Publications by authors named "Mary Kay Floeter"

56 Publications

Clinical care and therapeutic trials in PLS.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11;21(sup1):67-73

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Primary lateral sclerosis (PLS) is an extremely rare central nervous system degenerative disorder characterized by slowly progressive upper motor neuron loss leading to severe limb and bulbar dysfunction and disability. Although not necessarily life-shortening, PLS disease burden is substantial and improved symptomatic treatments are a major unmet need, especially for the often refractory spasticity that is a core feature of the syndrome. In Section 1, we describe clinical care needs and emphasize a highly personalized approach that can be best attained through multidisciplinary management. In Section 2, we describe progress in clinical trials in PLS that includes advances in symptomatic treatment, disease-modifying therapy, and emerging innovative trials.
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http://dx.doi.org/10.1080/21678421.2020.1837180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899088PMC
November 2020

Measuring disease progression in primary lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11;21(sup1):59-66

National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

Quantitative measures of disease severity are essential outcome measures for clinical trials. The slow progression of disease in primary lateral sclerosis (PLS) requires clinical measures that are sensitive to changes occurring within the time frame of a clinical trial. Proposed clinical outcome measures include the PLS functional rating scale (PLSFRS), burden scores derived from clinical examination findings, and quantitative measures of motor performance. The PLSFRS has good inter-rater reliability and showed greater longitudinal change over 6- and 12-months compared to the revised ALS functional rating scale. Examination-based upper motor neuron burden (UMNB) scales also have good reliability, and longitudinal studies are in process. Quantitative measures of strength, dexterity, gait, and speech have the potential to provide objective and precise measures of clinical change, but have been the least studied in persons with PLS.
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http://dx.doi.org/10.1080/21678421.2020.1837179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899091PMC
November 2020

Longitudinal changes in network homogeneity in presymptomatic C9orf72 mutation carriers.

Neurobiol Aging 2021 03 8;99:1-10. Epub 2020 Dec 8.

Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address:

The risk for carriers of repeat expansion mutations in C9orf72 to develop amyotrophic lateral sclerosis and frontotemporal dementia increases with age. Functional magnetic resonance imaging studies have shown reduced connectivity in symptomatic carriers, but it is not known whether connectivity declines throughout life as an acceleration of the normal aging pattern. In this study, we examined intra-network homogeneity (NeHo) in 5 functional networks in 15 presymptomatic C9+ carriers over an 18-month period and compared to repeated scans in 34 healthy controls and 27 symptomatic C9+ carriers. The longitudinal trajectory of NeHo in the somatomotor, dorsal attention, and default mode networks in presymptomatic carriers differed from aging controls and symptomatic carriers. In somatomotor networks, NeHo increased over time in regions adjacent to regions where symptomatic carriers had reduced NeHo. In the default network, the posterior cingulate exhibited age-dependent increases in NeHo. These findings are evidence against the proposal that the decline in functional connectivity seen in symptomatic carriers represents a lifelong acceleration of the healthy aging process.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.014DOI Listing
March 2021

Resting State Functional Connectivity Is Decreased Globally Across the Mutation Spectrum.

Front Neurol 2020 19;11:598474. Epub 2020 Nov 19.

Motor Neuron Disease Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.

A repeat expansion mutation in the gene causes amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or symptoms of both, and has been associated with gray and white matter changes in brain MRI scans. We used graph theory to examine the network properties of brain function at rest in a population of mixed-phenotype mutation carriers (C9+). Twenty-five C9+ subjects (pre-symptomatic, or diagnosed with ALS, behavioral variant FTD (bvFTD), or both ALS and FTD) and twenty-six healthy controls underwent resting state fMRI. When comparing all C9+ subjects with healthy controls, both global and connection-specific decreases in resting state connectivity were observed, with no substantial reorganization of network hubs. However, when analyzing subgroups of the symptomatic C9+ patients, those with bvFTD (with and without comorbid ALS) show remarkable reorganization of hubs compared to patients with ALS alone (without bvFTD), indicating that subcortical regions become more connected in the network relative to other regions. Additionally, network connectivity measures of the right hippocampus and bilateral thalami increased with increasing scores on the Frontal Behavioral Inventory, indicative of worsening behavioral impairment. These results indicate that while mutation carriers across the ALS-FTD spectrum have global decreased resting state brain connectivity, phenotype-specific effects can also be observed at more local network levels.
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http://dx.doi.org/10.3389/fneur.2020.598474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710968PMC
November 2020

Longitudinal changes in resting state networks in early presymptomatic carriers of C9orf72 expansions.

Neuroimage Clin 2020 20;28:102354. Epub 2020 Jul 20.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 10 Center Drive, 20892-1140, USA. Electronic address:

Previous cross-sectional imaging studies found differences in brain structure and in resting state networks between presymptomatic carriers of mutations in C9orf72 (C9+) and healthy controls. We carried out a prospective longitudinal study of clinical and resting state functional imaging in a cohort of 15 presymptomatic C9+ carriers to determine whether differences in resting state connectivity prior to developing symptoms reflect static developmental differences or ongoing low-grade degenerative changes. Presymptomatic C9+ carriers were scanned at baseline with follow-up scanning at 6- and 18-months and compared to a cohort of 14 healthy controls scanned longitudinally. Resting state networks associated with manifest disease were visualized by comparing 27 symptomatic C9+ carriers to 34 healthy controls. Motor, salience, thalamic, and speech production networks were visualized using a seed-based analysis. Neurofilament light chain was measured in serum obtained at the time of the scans. Neither clinical measures of motor, cognitive, and behavioral function nor neurofilament levels changed over follow-up in presymptomatic C9+ carriers. In thalamic networks, there was a reduction in connectivity in presymptomatic carriers at all timepoints with a constant difference compared to healthy controls. In contrast, precuneus/posterior cingulate regions exhibited declining functional connectivity compared to controls over the 18-month follow-up, particularly in motor networks. These were regions that also exhibited reduced functional connectivity in symptomatic C9+ carriers. Reduced connectivity over time also occurred in small regions of frontal and temporal cortex within salience and thalamic networks in presymptomatic C9+ carriers. A few areas of increased connectivity occurred, including cortex near the motor seed and within the speech production network. Overall, changes in functional connectivity over time favor the explanation of ongoing low-grade alterations in presymptomatic C9+ carriers in most networks, with the exception of thalamic networks where functional connectivity reductions were stable over time. The loss of connectivity to parietal cortex regions in several different networks may be a distinct feature of C9orf72-related degeneration. Longitudinal studies of carriers who phenoconvert will be important to determine the prognostic significance of presymptomatic functional connectivity alterations.
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http://dx.doi.org/10.1016/j.nicl.2020.102354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406915PMC
July 2020

Longitudinal evaluation of upper motor neuron burden scales in primary lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2021 02 13;22(1-2):23-29. Epub 2020 Jul 13.

Biostatistics Unit, Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Objective: To assess whether published scales for measuring upper motor neuron burden (UMNB) show longitudinal change in patients with primary lateral sclerosis (PLS). Retrospective calculation of three UMNB scales on a prospectively collected dataset from 53 patients with PLS enrolled in a longitudinal natural history study with at least 2 evaluation visits. UMNB scales were calculated according to their published descriptions. Non-linear trends over time of UMNB scale scores and slopes were calculated for each patient and correlations between UMNB scores and clinical measures were assessed. All three UMNB scales exhibited increasing scores over the first 7.8 years of symptoms, with a flattening in slope after approximately 8 years. A scale used in imaging studies and the UPENN UMNS scale provided a better fit to the dataset than the MGH UMNB scale. All three UMNB scales exhibited moderate correlations with some clinical measures of movement, such as finger-tapping rate and timed gait. Correlations were strongest for the UPENN UMNS, which was also moderately correlated with the revised ALS functional rating scale. In a cohort of PLS patients enrolled in a natural history study, the three UMNB scales exhibited modest linear increases over the first 8 years of symptoms, followed by a plateau. Future clinical trials in PLS should consider stratification of patients by disease duration. UMNB scales may be useful secondary outcomes, but more sensitive primary outcome measures are needed for clinical trials for PLS.
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http://dx.doi.org/10.1080/21678421.2020.1790609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935469PMC
February 2021

Electrical impedance myography (EIM) in a natural history study of mutation carriers.

Amyotroph Lateral Scler Frontotemporal Degener 2020 08 21;21(5-6):445-451. Epub 2020 Apr 21.

EMG Section, NINDS, NIH, Bethesda, MD, USA.

Electrical Impedance Myography (EIM) was used to evaluate disease progression in subjects with expansion mutations and to assess correlations with Medical Research Council (MRC) Scale and revised ALS Functional Rating Scale (ALSFRS-R) measurements. Four types of clinical presentations were assessed; Amyotrophic Lateral Sclerosis (ALS), Frontotemporal dementia (FTD) or other dementia, ALS-FTD, and asymptomatic (ASYMP). Subjects were divided into an ALS Group (ALS/ALS-FTD) and non-ALS Group (FTD/ASYMP) based on initial visit and evaluated at 0, 6, 18, and 30 months with EIM of 4 arm and 4 leg muscles, ALSFRS-R, and MRC scales. The change in EIM from baseline and correlation with the functional scale and strength testing were analyzed. EIM 50kHz phase values significantly declined over time in the ALS group ( = 31) compared to the non-ALS group (FTD/ASYMP) ( = 19). In the ALS group, the decline in EIM was correlated with decline in the ALSFRS-R and MRC scores using within-subject correlations. In clinical trials with small populations of genetically associated ALS such as -related ALS, EIM may be a useful quantitative biomarker. We did not detect decline in asymptomatic subjects, but longer term studies may detect early changes in this group.
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http://dx.doi.org/10.1080/21678421.2020.1752247DOI Listing
August 2020

Motor function decline correlates with behavioral impairment in mutation carriers.

Neurology 2020 01 17;94(3):134-136. Epub 2019 Dec 17.

From the National Institute of Neurological Disorders and Stroke (J.F., M.K.F.), National Institutes of Health, Bethesda, MD, and Department of Neurology (S.G.), George Washington University, Washington, DC.

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http://dx.doi.org/10.1212/WNL.0000000000008810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108805PMC
January 2020

Primary lateral sclerosis (PLS) functional rating scale: PLS-specific clinimetric scale.

Muscle Nerve 2020 02 13;61(2):163-172. Epub 2019 Dec 13.

Department of Neurology, Eleanor and Lou Gehrig ALS Center, Columbia University Irvine Medical Center, New York, New York.

Introduction: Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS).

Methods: A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment.

Results: The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher.

Discussion: The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.
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http://dx.doi.org/10.1002/mus.26765DOI Listing
February 2020

Transcutaneous spinal direct current stimulation improves locomotor learning in healthy humans.

Brain Stimul 2019 May - Jun;12(3):628-634. Epub 2019 Jan 29.

Human Cortical Physiology and Neurorehabilitation Section, NINDS, USA.

Background: Ambulation is an essential aspect of daily living and is often impaired after brain and spinal cord injuries. Despite the implementation of standard neurorehabilitative care, locomotor recovery is often incomplete.

Objective: In this randomized, sham-controlled, double-blind, parallel design study, we aimed to determine if anodal transcutaneous spinal direct current stimulation (anodal tsDCS) could improve training effects on locomotion compared to sham (sham tsDCS) in healthy subjects.

Methods: 43 participants underwent a single backwards locomotion training (BLT) session on a reverse treadmill with concurrent anodal (n = 22) or sham (n = 21) tsDCS. The primary outcome measure was speed gain measured 24 h post-training. We hypothesized that anodal tsDCS + BLT would improve training effects on backward locomotor speed compared to sham tsDCS + BLT. A subset of participants (n = 31) returned for two additional training days of either anodal (n = 16) or sham (n = 15) tsDCS and underwent (n = 29) H-reflex testing immediately before, immediately after, and 30 min post-training over three consecutive days.

Results: A single session of anodal tsDCS + BLT elicited greater speed gain at 24 h relative to sham tsDCS + BLT (p = 0.008, two-sample t-test, adjusted for one interim analysis after the initial 12 subjects). Anodal tsDCS + BLT resulted in higher retention of the acquired skill at day 30 relative to sham tsDCS + BLT (p = 0.002) in the absence of significant group differences in online or offline learning over the three training days (p = 0.467 and p = 0.131). BLT resulted in transient down-regulation of H-reflex amplitude (Hmax/Mmax) in both test groups (p < 0.0001). However, the concurrent application of anodal-tsDCS with BLT elicited a longer lasting effect than sham-tsDCS + BLT (p = 0.050).

Conclusion: tsDCS improved locomotor skill acquisition and retention in healthy subjects and prolonged the physiological exercise-mediated downregulation of excitability of the alpha motoneuron pool. These results suggest that this strategy is worth exploring in neurorehabilitation of locomotor function.
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http://dx.doi.org/10.1016/j.brs.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326485PMC
July 2019

Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Associated With Hexanucleotide Expansion Mutations in .

Front Neurol 2018 5;9:1063. Epub 2018 Dec 5.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States.

Now that genetic testing can identify persons at risk for developing amyotrophic lateral sclerosis (ALS) many decades before symptoms begin, there is a critical need for biomarkers that signal the onset and progression of degeneration. The search for candidate disease biomarkers in patients with mutations in the gene has included imaging, physiology, and biofluid measurements. In cross-sectional imaging studies, C9+ ALS patients display diffuse reductions of gray and white matter integrity compared to ALS patients without mutations. This structural imaging signature overlaps with frontotemporal dementia (FTD), reflecting the frequent co-occurrence of cognitive impairment, even frank FTD, in C9+ ALS patients. Changes in functional connectivity occur as critical components of the networks associated with cognition and behavior degenerate. In presymptomatic C9+carriers, subtle differences in volumes of subcortical structures and functional connectivity can be detected, often decades before the typical family age of symptom onset. Dipeptide repeat proteins produced by the repeat expansion mutation are also measurable in the cerebrospinal fluid (CSF) of presymptomatic gene carriers, possibly throughout their lives. In contrast, a rise in the level of neurofilament proteins in the CSF appears to presage the onset of degeneration in presymptomatic carriers in one longitudinal study. Cross-sectional studies indicate that neurofilament protein levels may provide prognostic information for survival in C9+ ALS patients. Longitudinal studies will be needed to validate the candidate biomarkers discussed here. Understanding how these candidate biomarkers change over time is critical if they are to be used in future therapeutic decisions.
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http://dx.doi.org/10.3389/fneur.2018.01063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289985PMC
December 2018

Loss of functional connectivity is an early imaging marker in primary lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2018 11 9;19(7-8):562-569. Epub 2018 Oct 9.

a National Institute of Neurological Disorders and Stroke , National Institutes of Health , Bethesda , MD , USA.

Objective: The clinical diagnosis of primary lateral sclerosis can only be made after upper motor neuron symptoms have progressed for several years without developing lower motor neuron signs. The goal of the study was to identify neuroimaging changes that occur early in primary lateral sclerosis, prior to clinical diagnosis.

Methods: MRI scans were obtained on 13 patients with adult-onset progressive spasticity for five years or less who were followed longitudinally to confirm a clinical diagnosis of primary lateral sclerosis. Resting state functional MRI, diffusion tensor imaging, and anatomical images were obtained. These "pre-PLS" patients were compared to 18 patients with longstanding, established primary lateral sclerosis and 28 controls.

Results: Pre-PLS patients had a marked reduction in seed-based resting-state motor network connectivity compared to the controls and patients with longstanding disease. White matter regions with reduced fractional anisotropy were similar in the two patient groups compared to the controls. Patients with longstanding disease had cortical thinning of the precentral gyrus. A slight thinning of the right precentral gyrus was detected in initial pre-PLS patients' scans. Follow-up scans in eight pre-PLS patients 1-2 years later showed increasing motor connectivity, thinning of the precentral gyrus, and no change in diffusion measures of the corticospinal tract or callosal motor region.

Conclusions: Loss of motor functional connectivity is an early imaging marker in primary lateral sclerosis. This differs from literature descriptions of amyotrophic lateral sclerosis, warranting further studies to test whether resting-state functional MRI can differentiate between amyotrophic lateral sclerosis and primary lateral sclerosis at early disease stages.
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http://dx.doi.org/10.1080/21678421.2018.1517180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456429PMC
November 2018

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Neuron 2018 03;97(6):1268-1283.e6

Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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http://dx.doi.org/10.1016/j.neuron.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867896PMC
March 2018

Longitudinal diffusion imaging across the clinical spectrum.

J Neurol Neurosurg Psychiatry 2018 01 20;89(1):53-60. Epub 2017 Oct 20.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Discrepancies between diffusion tensor imaging (DTI) findings and functional rating scales in amyotrophic lateral sclerosis (ALS) may be due to symptom heterogeneity, particularly coexisting cognitive-behavioural dysfunction affecting non-motor regions of the brain. Carriers of expansion mutations in the gene, whose motor and cognitive-behavioural symptoms span a range from ALS to frontotemporal dementia, present an opportunity to evaluate the relationship between symptom heterogeneity and DTI changes.

Methods: Twenty-eight mutation carriers with varied cognitive and motor symptoms underwent clinical evaluation and DTI imaging. Twenty returned for two or more follow-up evaluations. Each evaluation included motor, executive and behavioural scales and disease staging using the King's college staging system.

Results: Widespread reduction of white matter integrity occurred in mutation carriers compared with 28 controls. The ALS Functional Rating Scale (ALSFRS-R) and King's stage correlated with DTI measures of the corticospinal tract and mid-callosum. Cognitive and behavioural scores correlated with diffusion measures of frontal white matter. King's stage, but not ALSFRS-R, correlated with anterior callosum DTI measures. Over a 6-month follow-up, DTI changes spread from anterior to posterior, and from deep to superficial subcortical white matter. In carriers with ALS or ALS-FTD, changes in corticospinal tractography measures correlated with changes in ALSFRS-R.

Conclusion: Discrepancies between DTI findings and clinical measures of disease severity in ALS may partly be accounted for by cognitive-behavioural deficits affecting extramotor white matter tracts. Both ALSFRS-R and King's stage correlated with corticospinal DTI measures. Group-level DTI changes could be detected over 6 months.
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http://dx.doi.org/10.1136/jnnp-2017-316799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454927PMC
January 2018

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis.

Ann Neurol 2017 Jul;82(1):139-146

Department of Neuroscience, Mayo Clinic, Jacksonville, FL.

As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.
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http://dx.doi.org/10.1002/ana.24980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676468PMC
July 2017

Single-fiber electromyography in the orbicularis oculi muscle in patients with ocular myasthenia gravis symptoms: does abnormal jitter predict response to treatment?

BMC Neurol 2017 Jun 7;17(1):108. Epub 2017 Jun 7.

EMG Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Background: Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of orbicularis oculi SFEMG to diagnose and exclude myasthenia gravis and predict response to therapy.

Methods: Orbicularis oculi SFEMG studies were conducted in 142 consecutive patients with symptoms and/or findings of OMG and negative AChR antibody during the period of 5 years. Retrospective chart review was conducted 2 years after the SFEMG to determine whether treatments were given and responses to treatment.

Results: Orbicularis oculi SFEMG was abnormal in 31 patients and normal in 111 patients. Twenty-nine patients with abnormal SFEMG were treated, and 25 had a good response. Twenty-four patients with normal SFEMG received treatment; none responded to treatment or developed generalized myasthenia.

Conclusion: An abnormal orbicularis oculi SFEMG in patients with seronegative OMG has a high predictive value for response to therapy. Our study findings may affect the treatment decisions in practice and aid better management of myasthenic patients.
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http://dx.doi.org/10.1186/s12883-017-0891-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463377PMC
June 2017

Pathology of callosal damage in ALS: An , 7 T diffusion tensor MRI study.

Neuroimage Clin 2017 30;15:200-208. Epub 2017 Apr 30.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States. Electronic address:

Objectives: The goal of this study was to better understand the changes in tissue microstructure that underlie white matter diffusion changes in ALS patients.

Methods: Diffusion tensor imaging was carried out in postmortem brains of 4 ALS patients and two subjects without neurological disease on a 7 T MRI scanner using steady-state free precession sequences. Fractional anisotropy (FA) was measured in the genu, body, and splenium of the corpus callosum in formalin-fixed hemispheres. FA of the body and genu was expressed as ratio to FA of the splenium, a region unaffected in ALS. After imaging, tissue sections of the same segments of the callosum were stained for markers of different tissue components. Coded image fields were rated for pathological changes by blinded raters.

Results: The FA body/FA splenium ratio was reduced in ALS patients compared to controls. Patchy areas of myelin pallor and cells immunostained for CD68, a microglial-macrophage marker, were only observed in the body of the callosum of ALS patients. Blinded ratings showed increased CD68 + microglial cells in the body of the corpus callosum in ALS patients, especially those with mutations, and increased reactive astrocytes throughout the callosum.

Conclusion: Reduced FA of the corpus callosum in ALS results from complex changes in tissue microstructure. Callosal segments with reduced FA had large numbers of microglia-macrophages in addition to loss of myelinated axons and astrogliosis. Microglial inflammation contributed to reduced FA in ALS, and may contribute to a pro-inflammatory state, but further work is needed to determine their role.
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http://dx.doi.org/10.1016/j.nicl.2017.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429246PMC
March 2018

Poly(GP) proteins are a useful pharmacodynamic marker for -associated amyotrophic lateral sclerosis.

Sci Transl Med 2017 03;9(383)

Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a GC repeat expansion in the gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. GC repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in -associated ALS (c9ALS). Therapeutics that target GC RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from GC RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target GC RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in GC RNA and downstream GC RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of GC RNA-based therapies in symptomatic repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.
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http://dx.doi.org/10.1126/scitranslmed.aai7866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576451PMC
March 2017

Longitudinal imaging in mutation carriers: Relationship to phenotype.

Neuroimage Clin 2016 22;12:1035-1043. Epub 2016 Oct 22.

Department of Neurology, University of Maryland, 110 S. Paca Street, Baltimore, MD 21201, United States.

Expansion mutations in the gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for -associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6-month time frame, and appears to be faster in patients with cognitive impairment.
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http://dx.doi.org/10.1016/j.nicl.2016.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153604PMC
November 2017

Phenotypic and molecular analyses of primary lateral sclerosis.

Neurol Genet 2015 Jun 14;1(1):e3. Epub 2015 Apr 14.

Department of Neurology (H.M., J.H., J.S.), Eleanor and Lou Gehrig MDA/ALS Research Center, Columbia University Medical Center (CUMC), New York, NY; Department of Pathology and Cell Biology (P.L.N.), Personalized Genomic Medicine Laboratory, CUMC, New York, NY; Department of Biostatistics (C.G.), Virginia Commonwealth University, Richmond, VA; Department of Neurology (J.M.), University of California, San Francisco, CA; Departments of Biostatistics and Psychiatry (H.A., R.G.), Mailman School of Medicine, CUMC, New York, NY; Clinical Neuroscience Program (M.K.F.), NINDS, NIH, Bethesda, MD; Department of Neurology (R.J.B.), University of Kansas, Lawrence, KS; Department of Neurology (S.N.), University of Texas Southwestern Medical Center, Dallas, TX; Department of Neurology (C.S.), Western University, London, Ontario, Canada; Department of Neurology (E.K.), University of Kentucky, Lexington, KY; and Department of Epidemiology (P.F.-L), Mailman School of Public Health, CUMC, New York, NY.

Objective: To understand phenotypic and molecular characteristics of patients with clinically "definite" primary lateral sclerosis (PLS) in a prospective study.

Methods: Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the C9ORF72 mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause.

Results: K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified C9ORF72 expansion in one patient. Well-characterized pathogenic mutations were identified in SPG7, DCTN1, and PARK2. Most cases showed no known relevant mutations.

Conclusions: Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential.
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http://dx.doi.org/10.1212/01.NXG.0000464294.88607.ddDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821084PMC
June 2015

Cortical hyperexcitability in patients with C9ORF72 mutations: Relationship to phenotype.

Muscle Nerve 2016 08 25;54(2):264-9. Epub 2016 May 25.

Motor Neuron Disorders Unit, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Patients with mutations in C9orf72 can have amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or ALS-FTD. The goals were to establish whether cortical hyperexcitability occurs in C9orf72 patients with different clinical presentations.

Methods: Cortical thresholds and silent periods were measured in thenar muscles in 19 participants with C9orf72 expansions and 21 healthy controls using transcranial magnetic stimulation (TMS). El Escorial and Rascovsky criteria were used to diagnose ALS and FTD. Fourteen participants with C9orf72 expansions were re-tested 6 months later. Correlations with finger-tapping speed, timed peg test, the ALS functional rating scale, and Dementia Rating Scale were examined.

Results: Most participants with C9orf72 expansions had normal or low cortical thresholds. Among them, ALS patients had the lowest thresholds and significantly shorter silent periods. Thresholds correlated with timed peg-test scores. TMS did not correlate with the Dementia Rating Scale.

Conclusions: TMS measures of cortical excitability may serve as noninvasive biomarkers of ALS disease activity. Muscle Nerve, 2016 Muscle Nerve 54: 264-269, 2016.
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http://dx.doi.org/10.1002/mus.25047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940214PMC
August 2016

Primary Lateral Sclerosis.

Neurol Clin 2015 Nov 8;33(4):749-60. Epub 2015 Sep 8.

Department of Neurology, Columbia University Medical Center, 710 West 168th Street, New York City, NY 10032, USA.

Primary lateral sclerosis is characterized by insidious onset of progressive upper motor neuron dysfunction in the absence of clinical signs of lower motor neuron involvement. Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. The diagnosis is made based on clinical history, typical examination findings, and diagnostic testing negative for other causes of upper motor neuron dysfunction. Electromyogram is normal, or only shows mild neurogenic findings in a few muscles, not meeting El Escorial criteria. Treatment is largely supportive.
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http://dx.doi.org/10.1016/j.ncl.2015.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628724PMC
November 2015

Cerebro-cerebellar connectivity is increased in primary lateral sclerosis.

Neuroimage Clin 2015 9;7:288-96. Epub 2014 Dec 9.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.
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http://dx.doi.org/10.1016/j.nicl.2014.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300015PMC
September 2015

Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS.

Neuron 2014 Sep 14;83(5):1043-50. Epub 2014 Aug 14.

Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1, Jupiter, FL 33458, USA. Electronic address:

A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins." Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.
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http://dx.doi.org/10.1016/j.neuron.2014.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232217PMC
September 2014

Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders.

Neurology 2014 Aug 9;83(7):620-7. Epub 2014 Jul 9.

From the National Institute of Neurological Disorders and Stroke (M.K.F., R.K., M.P.K., O.S., M.S., L.D., T.W., A.M.), NIH, Bethesda, MD; and Departments of Psychiatry and Neurology (E.D.H.), Columbia University, New York, NY.

Objective: The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA.

Methods: Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Forty-seven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA.

Results: Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle.

Conclusions: PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a "dysmetria" of emotional expression resulting from cerebellar dysmodulation.
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http://dx.doi.org/10.1212/WNL.0000000000000693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141995PMC
August 2014

Disease spread through contiguity and axonal tracts in primary lateral sclerosis.

Muscle Nerve 2014 Mar 27;49(3):439-41. Epub 2014 Jan 27.

Spasticity and Spinal Physiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, CRC Room 7-5680, Bethesda, Maryland, 20892-1404, USA.

Our goal in this report was to determine whether symptom progression in primary lateral sclerosis (PLS) was consistent with disease spread through axonal pathways or contiguous cortical regions. The date of symptom onset in each limb and cranial region was obtained from 45 PLS patient charts. Each appearance of symptoms in a new body region was classified as axonal, contiguous, possibly contiguous, or unrelated, according to whether the somatotopic representations were adjacent in the cortex. Of 152 spread events, the first spread event was equally divided between axonal (22) and contiguous (23), but the majority of subsequent spread events were classified as contiguous. Symptom progression in PLS patients is consistent with disease spread along axonal tracts and by local cortical spread. Both were equally likely for the first spread event, but local cortical spread was predominant thereafter, suggesting that late degeneration does not advance through long axonal tracts.
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http://dx.doi.org/10.1002/mus.24116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545964PMC
March 2014

Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis.

Dement Geriatr Cogn Dis Extra 2013 16;3(1):233-50. Epub 2013 Aug 16.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md., USA.

Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.

Methods: The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model.

Results: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores.

Conclusion: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.
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http://dx.doi.org/10.1159/000353456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776403PMC
September 2013

Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis.

Amyotroph Lateral Scler Frontotemporal Degener 2013 May;14 Suppl 1:5-18

Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.

Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable.
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http://dx.doi.org/10.3109/21678421.2013.778548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779649PMC
May 2013