Abstract
Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain ...barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. This was achieved using single and double-labeling immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy. In the sALS spinal cord, P-TDP43 Ser403-404 deposits were elongated and parallel to the lumen, whereas others were granular, seldom forming clusters. In the frontal cortex, the inclusions were granular, or elongated and parallel to the lumen, or forming small globules within or in the external surface of the blood vessel wall. Other deposits were localized in the perivascular space. The present findings are in line with previous observations of TDP-43 vasculopathy in a subset of FTLD-TDP cases and identify this pathology in the spinal cord and frontal cortex in a subset of cases within the sALS/FTLD-TDP spectrum.
•Objective approaches are needed to diagnose bulbar involvement in ALS patients.•The proposed voiceprint may lead to the development of a cheap and easy-to-use tool to identify this dysfunction.•It ...can help multidisciplinary clinical teams with the diagnosis of the disease and monitor progress.•Curing the annotated corpus significantly improves classification results, an accuracy greater than 93% is achieved.•This methodology could be applied in many other neurological or respiratory diseases.
Background and Objective: Bulbar dysfunction is a term used in amyotrophic lateral sclerosis (ALS). It refers to motor neuron disability in the corticobulbar area of the brainstem which leads to a dysfunction of speech and swallowing. One of the earliest symptoms of bulbar dysfunction is voice deterioration characterized by grossly defective articulation, extremely slow laborious speech, marked hypernasality and severe harshness. Recently, research efforts have focused on voice analysis to capture this dysfunction. The main aim of this paper is to provide a new methodology to diagnose this dysfunction automatically at early stages of the disease, earlier than clinicians can do.
Methods: The study focused on the creation of a voiceprint consisting of a pattern generated from the quasi-periodic components of a steady portion of the five Spanish vowels and the computation of the five principal and independent components of this pattern. Then, a set of statistically significant features was obtained using multivariate analysis of variance and the outcomes of the most common supervised classification models were obtained.
Results: The best model (random forest) obtained an accuracy, sensitivity and specificity of 88.3%, 85.0% and 95.0% respectively when classifying bulbar vs. control participants but the results worsened when classifying bulbar vs. no-bulbar patients (accuracy, sensitivity and specificity of 78.7%, 80.0% and 77.5% respectively for support vector machines). Due to the great uncertainty found in the annotated corpus of the ALS patients without bulbar involvement, we used a safe semi-supervised support vector machine to relabel the ALS participants diagnosed without bulbar involvement as bulbar and no-bulbar. The performance of the results obtained increased, especially when classifying bulbar and no-bulbar patients obtaining an accuracy, sensitivity and specificity of 91.0%, 83.3% and 100.0% respectively for support vector machines. This demonstrates that our model can improve the diagnosis of bulbar dysfunction compared not only with clinicians, but also the methods published to date.
Conclusions: The results obtained demonstrate the efficiency and applicability of the methodology presented in this paper. It may lead to the development of a cheap and easy-to-use tool to identify this dysfunction in early stages of the disease and monitor progress.
Abstract
Molecular alterations compromising key metabolic pathways are poorly understood in sporadic frontotemporal lobar degeneration with TDP-43 pathology (sFTLD-TDP). Whole-transcriptome array, ...RT-qPCR validation, gel electrophoresis, and Western blotting, and mitochondrial electron transport chain (ETC) activity were comparatively examined in frontal cortex (area 8) of 16 sFTLD-TDP cases and 14 controls. Assessment of 111 genes by RT-qPCR showed deregulation of 81 genes linked to neurotransmission and synapses, neuronal architecture, cytoskeleton of axons and dendrites, vesicle trafficking, purines, mitochondria, and energy metabolism in sFTLD-TDP. Western blotting studies disclosed downregulation of several mitochondrial subunits encoded by genomic DNA and MT-CO1 encoded by the mitochondrial DNA. Mitochondrial ETC activity of complexes I, IV, and V was decreased in sFTLD-TDP. These findings provide robust information about downregulation of genes involved in vital biochemical pathways and in synaptic neurotransmission which may help to increase understanding about the biochemical substrates of clinical manifestations in sFTLD-TDP.
The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for ...neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPβ, Aβ40, Aβ42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (
= 0.04) and HFMSE (
= 0.05) at 24 months. A reduction in sAPPβ levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aβ40, and Aβ42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.
: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug ...development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings.
: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases.
: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023.
: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%).
: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.
Amyotrophic Lateral Sclerosis (ALS) is a rare disease in primary care (PC), it represents a challenge for the family doctor, especially in home care.
To know the incidence and prevalence of ALS in an ...area of ??PA management, the clinical characteristics and use of health resources.
Observational study.
PC-Direction Costa de Ponent, South Metropolitan Health Region, Barcelona, Catalonia, Spain.
Patients with ALS ≥18 years diagnosed until 03/01/2017. Main measurements Age, sex, characteristics: form of appearance (spinal, bulbar, others), interval between onset of symptoms and diagnosis, percutaneous gastrostomy carriers, ventilation non-invasive or invasive. Identification in PC as a Complex Chronic Patient or with palliative needs (CCP). Inclusion in home care programs (PAD). Model of attention hospitable.
81 patients, mean age 65.6 years (± 11.7), men 49.4%. Shape of onset: spinal 69%, bulbar 21%, another 4%. Interval between the onset of symptoms and diagnosis 12 months. Identified as a CCP 13.6%, 29 patients (35.8%) included in PAD. Attended in comprehensive hospital model 79 patients (97.5%). Prevalence 6.1/100,000 inhabitants in 2017. Annual incidence between 1.2 cases/100,000 inhabitants/year in 2012 and 3.5 cases/100,000 inhabitants/year in 2016.
The use of percutaneous gastrostomy in ALS favors the identification as CCP or with palliative needs and inclusion in PAD. The use of non-invasive ventilation favors inclusion in PAD. The incidence and prevalence data for ALS are higher than those described above in the same area. Early identification is necessary of these patients in the chronic care models in PC teams.
Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or ...prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sALS.
ABSTRACT
To evaluate senescence mechanisms, including senescence-associated secretory phenotype (SASP), in the motor neuron disease model hSOD1-G93A, we quantified the expression of p16 and p21 and ...senescence-associated β-galactosidase (SA-β-gal) in nervous tissue. As SASP markers, we measured the mRNA levels of Il1a, Il6, Ifna and Ifnb. Furthermore, we explored whether an alteration of alternative splicing is associated with senescence by measuring the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR DNA-binding protein (TDP-43; encoded by Tardbp). Transgenic mice showed an atypical senescence profile with high p16 and p21 mRNA and protein in glia, without the canonical increase in SA-β-gal activity. Consistent with SASP, there was an increase in Il1a and Il6 expression, associated with increased TNF-R and M-CSF protein levels, with females being partially protected. TDP-43 splicing activity was compromised in this model, and the senolytic drug Navitoclax did not alter the disease progression. This lack of effect was reproduced in vitro, in contrast to dasatinib and quercetin, which diminished p16 and p21. Our findings show a non-canonical profile of senescence biomarkers in the model hSOD1-G93A.
PDF
