optimized outcome measures than the existing ones to accurately evaluate the extent of CIPN, but also to ascertain the differences in the incidence, risk factors, clinical phenotype, and management of CIPN, according to the most commonly used neurotoxic chemotherapy classes. Perspectives for future research to pursue in order to cover the gaps in knowledge in the CIPN field will also be discussed.
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http://dx.doi.org/10.1111/jns.12337DOI Listing
October 2019

Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment.

J Peripher Nerv Syst 2019 Oct;24 Suppl 2:S63-S73

Department of Neurology, "Saint Andrew's" State General Hospital of Patras, Patras, Greece.

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.
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http://dx.doi.org/10.1111/jns.12334DOI Listing
October 2019

Platinum-induced peripheral neurotoxicity: From pathogenesis to treatment.

J Peripher Nerv Syst 2019 10;24 Suppl 2:S26-S39

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

Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.
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http://dx.doi.org/10.1111/jns.12335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818741PMC
October 2019

Dominant collagen XII mutations cause a distal myopathy.

Ann Clin Transl Neurol 2019 10 11;6(10):1980-1988. Epub 2019 Sep 11.

National Institutes of Health, NINDS, NNDCS, Bethesda, Maryland.

Objective: To characterize the natural history and clinical features of myopathies caused by mono-allelic, dominantly acting pathogenic variants in COL12A1.

Methods: Patients with dominant COL12A1-related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient-derived dermal fibroblast cultures for collagen XII.

Results: Four independent families with childhood-onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal-predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in-frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient-derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns.

Interpretation: This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1-related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele-specific knockdown using siRNAs specifically designed to target a patient's dominant COL12A1 disease allele.
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http://dx.doi.org/10.1002/acn3.50882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801183PMC
October 2019

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Support Care Cancer 2019 Oct 30;27(10):3729-3737. Epub 2019 Jul 30.

The Ohio State University Comprehensive Cancer Center, Columbus, USA.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.
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http://dx.doi.org/10.1007/s00520-019-04987-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728179PMC
October 2019

DNA methylation patterns in human iPSC-derived sensory neuronal differentiation.

Epigenetics 2019 09 6;14(9):927-937. Epub 2019 Jun 6.

a Department of Neurology, Mayo Clinic , Rochester , MN , USA.

Sensory neurons of the peripheral nervous system are critical in health and disease. Sensory neurons derived from induced pluripotent stem (iPS) cells are now being used increasingly for models of neuropathy, pain, and neurotoxicity. DNA methylation is critical for neurodevelopment and has been implicated in many neuronal diseases, but has not been examined in iPS-derived sensory neurons. In order to better characterize the iPS-derived sensory neuron model, we have undertaken a genome-wide DNA methylation study on the cells from human iPS to iPS-derived sensory neurons during differentiation through reduced representation and bisulfite sequencing. We report decreasing DNA methylation with iPS-derived sensory neuronal differentiation that is reflected in increasing numbers and proportions of hypomethylated individual CpGs and regions, as well as lowered DNMT3b expression. Furthermore, genes with changes in DNA methylation near their TSS suggest key pathways that may be involved in iPS-derived sensory neuronal differentiation. These findings provide insights into sensory neuronal differentiation and can be used for further modelling of disease states.
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http://dx.doi.org/10.1080/15592294.2019.1625672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691994PMC
September 2019

Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases.

Mayo Clin Proc 2019 05;94(5):892-905

Department of Neurology, Mayo Clinic, Rochester, MN.

Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson disease, and Alzheimer disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward effects.
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http://dx.doi.org/10.1016/j.mayocp.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643282PMC
May 2019

On the Association Between Fluoroquinolones and Neuropathy.

JAMA Neurol 2019 07;76(7):753-754

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1001/jamaneurol.2019.0886DOI Listing
July 2019

Clinical spectrum of neuropathy after primary total knee arthroplasty: A series of 54 cases.

Muscle Nerve 2019 06 4;59(6):679-682. Epub 2019 Apr 4.

Department of Neurology, Mayo Clinic, E8A. 200 1st Street SW, Rochester, Minnesota, 55905, USA.

Introduction: Neuropathy after total knee arthroplasty (TKA) can cause significant morbidity but is inconsistently reported.

Methods: We reviewed the clinical, electrodiagnostic and perioperative features of all patients who underwent primary TKA at our institution and developed a new neuropathy within 8 weeks postoperatively.

Results: Fifty-four cases were identified (incidence 0.37% [95% confidence interval, 0.28-0.49]) affecting the following nerve(s): peroneal (37), sciatic (11), ulnar (2), tibial (2), sural (1), and lumbosacral plexus (1). In all cases with follow-up data, motor recovery typically occurred within 1 year and was complete or near-complete.

Conclusions: Post-TKA neuropathy is uncommon, typically does not require intervention and usually resolves within 1 year. Post-TKA neuropathy most often affects the nerves surgically at risk. Anesthesia type does not correlate with post-TKA neuropathy. An inflammatory etiology for post-TKA neuropathy is rare but should be considered in specific cases. Muscle Nerve 59:679-682, 2019.
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http://dx.doi.org/10.1002/mus.26473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520178PMC
June 2019

A treatable hypertrophic neuropathy.

Pract Neurol 2019 02 17;19(1):80-82. Epub 2018 Nov 17.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA

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http://dx.doi.org/10.1136/practneurol-2018-002083DOI Listing
February 2019

Amyotrophic Lateral Sclerosis: An Update for 2018.

Mayo Clin Proc 2018 11 4;93(11):1617-1628. Epub 2018 Jul 4.

Department of Neurology, Mayo Clinic, Rochester, MN.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental. Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common known genetic cause of ALS and are seen in approximately 40% of patients with a family history and approximately 10% of those without. No environmental risk factors are proved to be causative, but many have been proposed, including military service. The diagnosis of ALS rests on a history of painless progressive weakness coupled with examination findings of upper and lower motor dysfunction. No diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for patients is best provided by a multidisciplinary team, and most interventions are directed at managing symptoms. Two medications with modest benefits have Food and Drug Administration approval for the treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein we review stem cell and antisense oligonucleotide gene therapies.
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http://dx.doi.org/10.1016/j.mayocp.2018.04.007DOI Listing
November 2018

Case-Based Learning in Translational Biomedical Research Education: Providing Realistic and Adaptive Skills for Early-Career Scientists.

Acad Med 2019 02;94(2):213-216

A.J. Greenberg-Worisek is assistant professor of epidemiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota. K.A. Campbell is assistant professor of molecular pharmacology and experimental therapeutics, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota. E.W. Klee is assistant professor of biomedical informatics, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota. N.P. Staff is associate professor of neurology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota. L.A. Schimmenti is professor of pediatrics, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota. K.M. Weavers is manager of research operations, Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota. S.C. Ekker is professor of biochemistry and molecular biology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota. A.J. Windebank is professor of neurology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.

Problem: Case-based learning is an established means of educating students in law, business, and medicine; however, this methodology is not often applied to educating translational biomedical researchers. The application of case-based learning to translational biomedical research education allows scholars to actively engage with real-world material and apply their newfound knowledge as it is acquired.

Approach: Through the Mayo Clinic Center for Clinical and Translational Science (CCaTS), three courses were delivered in 2009-2017 which emphasized case-based learning in clinical and translational science, entrepreneurship, and individualized medicine. Quantitative measures collected in student course reviews upon course completion were analyzed. Additionally, products arising from each course were identified, including publications and startups pitched.

Outcomes: Analyses demonstrate that case-based learning techniques are well suited to graduate biomedical research education. Furthermore, case studies can be employed throughout the entire clinical and translational spectrum, from basic and preclinical work through to clinical and population-based learning.

Next Steps: Within CCaTS, next steps include creating case-based courses in regulatory and team science to continue to allow scholars to learn and apply these critical skills to real-world material. The goal is to continue to provide immersive training opportunities in areas of clinical and translational science that cannot be readily learned in a traditional lecture-based class setting.
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http://dx.doi.org/10.1097/ACM.0000000000002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351155PMC
February 2019

Brachial Plexus Neuritis Associated With Anti-Programmed Cell Death-1 Antibodies: Report of 2 Cases.

Mayo Clin Proc Innov Qual Outcomes 2017 Sep 1;1(2):192-197. Epub 2017 Sep 1.

Department of Neurology, Mayo Clinic, Rochester, MN.

Recently, guidelines have been outlined for management of immune-related adverse events occurring with immune checkpoint inhibitors in cancer, irrespective of affected organ systems. Increasingly, these complications have been recognized as including diverse neuromuscular presentations, such as demyelinating and axonal length-dependent peripheral neuropathies, vasculitic neuropathy, myasthenia gravis, and myopathy. We present 2 cases of brachial plexopathy developing on anti-programmed cell death-1 checkpoint inhibitor therapies (pembrolizumab, nivolumab). Both cases had stereotypic lower-trunk brachial plexus-predominant onsets, and other clinical features distinguishing them from Parsonage-Turner syndrome (ie, idiopathic plexitis). Each case responded to withholding of anti-programmed cell death-1 therapy, along with initiation of high-dose methylprednisiolone therapy. However, both patients worsened when being weaned from corticosteroids. Discussed are the complexities in the decision to add a second-line immunosuppressant drug, such as infliximab, when dealing with neuritis attacks, for which improvement may be prolonged, given the inherent slow recovery seen with axonal injury. Integrated care with oncology and neurology is emphasized as best practice for affected patients.
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http://dx.doi.org/10.1016/j.mayocpiqo.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134904PMC
September 2017

Somatotopic heat pain thresholds and intraepidermal nerve fibers in health.

Muscle Nerve 2018 10 20;58(4):509-516. Epub 2018 Apr 20.

Department of Neurology, Mayo Clinic, 200 First Street SW Rochester, Minnesota, USA, 55905.

Introduction: For sequential and somatotopic assessment of small fiber neuropathy, heat pain (HP) tests of hypoalgesia might be used instead of decreased counts of epidermal nerve fibers (ENFs), but then healthy subject reference values of HP thresholds are needed.

Methods: Using the Computer Assisted Sensation Evaluator IVc system, HP thresholds of hypoalgesia were estimated for 10 unilateral sites and counts of ENFs for 4 of them in healthy subjects.

Results: In healthy subjects, small but statistically significant differences of both HP thresholds of hypoalgesia and counts of ENFs were observed among tested sites. Significant correlations between HP thresholds and counts of ENFs were not found.

Discussion: For the studied somatotopic sites, we provide ≥95th and ≥99th percentile reference limits for HP 0.5 and 5 of 1-10 HP thresholds of hypoalgesia and decreased counts of ENFs at ≤5th and ≤1st percentile levels. Muscle Nerve 58: 509-516, 2018.
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http://dx.doi.org/10.1002/mus.26128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139085PMC
October 2018

Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort.

J Neurol Neurosurg Psychiatry 2018 06 8;89(6):636-641. Epub 2018 Feb 8.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: To assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival.

Methods: Olmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments and International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes for all subjects.

Results: A total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. Five-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06-3.69).

Conclusions: Results from our population-based study are consistent with previous reports of high incidence of CIPN in the first 2 years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study among survivors.
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http://dx.doi.org/10.1136/jnnp-2017-317215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970026PMC
June 2018