Dysfunction In Amyotrophic Lateral Sclerosis Research Articles

Pathological insights derived from neuroimaging in amyotrophic lateral sclerosis: emerging clinical applications.

Neuroimaging has been instrumental in shaping current understanding of the pathoanatomical signature of amyotrophic lateral sclerosis (ALS) across clinically well defined patient cohorts. The potential utility of imaging as an objective disease marker, however, remains poorly defined. Increasingly advanced quantitative and computational imaging studies have highlighted emerging clinical applications for neuroimaging as a complementary clinical modality for diagnosis, monitoring, and modelling disease propagation. Multimodal neuroimaging has demonstrated novel approaches for capturing primary motor disease. Extra-motor subcortical dysfunction is increasingly recognized as key modulators of disease propagation. The neural signature of cortical and subcortical dysfunction in ALS has been well defined at the population level. Objective metrics of focal primary motor dysfunction are increasingly sensitive and translatable to the individual patient level. Integrity of extra-motor subcortical abnormalities are recognized to represent critical pathways of the ALS disease 'connectome', predicting pathological spread. Neuroimaging plays a pivotal role in capturing upper motor neuron pathology in ALS. Their potential clinical role as objective disease markers for disease classification, longitudinal monitoring, and prognosis in ALS have become increasingly well defined.

Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis

Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23–75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.

ECAS correlation with metabolic alterations on FDG-PET imaging in ALS

Background: Cognitive impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is an ALS-specific multi-domain screening tool. Few studies have examined the relationship between ECAS scores and [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) findings. Objective: To assess the relationship between ECAS scores and glucose metabolism patterns on [18F]FDG -PET images in ALS. Methods: We collected [18F]FDG-PET images from 65 patients with ALS and 39 healthy controls. ECAS scores were collected on all patients and we calculated the correlation to [18F]FDG-PET in order to investigate the potential links between cognition and glucose metabolism. Results: We observed hypometabolism in the frontal cortex, insula, and limbic system, together with hypermetabolism in the cerebellum in patients with ALS compared to controls. A lower ECAS total score was associated with lower glucose metabolism in the right orbitofrontal gyrus and higher glucose metabolism in lateral occipital, medial occipital, and cerebellar regions, among patients with ALS. Similar results, although less widespread, were observed in the analyses of ECAS ALS-specific scores. Conclusions: The metabolic patterns in [18F]FDG -PET show that changes in the glucose metabolism of corresponding areas are related to cognitive dysfunction in ALS, and can be detected using the ECAS.

Autonomic Dysfunction in Amyotrophic Lateral Sclerosis - A Case-Control Study.

This study aimed to explore autonomic nervous system involvement in amyotrophic lateral sclerosis (ALS) patients by evaluating sympathetic skin response (SSR). The study included 35 sporadic (ALS) patients (cases), and 35 healthy age and sex-matched participants (controls) aged <60 years. SSR was recorded in the electrophysiology lab of the Neurology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Patients with diseases associated with peripheral or autonomic neuropathy were excluded. Prolonged latency (delayed SSR) or an absent response was considered abnormal SSR. SSR was found to be abnormal in 17 (48.6 %) ALS cases, with an absent response in the upper limbs of six cases (17.1%). Abnormal SSR was more prevalent in the lower limbs, with 33 (94.3%) and 20 (57.1%) cases having a delayed or absent response, respectively. In comparison, SSR was normal in all control participants (P-value <0.05). Abnormal SSR was significantly more common in the lower limbs of ALS cases with bulbar palsy than those without bulbar palsy (P-value=0.04). There was no association of SSR with disease severity and duration. ALS is significantly associated with abnormal SSR, indicating autonomic nervous system involvement. There could also be an association between bulbar palsy and abnormal SSR among ALS patients. Further studies should be carried out to determine the association of abnormal SSR with disease severity, duration, and type.

A multimodal approach to automated hierarchical assessment of bulbar involvement in amyotrophic lateral sclerosis.

As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement leads to progressive declines of speech and swallowing functions, significantly impacting social, emotional, and physical health, and quality of life. Standard clinical tools for bulbar assessment focus primarily on clinical symptoms and functional outcomes. However, ALS is known to have a long, clinically silent prodromal stage characterized by complex subclinical changes at various levels of the bulbar motor system. These changes accumulate over time and eventually culminate in clinical symptoms and functional declines. Detection of these subclinical changes is critical, both for mechanistic understanding of bulbar neuromuscular pathology and for optimal clinical management of bulbar dysfunction in ALS. To this end, we developed a novel multimodal measurement tool based on two clinically readily available, noninvasive instruments-facial surface electromyography (sEMG) and acoustic techniques-to hierarchically assess seven constructs of bulbar/speech motor control at the neuromuscular and acoustic levels. These constructs, including prosody, pause, functional connectivity, amplitude, rhythm, complexity, and regularity, are both mechanically and clinically relevant to bulbar involvement. Using a custom-developed, fully automated data analytic algorithm, a variety of features were extracted from the sEMG and acoustic recordings of a speech task performed by 13 individuals with ALS and 10 neurologically healthy controls. These features were then factorized into 10 composite outcome measures using confirmatory factor analysis. Statistical and machine learning techniques were applied to these composite outcome measures to evaluate their reliability (internal consistency), validity (concurrent and construct), and efficacy for early detection and progress monitoring of bulbar involvement in ALS. The composite outcome measures were demonstrated to (1) be internally consistent and structurally valid in measuring the targeted constructs; (2) hold concurrent validity with the existing clinical and functional criteria for bulbar assessment; and (3) outperform the outcome measures obtained from each constituent modality in differentiating individuals with ALS from healthy controls. Moreover, the composite outcome measures combined demonstrated high efficacy for detecting subclinical changes in the targeted constructs, both during the prodromal stage and during the transition from prodromal to symptomatic stages. The findings provided compelling initial evidence for the utility of the multimodal measurement tool for improving early detection and progress monitoring of bulbar involvement in ALS, which have important implications in facilitating timely access to and delivery of optimal clinical care of bulbar dysfunction.

Bridging the Gap: Harnessing Plant Bioactive Molecules to Target Gut Microbiome Dysfunctions in Amyotrophic Lateral Sclerosis.

The correlation between neurodegenerative diseases and the gut microbiome is increasingly evident, with amyotrophic lateral sclerosis (ALS) being particularly notable for its severity and lack of therapeutic options. The gut microbiota, implicated in the pathogenesis and development of ALS, plays a crucial role in the disease. Bioactive plant molecules, specifically volatile compounds in essential oils, offer a promising therapeutic avenue due to their anti-inflammatory properties and gut-modulating effects. Our narrative review aimed to identify microbiota-associated bacteria in ALS and analyze the benefits of administering bioactive plant molecules as much-needed therapeutic options in the management of this disease. A comprehensive search of PubMed database articles published before December 2023, encompassing research on cell, human, and animal ALS models, was conducted. After selecting, analyzing, and discussing key articles, bacteria linked to ALS pathogenesis and physiopathology were identified. Notably, positively highlighted bacteria included Akkermansia muciniphila (Verrucomicrobia phylum), Faecalibacterium prausnitzii, and Butyrivibrio spp. (Firmicutes phylum). Conversely, members of the Escherichia coli spp. (Proteobacteria phylum) and Ruminococcus spp. (Firmicutes phylum) stood out negatively in respect to ALS development. These bacteria were associated with molecular changes linked to ALS pathogenesis and evolution. Bioactive plant molecules can be directly associated with improvements in the microbiome, due to their role in reducing inflammation and oxidative stress, emerging as one of the most promising natural agents for enriching present-day ALS treatments.

Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.

The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.

Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons and severe skeletal muscle atrophy. The etiology of ALS is linked to skeletal muscle, which can activate a retrograde signaling cascade that destroys motor neurons. This is why satellite cells and mitochondria play a crucial role in the health and performance of skeletal muscles. This review presents current knowledge on the involvement of mitochondrial dysfunction, skeletal muscle atrophy, muscle satellite cells, and neuromuscular junction (NMJ) in ALS. It also discusses current therapeutic strategies, including exercise, drugs, stem cells, gene therapy, and the prospective use of mitochondrial transplantation as a viable therapeutic strategy.

Cognitive reserve in ALS: the role of occupational skills and requirements

Objective Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS. Methods Individuals with ALS (n = 150) were recruited from the University of Pennsylvania’s Comprehensive ALS Clinic. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) measured cognition, and the Penn Upper Motor Neuron (PUMNS) and ALS Functional Rating Scales (ALSFRS-R) measured motor symptoms. We derived 17 factors representing distinct occupational skills and requirements from the Occupational Information Network (O*NET), which were related to cognitive and motor scores using multiple linear regression. Results Occupational roles involving greater reasoning ability (β = 2.12, p < .05), social ability (β = 1.73, p < .05), analytic skills, (β = 3.12, p < .01) and humanities knowledge (β = 1.83, p<.01) were associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=−2.57, p < .01) and technical skills (β=−2.16, p<.01) were associated with lower ECAS scores. Jobs requiring more precision skills (β = 1.91, p < .05) were associated with greater motor dysfunction on the PUMNS. Conclusions Occupational histories involving more cognitively complex skills and activities were related to preserved cognitive functioning in ALS consistent with the cognitive reserve hypothesis, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. Jobs involving more repetitive movements were associated with worse motor functioning, possibly due to overuse. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.

Neurofilament Light Chain Levels Interact with Neurodegenerative Patterns and Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS. We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed. We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains. Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.

PICking out progressive PIC alterations in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motoneuron death. Alterations to motoneuron excitability in ALS are suspected to contribute to motoneuron degeneration. Therefore, mechanisms underlying changes in motoneuron excitability are being thoroughly investigated. A recent publication from Trajano et al. (Trajano GS, Orssatto LB, McCombe PA, Rivlin W, Tang L, Henderson RD. J Physiol 601: 4723-4735, 2023) examined temporal changes to persistent inward currents (PICs) in ALS patients. They show that delta frequency (ΔF, an estimate of PICs) has opposite temporal trends in stronger and weaker muscles of ALS patients. This study is very important to aid in the understanding of disease mechanisms. This Neuro Forum article explores some important considerations for interpreting the results of this study, including treatment effects, potential sex differences, and a lack of comparison to healthy individuals.

Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Segmental motor neuron dysfunction in amyotrophic lateral sclerosis: Insights from H reflex paradigms.

In amyotrophic lateral sclerosis (ALS), the role of spinal interneurons in ALS is underrecognized. We aimed to investigate pre- and post-synaptic modulation of spinal motor neuron excitability by studying the H reflex, to understand spinal interneuron function in ALS. We evaluated the soleus H reflex, and three different modulation paradigms, to study segmental spinal inhibitory mechanisms. Homonymous recurrent inhibition (H'RI ) was assessed using the paired H reflex technique. Presynaptic inhibition of Ia afferents (H'Pre ) was evaluated using D1 inhibition after stimulation of the common peroneal nerve. We also studied inhibition of the H reflex after cutaneous stimulation of the sural nerve (H'Pos ). Fifteen ALS patients (median age 57.0 years), with minimal signs of lower motor neuron involvement and good functional status, and a control group of 10 healthy people (median age 57.0 years) were studied. ALS patients showed reduced inhibition, compared to controls, in all paradigms (H'RI 0.35 vs. 0.11, p = .036; H'Pre 1.0 vs. 5.0, p = .001; H'Pos 0.0 vs. 2.5, p = .031). The clinical UMN score was a significant predictor of the amount of recurrent and presynaptic inhibition. Spinal inhibitory mechanisms are impaired in ALS. We argue that hyperreflexia could be associated with dysfunction of spinal inhibitory interneurons. In this case, an interneuronopathy could be deemed a major feature of ALS.

Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems.

Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models.

Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.

The utility of diaphragm ultrasound thickening indices for assessing respiratory decompensation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) leads to diaphragmatic weakness at some point during its course, which is a major cause of respiratory insufficiency. The aim of this study was to evaluate ultrasound-based measures for assessing the diaphragmatic competency and the need for ventilatory support. Twenty-six subjects with ALS and 12 healthy controls were enrolled. All participants underwent B-mode diaphragm ultrasound (DUS). Diaphragm thickness and thickening indices were recorded. In the subjects with ALS, further assessments included functional scales and spirometry. We investigated the diagnostic accuracy of DUS thickening indices in predicting diaphragmatic dysfunction and the correlation between clinical, spirometric, and DUS data. Significant relationships were found between forced vital capacity and all diaphragmatic thickening indices. Similarly, all diaphragmatic thickening indices correlated with both Milano Torino staging and disease progression rate. Only thickening fraction (TFdi) correlated with score on the revised ALS Functional Rating Scale (r = 0.459, P = .024). TFdi had better accuracy in predicting diaphragmatic dysfunction (area under the curve [AUC] = 0.839, 95% confidence interval [CI] 0.643 to 0.953) and the need for initiation of noninvasive ventilation (NIV) (AUC = 0.989, 95% CI 0.847 to 1.000) compared with the other indices. A TFdi cut-off point of 0.50 was a sensitive threshold to consider NIV. DUS successfully identifies diaphragmatic dysfunction in ALS, being a valuable accessory modality for investigating respiratory symptoms. TFdi was found to be the most useful DUS index, which encourages further investigation.

The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.

Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.

TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains

BackgroundInclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis.MethodsTo investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively.ResultsWe detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls.ConclusionsOverall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.

A Clinical Scale for Rating the Severity of Bulbar Lower Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the UMN and LMN burden in ALS. However, concerning the bulbar LMN burden, the available scoring systems solely assess the presence/absence of bulbar LMN signs without providing a degree of impairment. Therefore, in this study, we proposed a novel scale to stratify subjects with ALS according to the bulbar LMN involvement and assessed its prognostic value. We developed a four-item scale based on the LMN signs according to the El Escorial criteria. Ten raters, specializing in ALS or neurocognitive disorders, retrospectively applied the scale to the first evaluation of 195 patients with ALS. Cohen's kappa (Cohen's k) and an intra-class correlation coefficient (ICC) were used to assess the inter-rater reliability. The Kaplan-Mayer estimator was used to estimate survival distribution according to the bulbar scale scores. The raters showed a substantial to excellent agreement with Cohen's k, ranging from 0.834 to 0.975, with an overall ICC of 0.922 (95% CI = 0.906-0.936). The survival distribution was statistically different across the three bulbar scale scores (χ2(2) = 9.50, p < 0.01). Our bulbar LMN scale represents a reliable measure of the bulbar LMN signs in ALS. This easy-to-administer clinical scale could provide unique information in phenotyping and predicting survival in ALS.

Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.