chinese medicine, neuron disease, amyotrophic lateral sclerosis
Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model
Amyotrophic lateral sclerosis is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. Methods. We obtained data for patients from 14 specialised ALS centres in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK.
All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations using internal-external cross-validation, and quantified the discrimination using the concordance statistic and calibration using a calibration slope.
Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset, age at onset, definite versus probable or possible ALS, diagnostic delay, forced vital capacity, progression rate, frontotemporal dementia, and presence of a C9orf72 repeat expansion, all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 and the calibration slope was 1·01. The model was used to define five groups with distinct median predicted and observed times in months from symptom onset to the composite survival outcome: very short 17·7, 16·5; short 25·3, 25·2; intermediate 32·2, 32·8; long 43·7, 44·6; and very long 91·0, 85·6. We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only.
Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis
A list of the potential biomarkers of metabolism in ALS, and their quality relative to the aforementioned identifying attributes are summarized in Table 1. Metabolic alterations in ALS offer opportunities to use metabolism biomarkers for the diagnosis, categorization, and tracking of disease. Not surprisingly, these observations, while serving as markers for disease progression, have resulted in the adoption of interventions aimed at slowing weight loss in ALS. Skeletal Muscle Pathology With findings suggesting that FFM is a prognostic factor in ALS, analysis of skeletal muscle, the primary component of FFM, may offer insights into tissue-specific metabolism biomarkers. Investigated a cohort of patients with primary lateral sclerosis, while the study by Ludolph et al.
While the assessment of glucose tolerance and insulin resistance is relatively straightforward, these tests lack reproducibility and specificity to ALS. Therefore, although glucose metabolism is altered in ALS, it cannot be used as an independent biomarker for ALS diagnosis and prognosis. Conclusion The complexity and heterogeneity of disease between patients limits the scope for the use of a single reliable biomarker of ALS. Significant changes in metabolism seen in ALS may represent a potential avenue for biomarker development. As investigations into the cause for metabolic derangements in ALS are ongoing, and little emphasis has been placed on the development of metabolism biomarkers as diagnostic or prognostic indicators, few reliable metabolism biomarkers exist.
Because metabolic alterations in ALS likely arise from the dysregulation of a number of processes, the utility of biomarkers for assessing early or progressive changes in the metabolic state of ALS patients would necessitate the development of a panel that captures the spectrum of metabolic changes that occur at the systemic and cellular level. A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS. Amyotroph Lateral Scler. Life course body mass index and risk and prognosis of amyotrophic lateral sclerosis: results from the ALS registry Swabia. Relationship of creatine kinase to body composition, disease state, and longevity in ALS.
Amyotroph Lateral Scler Frontotemporal Degener. Park Y, Park J, Kim Y, Baek H, Kim SH. Association between nutritional status and disease severity using the amyotrophic lateral sclerosis functional rating scale in ALS patients.
AMYOTROPHIC LATERAL SCLEROSIS 17; ALS17
AMYOTROPHIC LATERAL SCLEROSIS, CHMP2B-RELATED. TEXT. A number sign is used with this entry because amyotrophic lateral sclerosis-17 is caused by heterozygous mutation in the CHMP2B gene on chromosome 3p. Mutation in the CHMP2B gene can also cause frontotemporal dementia. ALS17 is an adult-onset progressive neurodegenerative disorder with predominantly lower motor neuron involvement, manifest as muscle weakness and wasting of the upper and lower limbs, bulbar signs, and respiratory insufficiency.
A cousin reportedly died of ALS. Neuropathologic examination showed a predominantly lower motor neuron disease with intraneuronal inclusions immunopositive for ubiquitin and p62/sequestosome within lower motor neurons in the ventral horn of the spinal cord. Although initial studies showed no
upper motor neuron pathology in the motor cortex, special repeat studies showed SQSTM1-reactive inclusions within oligodendroglia in the cerebral motor cortex. He developed motor disturbances, including atrophy of the tongue and facial muscles, spastic dysarthria, pseudobulbar paresis, and progressive paresis of the limbs, consistent with a diagnosis of ALS. He had brisk tendon reflexes and extensor plantar responses.
His father reportedly had motor disturbances and frontal lobe dysfunction. All had symptoms of predominant lower motor neuron degeneration without upper motor neuron involvement. Showed no evidence of corticospinal involvement on conventional stains, consistent with the lack of upper motor neuron clinical signs. The lower motor neuron pathology was typical of the primary muscular atrophy variant of ALS. There was severe loss of motor neurons at all levels of the spinal cord, and surviving neurons had UBB-/p62-/TDP43-positive inclusion bodies.
Identified mutations in the CHMP2B gene in 4 of 433 patients with ALS. However, CHMP2B mutations were found in 10% of those with the lower motor neuron variant of ALS, suggesting an enrichment of mutations in patients with that specific disease subtype. Microarray analysis of motor neurons with CHMP2B mutations showed downregulation of genes involved in axonal transport, autophagy induction, protein translation, and certain signaling pathways, such as MAPK-related pathways. Hypothesized that CHMP2B mutations may contribute to motor neuron injury through dysfunction of the autophagic clearance of cellular proteins.