Objective
Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high‐caloric diet increases survival. ...Therefore, we sought to evaluate the efficacy of a high‐caloric fatty diet (HCFD) for increasing survival.
Methods
A 1:1 randomized, placebo‐controlled, parallel‐group, double‐blinded trial (LIPCAL‐ALS study) was conducted between February 2015 and September 2018. Patients were followed up at 3, 6, 9, 12, 15, and 18 months after randomization. The study was performed at 12 sites of the clinical and scientific network of German motor neuron disease centers (ALS/MND‐NET). Eligible patients were randomly assigned (1:1) to receive either HCFD (405kcal/day, 100% fat) or placebo in addition to riluzole (100mg/day). The primary endpoint was survival time, defined as time to death or time to study cutoff date.
Results
Two hundred one patients (80 female, 121 male, age = 62.4 ± 10.8 years) were included. The confirmatory analysis of the primary outcome survival showed a survival probability of 0.39 (95% confidence interval CI = 0.27–0.51) in the placebo group and 0.37 (95% CI = 0.25–0.49) in the HCFD group, both after 28 months (point in time of the last event). The hazard ratio was 0.97, 1‐sided 97.5% CI = −∞ to 1.44, p = 0.44.
Interpretation
The results provide no evidence for a life‐prolonging effect of HCFD for the whole amyotrophic lateral sclerosis population. However, post hoc analysis revealed a significant survival benefit for the subgroup of fast‐progressing patients. ANN NEUROL 2020;87:206–216
Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) ...and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
Background and purpose
Respiratory insufficiency is a common symptom during the course of amyotrophic lateral sclerosis (ALS). The diagnostic workup may be challenging and includes a wide array of ...diagnostic measures. In this study, the aim was to analyze the relationship between hypercapnia‐associated symptoms, blood gas parameters and pulmonary function tests.
Methods
In total, 109 patients (56 women, 53 men, 62.4 ± 11.9 years) with definite, possible or probable ALS according to El Escorial criteria were included. All patients received either arterial blood gas analysis, nocturnal capnometry or both. Pulmonary function was assessed by spirometry and peak cough flow. Clinical symptoms potentially indicating hypercapnia were assessed using 17 dichotomous (yes/no) items.
Results
Of 109 ALS patients, 40 had hypercapnia. The highest accuracy and specificity for predicting hypercapnia was observed for dyspnea at rest (Youden's index 17%, 95% confidence interval CI 2%–34%; sensitivity 23%, 95% CI 9%–38%; specificity 95%, 95% CI 88%–100%). Daytime fatigue yielded the highest sensitivity of 58% (95% CI 40%–76%). Logistic regression for all assessed symptoms combined yielded an area under the receiver operating charteristic curve of 0.8 (95% CI 0.7–0.9). Compared to the clinical symptoms, forced vital capacity and peak cough flow showed higher sensitivity (70% and 87%, respectively) but lacked specificity (33% and 20%).
Conclusion
Evaluation of the presence of hypercapnic symptoms can be utilized to predict incipient respiratory insufficiency and should complement pulmonary function tests. Further studies are needed to validate specific questionnaires in this regard. No single hypercapnia‐associated symptom or pulmonary function test on its own seems sufficient to safely predict hypercapnia.
In this prospective study in ALS patients (n = 109), the diagnostic value of clinical symptoms as well as pulmonary function tests (spirometry and peak cough flow) was investigated to predict hypercapnia measured by nocturnal hypercapnia and morning blood gas analysis. It was found that the evaluation of multiple clinical symptoms combined showed a good predictive power to detect hypercapnic patients. No single clinical symptom alone had sufficient sensitivity and specificity. Compared to the clinical symptoms, spirometry and peak cough flow showed higher sensitivity but lacked specificity. It was found that, especially in bulbar patients, spirometry measurements were not reliable. Therefore, based on our data, using a combination of clinical signs and objective respiratory function tests is recommended for early and reliable detection of respiratory insufficiency.
Diffusion tensor imaging (DTI) allows the in vivo imaging of pathological white matter alterations, either with unbiased voxel-wise or hypothesis-guided tract-based analysis. Alterations of diffusion ...metrics are indicative of the cerebral status of patients with amyotrophic lateral sclerosis (ALS) at the individual level. Using machine learning (ML) models to analyze complex and high-dimensional neuroimaging data sets, new opportunities for DTI-based biomarkers in ALS arise. This review aims to summarize how different ML models based on DTI parameters can be used for supervised diagnostic classifications and to provide individualized patient stratification with unsupervised approaches in ALS. To capture the whole spectrum of neuropathological signatures, DTI might be combined with additional modalities, such as structural T1w 3-D MRI in ML models. To further improve the power of ML in ALS and enable the application of deep learning models, standardized DTI protocols and multi-center collaborations are needed to validate multimodal DTI biomarkers. The application of ML models to multiparametric MRI/multimodal DTI-based data sets will enable a detailed assessment of neuropathological signatures in patients with ALS and the development of novel neuroimaging biomarkers that could be used in the clinical workup.
Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers.
High-resolution ...three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI).
We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p
0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434,
+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060,
+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI.
Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.
The introduction of genetics revolutionized the field of neurodegenerative and neuromuscular diseases and has provided considerable insight into the underlying pathomechanisms. Nevertheless, ...effective treatment options have been limited. This changed recently when antisense oligonucleotides (ASOs) could be translated from in vitro and experimental animal studies into clinical practice. In 2016, two ASOs were approved by the United States US Food and Drug Administration (FDA) and demonstrated remarkable efficacy in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). ASOs are synthetic single-stranded strings of nucleic acids. They selectively bind to specific premessenger ribonucleic acid (pre-mRNA)/mRNA sequences and alter protein synthesis by several mechanisms of action. Thus, apart from gene replacement, ASOs may therefore provide the most direct therapeutic strategy for influencing gene expression. In this review, we shall discuss basic mechanisms of ASO action, the role of chemical modifications needed to improve the pharmacodynamic and pharmacokinetic properties of ASOs, and we shall then focus on several ASOs developed for the treatment of neurodegenerative and neuromuscular disorders, including SMA, DMD, myotonic dystrophies, Huntington’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease.
Energy metabolism in amyotrophic lateral sclerosis Dupuis, Luc, Dr; Pradat, Pierre-François, MD; Ludolph, Albert C, Prof ...
Lancet neurology,
2011, January 2011, 2011-Jan, 2011-01-00, 20110101, Volume:
10, Issue:
1
Journal Article
Peer reviewed
Summary Amyotrophic lateral sclerosis (ALS) is characterised by the progressive degeneration of upper and lower motor neurons. Besides motor neuron degeneration, ALS is associated with several ...defects in energy metabolism, including weight loss, hypermetabolism, and hyperlipidaemia. Most of these abnormalities correlate with duration of survival, and available clinical evidence supports a negative contribution of defective energy metabolism to the overall pathogenic process. Findings from animal models of ALS support this view and provide insights into the underlying mechanisms. Altogether, these results have clinical consequences for the management of defective energy metabolism in patients with ALS and pave the way for future therapeutic interventions.
FUS is an RNA‐binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS‐containing aggregates are often associated with concomitant loss of ...nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell‐specific CRE‐mediated expression of wild‐type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.
Synopsis
Truncation of FUS, leading to cytoplasmic mislocalization, as well as loss of FUS leads to perinatal lethality in mice and alterations in RNA expression and splicing. However, only FUS cytoplasmic mislocalization triggers motor neuron degeneration through motor neuron intrinsic toxicity.
Cytoplasmic FUS mislocalization leads to perinatal death and motor neuron degeneration in knockin mice.
Complete loss of FUS leads to perinatal death in the absence of motor neuron degeneration.
Cytoplasmic FUS mislocalization leads to alterations in gene expression and RNA splicing partially overlapping with complete loss of FUS.
Selective rescue of cytoplasmic FUS mislocalization in motor neurons prevents motor neuron degeneration, but not perinatal death.
Cytoplasmic accumulation of ALS‐associated FUS mutants not only leads to nuclear loss‐of‐function phenotypes, but also to motor neuron degeneration via toxic gain‐of‐function mechanisms.
To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).
This single-centre, prospective, longitudinal study included ...the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.
Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (r
=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.
Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.
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