Serum and cerebrospinal neurofilament light chain levels in patients with acquired peripheral neuropathies

Neurofilament light chain (NFL) levels reflect axonal damage in different inflammatory and neurodegenerative central nervous system conditions, in correlation with disease severity. Our aim was to determine the possible diagnostic and prognostic value of serum and cerebrospinal fluid (CSF) NFL levels in subjects with different forms of acquired peripheral neuropathies (PN). Paired serum and CSF samples of 25 patients with acquired PN were analysed for NFL using an ultrasensitive technique (Quanterix, Simoa, Lexington, MA, USA) and compared with a group of 25 age‐matched healthy subjects. Demographic, clinical, CSF and neurophysiological data were reviewed. Cases with Guillain‐Barré syndrome (N = 5), multifocal motor neuropathy (N = 3), chronic inflammatory demyelinating polyneuropathy (CIDP) and variants (N = 12), anti‐myelin‐associated glycoprotein (MAG) neuropathy (N = 3), both CIDP and anti‐MAG neuropathy (N = 1), and non‐systemic vasculitic neuropathy (N = 1) were studied. NFL levels were significantly (P < 0.001) increased in patients with PN and were higher in the CSF (median: 1407 pg/mL, range: 140.2‐12 661) than in serum (median: 31.52 pg/mL, range: 4.33‐1178). A statistically significant correlation was observed between serum and CSF levels in cases with blood‐nerve‐barrier damage (r = 0.71, P < 0.01), and between serum NFL levels and disease activity at sampling (r = 0.52, P < 0.01) and at last follow‐up (r = 0.53, P < 0.01) in all subjects. The increase of NFL values in both serum and CSF of patients with acquired PN and the significant correlation between serum NFL levels, disease severity and final outcome support the possible role of NFL as disease activity and prognostic biomarker also in peripheral nervous system disorders.     

Clinical and genetic associations of autoantibodies to 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme a reductase in patients with immune‐mediated myositis and necrotizing myopathy

Introduction: Inhibition of 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune‐mediated necrotizing myopathy (IMNM). Anti‐HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti‐HMGCR in IIM/IMNM. Methods: Anti‐HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. Results: Anti‐HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti‐HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA‐DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti‐HMGCR antibodies was among HLA‐DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti‐HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti‐HMGCR⁺ patients there was a trend toward increased malignancy (P = 0.15). Conclusions: Anti‐HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA‐DR11. Muscle Nerve 52 : 196–203, 2015     

Cerebrospinal fluid biomarkers of white matter lesions – cross‐sectional results from the LADIS study

Background and purpose: White matter lesions (WMLs) caused by small vessel disease are common in elderly people and contribute to cognitive impairment. There are no established biochemical markers for WMLs. We aimed to study the relation between degree of WMLs rated on magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) levels of structural biomarkers associated with Alzheimer’s disease (AD) and subcortical vascular dementia. Methods: Fifty‐three non‐demented elderly individuals with WMLs were subjected to lumbar puncture. Degree of WMLs was rated using the Fazekas scale. Volumetric assessment of WMLs was performed. CSF samples were analyzed for the 40 and 42 amino acid fragments of amyloid β, α‐ and β‐cleaved soluble amyloid precursor protein, total tau (T‐tau), hyperphosphorylated tau (P‐tau₁₈₁), neurofilament light protein (NFL), sulfatide and CSF/Serum‐albumin ratio. Results: Fifteen subjects had mild, 23 had moderate and 15 had severe degree of WMLs. CSF‐NFL levels differed between the groups (P < 0.001) and correlated with the volume of WMLs (r = 0.477, P < 0.001). CSF sulfatide concentration displayed similar changes but less strongly. T‐tau, P‐tau₁₈₁ and the different amyloid markers as well as CSF/S‐albumin ratio did not differ significantly between the groups. Conclusions: The association of increased CSF‐NFL levels with increasing severity of WMLs in non‐demented subjects suggests that NFL is a marker for axonal damage in response to small vessel disease in the brain. This manifestation may be distinct from or earlier than the neurodegenerative process seen in AD, as reflected by the lack of association between WMLs and AD biomarkers.     

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.     

Free insulin‐like growth factor (IGF)‐1 and IGF‐binding proteins‐2 and ‐3 in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients

Background: The insulin‐like growth factor‐1 (IGF‐1) signaling system is regulated by many factors which interact in regulating the bioavailability of IGF‐I. In this context, little information is available on free IGF‐1, the bioactive form of IGF‐1, in amyotrophic lateral sclerosis (ALS). Methods: We investigated the endogenous expression of IGF‐1, and two related binding proteins (IGF‐binding proteins, IGFBP‐2 and BP‐3) in serum and cerebrospinal fluid (CSF) of 54 sporadic ALS (sALS) patients. Twenty‐five healthy individuals and 25 with other neurological diseases (OND) were used as controls. Total and free IGF‐1, and IGFBP‐3 levels were detected by immunoradiometric assay (IRMA); IGFBP‐2 levels were determined by radioimmunoassay (RIA). Results: Total and free IGF‐1, IGFBP‐2 and BP‐3 serum levels were not significantly different between patients and controls, although in sALS patients free IGF‐1 was negatively correlated with ALS‐Functional Rating Scale‐revised (ALS‐FRS‐R) score (r = ?0.4; P = 0.046) and forced vital capacity (FVC) (r = ?0.55; P < 0.04). In CSF, free IGF‐1 was significantly increased in sALS patients compared with OND (P < 0.0001). Conclusions: Though in the serum we did not find significant differences amongst the three groups, IGF‐1 bioavailability, represented by the free IGF‐1 levels, correlated with disease severity. In the CSF, the significant increment of the free fraction of IGF‐1 suggests an up‐regulation of the IGF‐1 system in the intrathecal compartment of sALS patients. Since IGF‐1 is a trophic factor for different tissues, we speculate that high levels of the free IGF‐1 in sALS might reflect a physiological defensive mechanism promoted in response to neural degeneration and/or muscle atrophy.     

Circulating L-selectin in multiple sclerosis patients with active, gadolinium-enhancing brain plaques

Leukocyte migration into inflammatory lesions is controlled by adhesion molecules. L-selectin is the adhesion molecule on leukocytes that is responsible for making the initial contact with endothelium. After establishing this contact, L-selectin is shed from the cell surface and present in the circulation as a functional soluble receptor. To investigate this initial adhesive event, we evaluated the presence of soluble L-selectin (sL-selectin) in serum and CSF of patients with multiple sclerosis (MS), viral encephalitis, and controls. MS patients with active, gadolinium-enhancing lesions on magnetic resonance imaging had significantly higher sL-selectin serum levels than controls (P < 0.05). These levels in MS patients correlated with the size of the enhancing lesions (P < 0.05), and with sL-selectin levels in CSF (P < 0.001). In viral encephalitis, in contrast, sL-selectin is elevated in CSF only (P < 0.001) and may derive from intrathecal leukocytes. These results show that the earliest adhesive events mediated by L-selectin indeed operate in active MS, and that sL-selectin will be of value in quantitating the extent of this inflammatory process.     

Cerebrospinal fluid antibodies to tubulin are elevated in the patients with multiple sclerosis

Background and purpose: The aim of this study was to compare the levels of anti‐tubulin antibodies (anti‐TU) in cerebrospinal fluid (CSF) and serum using bovine tubulin as the antigen in one enzyme‐linked immunosorbent assay (ELISA) method (anti‐TUb antibodies) and a synthetic neuron‐specific octapeptide of tubulin in a second ELISA method (anti‐TUs antibodies). Methods: Paired CSF and serum samples were obtained from 34 multiple sclerosis (MS) patients, 13 patients with various other neurological diseases (control diseases) and 17 normal control patients (CN). Results: CSF levels of anti‐TUs and anti‐TUb antibodies were significantly lower in the CN group when compared to those in the MS group. On the contrary, serum levels of anti‐TU antibodies did not differ among groups. The intrathecal synthesis of anti‐TUs antibodies in comparison with anti‐TUb was significantly increased in all groups. Significant correlations between anti‐TUb and anti‐TUs antibodies were observed in the CSF of all three groups. However, with regard to serum, a similar relationship was only found in the MS group. Conclusions: The estimation of anti‐TU in CSF can contribute to the overall assessment of axonal damage; on the contrary serum anti‐tubulin antibodies were not useful for differential purposes in MS. The antibodies to the neuron‐specific portion of tubulin seemed to be synthesised predominantly intrathecally.     

Interleukin‐17 and interleukin‐23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation?

Rentzos M, Rombos A, Nikolaou C, Zoga M, Zouvelou V, Dimitrakopoulos A, Alexakis T, Tsoutsou A, Samakovli A, Michalopoulou M, Evdokimidis J. Interleukin‐17 and interleukin‐23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation?
Acta Neurol Scand: 2010: 122: 425–429.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background – There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Th17 cells are characterized by predominant production of IL‐17 and are suggested to be crucial in destructive autoimmunity. Interleukin‐23 (IL‐23) appears to play a supporting role in the continued stimulation and survival of Th17. Patients and methods – We measured by enzyme‐like immunosorbent assay (ELISA) serum and cerebrospinal fluid (CSF) levels of IL‐17 and IL‐23 in 22 patients with ALS and 19 patients with other non‐inflammatory neurological disorders (NIND) studied as a control group. IL‐17 and IL‐23 serum and CSF levels were also correlated with duration of the disease, the disability level and the clinical subtype of the disease onset in patients with ALS. Results – IL‐17 and IL‐23 serum levels were higher in patients with ALS as compared with patients with NIND (P = 0.015 and P = 0.002 respectively). IL‐17 and IL‐23 CSF levels were also increased in patients with ALS (P = 0.0006 and P = 0.000001 respectively). IL‐17 and IL‐23 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. Conclusions – Our findings suggest that these molecules may be involved in the pathogenetic mechanisms acting as potential markers of Th17 cells activation in ALS.     

Anti‐ganglioside antibodies in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients

Introduction: In this study we investigated the relationships between anti‐ganglioside antibodies and Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. Results: In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti‐ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. Conclusions: These results suggest that IgG anti‐GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55 : 470–475, 2017     

Natural history of muscle cramps in amyotrophic lateral sclerosis

Introduction: Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) that lacks efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials. Methods: We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months. Results: Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month‐to‐month and trended lower after the first year of illness (P = 0.26). Those with limb‐onset and age >60 years had more cramps than bulbar‐onset (P < 0.0001) and younger patients (P < 0.0001). Conclusions: The high variability of the number of cramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial. Muscle Nerve 53 : 513–517, 2016     

The relationship between ANT1 and NFL with autophagy and mitophagy markers in patients with multiple sclerosis

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease. Neurofilament light chain (NFL) is a novel adverting biomarker of axonal damage that suggested as a useful assistant in the monitoring of MS patients. It has been shown that the auto/mitophagy associated with MS pathogenesis. In this study, we aimed to study correlation between ATG5 and Parkin, as markers of autophagy and mitophagy respectively, with NFL and ANT1 in serum and cerebrospinal fluid (CSF) in MS subjects. ATG5, Parkin, NFL, and ANT1 levels were measured in a cross-sectional study of 40 MS patients compared with gender, age and BMI matching healthy volunteers. Based on our results, levels of ATG5, Parkin, and NFL significantly were elevated in both serum and CSF of MS patients comparing control individuals (p < 0.0001) but ANT1 levels significantly was decreased in both serum and CSF of MS patients comparing control individuals (p < 0.0001). The correlation indices between NFL, ANTI1, ATG5 and Parkin in both case and control groups showed a direct and moderate the correlation between ANTI1 and ATG5 in the CSF level of the control group (r = 0.554, P = 0.011). Our data support the feasibility of quantifying of NFL as a sensitive and clinically meaningful serum/CSF biomarker to follow-up nerve tissue injury in MS condition.     

Serum and CSF PDGF‐AA and FGF‐2 in relapsing‐remitting multiple sclerosis: a case–control study

Background and purpose: Fibroblast growth factor‐2 (FGF‐2) and platelet‐derived growth factor‐A (PDGF‐AA) are potent modulators of oligodendrocytes, the main responsible cells for myelin regeneration. We measured FGF‐2 and PDGF‐AA in the sera and cerebrospinal fluid (CSF) of patients with relapsing‐remitting multiple sclerosis (RR‐MS) and compared these values with control subjects. Methods: Twenty‐three patients with RR‐MS and 23 subjects without inflammatory and demyelinating diseases were included. Serum samples of the patients were collected in both relapse and remission phases and were analyzed with ELISA method. CSF was drawn during the relapse period. Blood and CSF were drawn from control subjects for comparison. Wilcoxon and Mann–Whitney U‐test and Spearman’s rank correlation were used for analysis. P values of <0.05 were considered significant. Results: Age and sex distribution were similar in both groups. Serum values of FGF‐2 were higher in relapse phase compared with remission phase, with a trend toward significance (P = 0.052). CSF PDGF‐AA showed significant negative correlation with disease duration (correlation coefficient = ?0.58, P = 0.004). Serum levels of PDGF did not differ between two phases significantly. There was no difference in serum and CSF values of these factors between patients and controls. When we compared patients with prolonged disease with controls, a significant difference between the CSF levels of PDGF‐AA was observed (mean ± SEM 2.78 ± 0.8 in controls vs. 0.55 ± 0.29 in patients with MS ≥ 2 years, P < 0.05). Conclusion: Our study was the first to show that CSF PDGF‐AA is related to disease duration. Supporting previous findings we showed that serum and CSF levels of these factors are weak indicators of disease severity.     

CSF neurofilament protein (NFL) — a marker of active HIV-related neurodegeneration

Abstract Background and methods The light subunit of the neurofilament protein (NFL), a major structural component of myelinated axons, is a sensitive indicator of axonal injury in the central nervous system (CNS) in a variety of neurodegenerative disorders. Cerebrospinal fluid (CSF) NFL concentrations were measured by ELISA (normal < 250 ng/l) in archived samples from 210 HIV-infected patients not taking antiretroviral treatment: 55 with AIDS dementia complex (ADC), 44 with various CNS opportunistic infections/tumours (CNS OIs), 95 without neurological symptoms or signs, and 16 with primary HIV infection (PHI). The effect of highly active antiretroviral treatment (HAART) was studied by repeated CSF sampling in four of the ADC patients initiating treatment. Results CSF NFL concentrations were significantly higher in patients with ADC (median 2590 ng/l, IQR 780–7360) and CNS OIs (2315 ng/l, 985–7390 ng/l) than in neuroasymptomatic patients (<250 ng/l, <250–300) or PHI (<250 ng/l, <250–280), p < 0.001. Among patients with ADC, those with more severe disease (stage 2–4) had higher levels than those with milder disease (stage 0.5–1), p < 0.01. CSF NFL declined during HAART to the limit of detection in parallel with virological response and neurological improvement in ADC.CSF NFL concentrations were higher in neuroasymptomatic patients with lower CD4-cell strata than higher, p < 0.001. This increase was less marked than in the ADC patients and noted in 26/58 neuroasymptomatic patients with CD4 counts <200/μl compared to 1/37 with CD4-cells ≥200/μl. Conclusions The findings of this study support the value of CSF NFL as a useful marker of ongoing CNS damage in HIV infection. Markedly elevated CSF NFL concentrations in patients without CNS OIs are associated with ADC, follow the grade of severity, and decrease after initiation of effective antiretroviral treatment. Nearly all previously suggested CSF markers of ADC relate to immune activation or HIV viral load that do not directly indicate brain injury. By contrast NFL is a sensitive marker of such injury, and should prove useful in evaluating the presence and activity of ongoing CNS injury in HIV infection. Drs. Abdulle and Mellgren contributed equally to this work.     

Acute optic neuritis: Myelin basic protein and proteolipid protein antibodies,affinity, and the HLA system

Anti—myelin basic protein, anti—proteolipid protein, and anti—myelin basic protein peptide (amino acid residues 1–20, 63–88, and 89–101) antibody—secreting cells were studied in 20 patients with idiopathic optic neuritis, 20 with optic neuritis as part of multiple sclerosis, and 20 neurological control subjects. Antibody-secreting cells were enumerated with an immunospot assay; the relative binding affinity of the antibodies was estimated by elution with thiocyanate. Patients with optic neuritis had more anti—myelin basic protein and anti—proteolipid protein antibodies than did control subjects (both p < 0.05); there was no difference between idiopathic optic neuritis and optic neuritis as a symptom of multiple sclerosis. Presence of the multiple sclerosis—associated DRB1 1501 gene was not associated with preferential synthesis of high-affinity antibodies reactive with a single myelin basic protein peptide or with preferential synthesis of either anti—myelin basic protein or anti—proteolipid protein antibodies. The results demonstrate a potential for intrathecal synthesis of both anti—myelin basic protein and anti—proteolipid protein antibodies of high apparent affinity in patients with optic neuritis.     

Lambert‐eaton myasthenic syndrome and merkel cell carcinoma

Introduction: We describe a patient who developed neuralgic amyotrophy (NA) related to hepatitis E virus (HEV) infection. Methods: The patient underwent neurological and electrodiagnostic examinations, high‐resolution analysis of serological changes, and HEV load profile, and was treated with intravenous immunoglobulin. Results: There was evidence of bilateral, asymmetric acute inflammatory cervical polyradiculopathy and possible brachial plexopathy. Positive serum anti‐HEV IgM was followed by seroconversion to anti‐HEV IgG positivity. A calculated anti‐HEV antibody index was compatible with intrathecal synthesis, and HEV genotype 3 RNA was found in serum and cerebrospinal fluid (CSF). Liver function tests returned to normal within 6 weeks. Conclusions: Bilateral involvement of cervical nerve roots and/or plexus, elevated liver function tests, and abnormal CSF are typical features of HEV‐associated NA. The pathogenesis involves possible immune‐mediated mechanisms. However, our findings support the hypothesis that HEV‐related NA is associated with direct infection. Muscle Nerve 54 : 325–327, 2016     

Distal Predominance of Electrodiagnostic Abnormalities in Early‐Stage Amyotrophic Lateral Sclerosis

Introduction: In this study we compared the electrodiagnostic (EDX) yield of limb muscles in revealing lower motor neuron (LMN) dysfunction by electromyography (EMG) in early‐stage amyotrophic lateral sclerosis (ALS). Methods: This investigation was undertaken as a retrospective review at a single center. Results: Our study included 122 consecutive patients with possible ALS, as defined by revised El Escorial criteria. Distal limb muscles showed more frequent EMG abnormalities than proximal muscles. EDX yield was found to be higher in the limb where weakness began and when clinical signs of LMN dysfunction were evident. Adoption of the Awaji criteria significantly increased the yield of EMG‐positive segments in the cervical (P < 0.0005) and lumbosacral (P < 0.0001) regions, and upgraded 19 patients into the probable category and 1 patient into the definite category. Discussion: EMG abnormalities are predominant in the distal limb in early‐stage ALS. A redefinition of an EDX‐positive cervical or lumbosacral segment, with an emphasis on distal limb muscles, may result in an earlier ALS diagnosis. Muscle Nerve 58 : 389–395, 2018     

Stratifying disease stages with different progression rates determined by electrophysiological tests in patients with amyotrophic lateral sclerosis

By determining the usefulness of motor unit number estimate (MUNE) and compound muscle action potential (CMAP) amplitude in patients with amyotrophic lateral sclerosis (ALS), we tried to find an effective way to stratify the disease stages. In all, 112 consecutive ALS patients were enrolled, among whom 73 were elicited in a longitudinal study. MUNE by the standard incremental technique, the average CMAP amplitude, total Medical Research Council (MRC) score, ALS‐functional rating score (ALS‐FRS), Appel ALS rating scale (AARS), and forced vital capacity (FVC) were performed at baseline and months 3, 6, and 12 after study entry. We found MUNE correlated with CMAP amplitude (P < 0.01) as well as MRC score (P < 0.01) in regionally concordant distal muscles. Both MUNE and CMAP amplitude correlated significantly with ALS‐FRS (P < 0.05) and AARS (P < 0.01). A MUNE decrease was observed at months 3, 6, and 12 compared with baseline, and the rate of change at month 3 was 50.47%. The decrease in MUNE over the first 3 months was significantly greater than other measurements. We arbitrarily divided the patients into three stages: (1) rapid progression: the rate of change of MUNE and CMAP amplitude during the first 3 months exceeded 50%; (2) moderate progression: the rate of change of MUNE was greater than 50% but CMAP amplitude was less than 50%; (3) slow progression: the rate of change of both MUNE and CMAP amplitude were less than 50%. Comparing the rate of ALS‐FRS descent per year using one‐way ANOVA showed a significant difference among the three groups (P < 0.01). Muscle Nerve 39: 304–309, 2009     

Cough peak flow decline rate predicts survival in patients with amyotrophic lateral sclerosis

Introduction: In this study we investigated the prognostic significance of cough peak flow (CPF) decline rate in patients with amyotrophic lateral sclerosis (ALS). Methods: Thirty-four patients with ALS participated in our investigation. We examined CPF, forced vital capacity (FVC), body mass index, and the revised ALS Functional Rating Scale (ALSFRS-R), and followed patients to death, tracheostomy, or non-invasive ventilator dependency. We analyzed the relationship between the rate of decline of each parameter and survival prognosis. Results: The CPF decline rate significantly correlated with the decline rates of the ALSFRS-R bulbar score (P < 0.0001) and FVC (P < 0.0001). Patients with a CPF decline rate ≥25% had shorter overall survival (P < 0.0001). Cox model multivariate analyses showed that the CPF decline rate was an independent prognostic factor for survival (P = 0.021). Discussion: The CPF decline rate reflects the progression of bulbar and respiratory dysfunction and predicts survival. Muscle Nerve 59 :168–173, 2019     

CSF neurofilament protein analysis in the differential diagnosis of ALS

Background

Cerebrospinal fluid (CSF) biomarkers have been studied to differentiate between patients with ALS and neurological controls, but not in comparison to clinically more relevant disorders mimicking ALS.

Methods

In this retrospective study, CSF concentrations of various brain-specific proteins were analyzed in patients with ALS (n = 32) and ALS-mimic disorders (n = 26).

Results

CSF concentrations of neurofilament light (NFL) and heavy chain (NFHp35), but not other brain-specific proteins, were significantly higher in patients with ALS than in patients with an ALS-mimic disorder, however with maximum sensitivity or specificity of 80 %. The mean CSF level of NFHp35 was 781 ng/L in the ALS group vs. 338 ng/L in the ALSmimic disorders group and for NFL the mean CSF levels were 62 ng/L vs. 24 ng/L.

Conclusion

Although CSF concentrations of NFL and NFHp35 are higher in patients with ALS, the diagnostic accuracy for differentiating ALS from ALS-mimic disorders seems insufficient. Our results suggest that, in the clinical work-up of patients suspected of ALS, application of CSF analysis alone is limited but may have potential in combination with other clinical and electrophysiological markers.     

Increased expression of TDP‐43 in the skin of amyotrophic lateral sclerosis

Suzuki M, Mikami H, Watanabe T, Yamano T, Yamazaki T, Nomura M, Yasui K, Ishikawa H, Ono S. Increased expression of TDP‐43 in the skin of amyotrophic lateral sclerosis. Acta Neurol Scand: 2010: 122: 367–372. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objectives – Transactivation‐responsive DNA‐binding protein‐43 (TDP‐43) was indentified as a major component of the ubiquitin‐positive inclusions in sporadic amyotrophic lateral sclerosis (ALS). However, there has been no study of TDP‐43 in ALS skin. The present study investigates TDP‐43 in ALS skin. Materials and methods – We made a quantitative immunohistochemical study of the expression of TDP‐43 in the skin from 15 patients with ALS and 15 control subjects. Results – The proportion of TDP‐43‐positive (TDP‐43+) cells in the epidermis in ALS patients was significantly higher (P < 0.001) than in controls. There was a significant positive relationship (r = 0.62, P < 0.02) between the proportion and duration of illness in ALS patients. The optical density of TDP‐43+ cells in the epidermis in ALS patients is markedly stronger (P < 0.001) than in controls. There was a significant positive relation (r = 0.72, P < 0.01) between the immunoreactivity and duration of illness in ALS patients. Conclusions – These data suggest that changes of TDP‐43 in ALS skin are likely to be related to the disease process and that metabolic alterations of TDP‐43 may take place in the skin of patients with ALS.