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Eklund, S., Israelsson, H., Brunström, M., Forsberg, K. & Malm, J. (2023). 10-year mortality, causes of death and cardiovascular comorbidities in idiopathic normal pressure hydrocephalus. Journal of Neurology
Open this publication in new window or tab >>10-year mortality, causes of death and cardiovascular comorbidities in idiopathic normal pressure hydrocephalus
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2023 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objective: The objective was to investigate 10-year mortality, causes of death and cardiovascular comorbidity in idiopathic normal pressure hydrocephalus (iNPH) and to evaluate their mutual associations.

Methods: This prospective cohort study included 176 CSF-shunted iNPH patients, and 368 age- and sex-matched controls. At inclusion, participants were medically examined, had blood analyzed and answered a questionnaire. The vascular comorbidities investigated were smoking, diabetes, body mass index, blood pressure (BP), hyperlipidemia, kidney function, atrial fibrillation and, cerebro- and cardiovascular disease.

Results: Survival was observed for a mean period of 10.3 ± 0.84 years. Shunted iNPH patients had an increased risk of death compared to controls (hazard ratio (HR) = 2.5, 95% CI 1.86–3.36; p < 0.001). After 10 years, 50% (n = 88) of iNPH patients and 24% (n = 88) of the controls were dead (p < 0.001). The risk of dying from cardiovascular disease, falls and neurological diseases were higher in iNPH (p < 0.05). The most common cause of death in iNPH was cardiovascular diseases (14% vs 7% for controls). Seven out of nine iNPH dying from falls had subdural hematomas. Systolic BP (HR = 0.985 95% CI 0.972–0.997, p = 0.018), atrial fibrillation (HR = 2.652, 95% CI 1.506–4.872, p < 0.001) and creatinine (HR = 1.018, 95% CI 1.010–1.027, p < 0.001) were independently associated with mortality for iNPH.

Discussion: This long-term and population-matched cohort study indicates that in spite of CSF-shunt treatment, iNPH has shorter life expectancy. It may be important to treat iNPH in supplementary ways to reduce mortality. Both cardiovascular comorbidities and lethal falls are contributing to the excess mortality in iNPH and reducing these preventable risks should be an established part of the treatment plan.

Place, publisher, year, edition, pages
Springer Science+Business Media B.V., 2023
Keywords
Cardiovascular disease, Causes of death, Comorbidities, Mortality, Normal pressure hydrocephalus
National Category
Neurology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-216638 (URN)10.1007/s00415-023-12067-5 (DOI)2-s2.0-85175579237 (Scopus ID)
Funder
Region Västerbotten
Available from: 2023-11-14 Created: 2023-11-14 Last updated: 2023-11-15
Dorst, J., Weydt, P., Brenner, D., Witzel, S., Kandler, K., Huss, A., . . . Ludolph, A. C. (2023). Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers. EBioMedicine, 90, Article ID 104521.
Open this publication in new window or tab >>Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers
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2023 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 90, article id 104521Article in journal (Refereed) Published
Abstract [en]

Background: The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum.

Methods: Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7 ± 14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47% male, age 47.4 ± 12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status.

Findings: Presymptomatic ALS gene carriers showed reduced LBM (p = 0.02), BCM (p = 0.004), Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p = 0.04), and increased ECM/BCM ratio (p = 0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p = 0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p = 0.60).

Interpretation: The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Amyotrophic lateral sclerosis, Metabolic, Metabolism, Mutations carriers, Presymptomatic
National Category
Neurosciences Medical Genetics
Identifiers
urn:nbn:se:umu:diva-206371 (URN)10.1016/j.ebiom.2023.104521 (DOI)000994634700001 ()36917918 (PubMedID)2-s2.0-85150898744 (Scopus ID)
Funder
The Swedish Brain Foundation, 2013-0279The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2020-035Swedish Research Council, 2012-3167Swedish Research Council, 2017-03100Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Umeå University, 223-2808-12Umeå University, 223-1881-13Umeå University, 2.1.12-1605-14Region Västerbotten, 56103-700282Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2023-04-04 Created: 2023-04-04 Last updated: 2023-09-05Bibliographically approved
Forsberg, K., Graffmo, K. S., Stenvall, E., Tabikh, N., Marklund, S. L., Brännström, T. & Andersen, P. M. (2023). Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation. Acta Neuropathologica, 145(1), 13-28
Open this publication in new window or tab >>Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation
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2023 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 145, no 1, p. 13-28Article in journal (Refereed) Published
Abstract [en]

Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2023
Keywords
Amyotrophic lateral sclerosis, D90A, Human autopsy, Neuronal inclusions, Superoxide dismutase-1
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-201353 (URN)10.1007/s00401-022-02519-z (DOI)000884616800001 ()36385230 (PubMedID)2-s2.0-85142073549 (Scopus ID)
Funder
The Swedish Brain Foundation, 2012- 0262The Swedish Brain Foundation, 2012-0305The Swedish Brain Foundation, 2013-0279The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2019-0320The Swedish Brain Foundation, 2020-0353The Swedish Brain Foundation, 2021-0402Swedish Research Council, 2009-3548Swedish Research Council, 2012-3167Swedish Research Council, 2017-03100Swedish Research Council, 2019-01707Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, d 2020.0232The Kempe FoundationsRegion Västerbotten, 2013-7590Region Västerbotten, 56103-7002829Region Västerbotten, RV-841161Region Västerbotten, RV-833421Region Västerbotten, RV-932195Region Västerbotten, RV-939329Region Västerbotten, RV-941598Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2022-12-08 Created: 2022-12-08 Last updated: 2023-01-11Bibliographically approved
Müller, K., Oh, K.-W., Nordin, A., Panthi, S., Kim, S. H., Nordin, F., . . . Andersen, P. M. (2022). De novo mutations in SOD1 are a cause of ALS. Journal of Neurology, Neurosurgery and Psychiatry, 93, 201-206
Open this publication in new window or tab >>De novo mutations in SOD1 are a cause of ALS
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2022 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 93, p. 201-206Article in journal (Refereed) Published
Abstract [en]

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.

Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.

Results: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.

Conclusions:  De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.

Data availability statement: Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2022
Keywords
Psychiatry and Mental health, Clinical Neurology, Surgery
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-189488 (URN)10.1136/jnnp-2021-327520 (DOI)000722681900001 ()2-s2.0-85120353083 (Scopus ID)
Funder
Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseSwedish Association of Persons with Neurological DisabilitiesKnut and Alice Wallenberg Foundation, 2012.0091, 2014.0305, 2020.0232The Swedish Brain Foundation, 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2020-0353Swedish Research Council, 2012-3167, 2017-03100Region Västerbotten
Available from: 2021-11-12 Created: 2021-11-12 Last updated: 2023-03-24Bibliographically approved
Masrori, P., Ospitalieri, S., Forsberg, K., Moens, T. G., Poesen, K., Race, V., . . . Van Damme, P. (2022). Respiratory onset of amyotrophic lateral sclerosis in a pregnant woman with a novel SOD1 mutation. European Journal of Neurology, 29(4), 1279-1283
Open this publication in new window or tab >>Respiratory onset of amyotrophic lateral sclerosis in a pregnant woman with a novel SOD1 mutation
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2022 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 29, no 4, p. 1279-1283Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), the importance of gene testing in ALS is increasing. This will likely lead to the identification of new variants for which the pathogenicity is not established. We aimed to study the pathogenicity of a newly identified variant in superoxide dismutase 1 (SOD1).

METHODS: Gene testing was performed using Sanger sequencing. SOD1 activity in erythrocytes was measured using spectrophotometry. Postmortem brain and spinal cord sections were stained with antibodies against phospho-TDP-43 and SOD1.

RESULTS: We identified a novel c.416G>T (p.Gly139Val) mutation in SOD1, which caused a rapidly progressive respiratory onset form of ALS. The mutation resulted in a 50% drop of SOD1 activity. Postmortem examination confirmed the absence of TDP-43 pathology and displayed typical SOD1 inclusions in remaining motor neurons, confirming the pathogenic nature of the mutation.

CONCLUSIONS: Novel variants of unknown pathogenicity will be identified as a result of a surge in gene testing in people with ALS. An in-depth study of a newly identified p.Gly139Val mutation in SOD1 confirmed the pathogenicity of this mutation. Future patients with this particular mutation should qualify for SOD1 silencing or editing therapies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
antisense oligonucleotides, gene silencing, novel mutation, respiratory onset of ALS, SOD1
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-193155 (URN)10.1111/ene.15224 (DOI)000765395700038 ()35253968 (PubMedID)2-s2.0-85125880986 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Swedish Research Council, 2017-03100The Swedish Brain Foundation, 2020-0353
Available from: 2022-03-22 Created: 2022-03-22 Last updated: 2022-03-22Bibliographically approved
Behzadi, A., Pujol-Calderón, F., Tjust, A. E., Wuolikainen, A., Höglund, K., Forsberg, K., . . . Andersen, P. M. (2021). Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics. Scientific Reports, 11(1), Article ID 22128.
Open this publication in new window or tab >>Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 22128Article in journal (Refereed) Published
Abstract [en]

Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-189808 (URN)10.1038/s41598-021-01499-6 (DOI)000717747400105 ()2-s2.0-85118949353 (Scopus ID)
Available from: 2021-11-22 Created: 2021-11-22 Last updated: 2024-03-25Bibliographically approved
Forsberg, K., Tjust, A. E., Zetterström, P., Marklund, S. L. & Andersen, P. M. (2020). ALS kan vara en prionsjukdom: Inklusioner av felvecklat SOD1-protein tycks finnas hos patienter med alla typer av ALS. Läkartidningen, 117, Article ID FYT4.
Open this publication in new window or tab >>ALS kan vara en prionsjukdom: Inklusioner av felvecklat SOD1-protein tycks finnas hos patienter med alla typer av ALS
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2020 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 117, article id FYT4Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Läkartidningen Förlag AB, 2020
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-179759 (URN)32154903 (PubMedID)2-s2.0-85081929668 (Scopus ID)
Note

Lakartidningen.se 2020-03-10

Available from: 2021-02-09 Created: 2021-02-09 Last updated: 2023-06-26Bibliographically approved
Pröbstel, A.-K., Zhou, X., Baumann, R., Wischnewski, S., Kutza, M., Rojas, O. L., . . . Baranzini, S. E. (2020). Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis. Science immunology, 5(53), Article ID eabc7191.
Open this publication in new window or tab >>Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis
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2020 (English)In: Science immunology, E-ISSN 2470-9468, Vol. 5, no 53, article id eabc7191Article in journal (Refereed) Published
Abstract [en]

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2020
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-179790 (URN)10.1126/sciimmunol.abc7191 (DOI)000620241200003 ()33219152 (PubMedID)2-s2.0-85096814923 (Scopus ID)
Available from: 2021-02-10 Created: 2021-02-10 Last updated: 2023-09-05Bibliographically approved
Yilmazer-Hanke, D., Mayer, T., Mueller, H.-P., Neugebauer, H., Abaei, A., Scheuerle, A., . . . Rasche, V. (2020). Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts. Acta neuropathologica communications, 8, Article ID 33.
Open this publication in new window or tab >>Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts
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2020 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 8, article id 33Article in journal (Refereed) Published
Abstract [en]

The identification of cerebral microinfarctions with magnetic resonance imaging (MRI) and histological methods remains challenging in aging and dementia. Here, we matched pathological changes in the microvasculature of cortical cerebral microinfarcts to MRI signals using single 100 μm-thick histological sections scanned with ultra-high-resolution 11.7 T MRI. Histologically, microinfarcts were located in superficial or deep cortical layers or transcortically, compatible with the pattern of layer-specific arteriolar blood supply of the cerebral cortex. Contrary to acute microinfarcts, at chronic stages the core region of microinfarcts showed pallor with extracellular accumulation of lipofuscin and depletion of neurons, a dense meshwork of collagen 4-positive microvessels with numerous string vessels, CD68-positive macrophages and glial fibrillary acidic protein (GFAP)-positive astrocytes. In MRI scans, cortical microinfarcts at chronic stages, called chronic cortical microinfarcts here, gave hypointense signals in T1-weighted and hyperintense signals in T2-weighted images when thinning of the tissue and cavitation and/or prominent iron accumulation were present. Iron accumulation in chronic microinfarcts, histologically verified with Prussian blue staining, also produced strong hypointense T2*-weighted signals. In summary, the microinfarct core was occupied by a dense microvascular meshwork with string vessels, which was invaded by macrophages and astroglia and contained various degrees of iron accumulation. While postmortem ultra-high-resolution single-section imaging improved MRI-histological matching and the structural characterization of chronic cortical cerebral microinfarcts, miniscule microinfarcts without thinning or iron accumulation could not be detected with certainty in the MRI scans. Moreover, string vessels at the infarct margin indicate disturbances in the microcirculation in and around microinfarcts, which might be exploitable in the diagnostics of cortical cerebral microinfarcts with MRI in vivo.

Place, publisher, year, edition, pages
Springer Nature, 2020
Keywords
Post-mortem magnetic resonance imaging, Histological matching, Microbleeds, String vessels, Cerebral microangiopathy, Small vessel disease
National Category
Neurosciences
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-169436 (URN)10.1186/s40478-020-00900-1 (DOI)000520441500002 ()32169123 (PubMedID)2-s2.0-85081687830 (Scopus ID)
Available from: 2020-04-07 Created: 2020-04-07 Last updated: 2023-03-24Bibliographically approved
Olesen, M. N., Wuolikainen, A., Nilsson, A. C., Wirenfeldt, M., Forsberg, K., Madsen, J. S., . . . Asgari, N. (2020). Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 7(3), Article ID e697.
Open this publication in new window or tab >>Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis
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2020 (English)In: Neurology: Neuroimmunology & Neuroinflammation, E-ISSN 2332-7812, Vol. 7, no 3, article id e697Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants.

Methods: This study is a retrospective case series with prospective follow-up (1994–2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes for SOD1 and C9orf72. Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform.

Results: Time from disease onset to death was longer for patients with ALS-causing SOD1 mutations (mSOD1, n = 24) than those with C9orf72 hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19; q = 0.001) and other ALS (OALS) (n = 119; q = 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-α) compared with those with C9orf72HRE ALS (q = 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS (q = 0.042 and q = 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05–1.30). Plasma TNF-α, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00–1.02], 1.15 [1.02–1.30], and 1.01 [1.00–1.01], respectively) of patients with OALS, plasma IL-1β (HR 5.90 [1.27–27.5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12–98.6]) of patients with mSOD1 ALS all correlated negatively with survival.

Conclusions: Differences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants.

Place, publisher, year, edition, pages
Wolters Kluwer, 2020
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-173325 (URN)10.1212/NXI.0000000000000697 (DOI)000541150500019 ()32123048 (PubMedID)2-s2.0-85080935579 (Scopus ID)
Funder
Swedish Research Council, 2012-0262Swedish Research Council, 2012-0305Swedish Research Council, 2013-0279Swedish Research Council, 2016-0303Swedish Research Council, 2012-3167Swedish Research Council, 2017-03100Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305The Kempe FoundationsTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseVästerbotten County Council, 56103-7002829
Available from: 2020-07-02 Created: 2020-07-02 Last updated: 2023-09-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2911-6026

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