Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.

BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point. METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register. RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score. DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.

Language impairment in sporadic and familial (type 8) amyotrophic lateral sclerosis: A comparative study.

INTRODUCTION/AIMS: Language is frequently affected in patients with sporadic amyotrophic lateral sclerosis (sALS), with reduced performance in naming, syntactic comprehension, grammatical expression, and orthographic processing. However, the language profile of patients with familial type 8 ALS (ALS8), linked to p.P56S VAPB mutation, remains unclear. We investigated language in patients with ALS8 by examining their auditory comprehension and verbal production. METHODS: We included three groups of participants: (1) patients with sALS (n = 20), (2) patients with familial ALS8 (n = 22), and (3) healthy controls (n = 21). The groups were matched for age, sex, and education level. All participants underwent a comprehensive language battery, including the Boston Diagnostic Aphasia Examination, the reduced Token test, letter fluency, categorical fluency (animals), word definition from the Cambridge Semantic Memory Research Battery, and a narrative discourse analysis. Participants also were evaluated using Addenbrooke's Cognitive Exam-Revised Version, the Hospital Anxiety and Depression Scale, and the ALS Functional Rating Scale-Revised. RESULTS: Compared to controls, sALS and ALS8 patients had impaired performance on oral (syntactic and phonological processing) comprehension and inappropriate discourse cohesion. sALS and ALS8 did not differ in any language measure. There was no correlation between language scores and functional and psychiatric scales. DISCUSSION: ALS8 patients exhibit language deficits that are independent of motor features. These findings are consistent with the current evidence suggesting that ALS8 has prominent non-motor features.

Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.

Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.

Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

Could the motor unit number index be an early prognostic biomarker for amyotrophic lateral sclerosis?

OBJECTIVE: To evaluate the associations between motor unit number index (MUNIX) and disease progression and prognosis in amyotrophic lateral sclerosis (ALS) in a large-scale longitudinal study. METHODS: MUNIX was performed at the patient's first visit, at 3, 6, and 12 months in 4 muscles. MUNIX data from the patients were compared with those from 38 age-matched healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), the forced vital capacity (FVC), and the survival of the patients. RESULTS: Eighty-two patients were included at baseline, 62 were evaluated at three months, 48 at six months, and 33 at twelve months. MUNIX score was lower in ALS patients compared to controls. At baseline, MUNIX was correlated with ALSFRS-R and FVC. Motor unit size index (MUSIX) was correlated with patient survival. Longitudinal analyses showed that MUNIX decline was greater than ALSFRS-R decline at each evaluation. A baseline MUNIX score greater than 378 predicted survival over the 12-month period with a sensitivity of 82% and a specificity of 56%. CONCLUSIONS: This longitudinal study suggests that MUNIX could be an early quantitative marker of disease progression and prognosis in ALS. SIGNIFICANCE: MUNIX might be considered as potential indicator for monitoring disease progression.

Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.

Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.

Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.

Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.

Contribution of neurophysiology to the diagnosis and monitoring of ALS.

This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which to build support for a diagnosis of ALS, demonstrating the pathophysiological processes of motor unit hyperexcitability, denervation and reinnervation. We consider development of the different diagnostic criteria and the role of EMG therein. While not formally recognised by established diagnostic criteria, we discuss the pioneering studies that have demonstrated the diagnostic potential of transcranial magnetic stimulation (TMS) of the motor cortex and highlight the growing evidence for TMS in the diagnostic process. Finally, accurately monitoring disease progression is crucial for the successful implementation of clinical trials. Neurophysiological measures of disease state have been incorporated into clinical trials for over 20 years and we review prominent techniques for assessing disease progression.

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.

Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.

OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment. RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.

Electromyography as a tool to motion analysis for people with Amyotrophic Lateral Sclerosis: A protocol for a systematic review.

Biomechanical analysis of human movement plays an essential role in understanding functional changes in people with Amyotrophic Lateral Sclerosis (ALS), providing information on muscle impairment. Studies suggest that surface electromyography (sEMG) may be able to quantify muscle activity, identify levels of fatigue, assess muscle strength, and monitor variation in limb movement. In this article, a systematic review protocol will analyze the psychometric properties of the sEMG regarding the clinical data on the skeletal muscles of people with ALS. This protocol uses the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological tool. A specific field structure was defined to reach each phase. Nine scientific databases (PubMed, Web of Science, Embase, Elsevier, IEEE, Google Scholar, SciELO, PEDro, LILACS E CENTRAL) were searched. The framework developed will extract data (i.e. study information, sample information, sEMG information, intervention, and outcomes) from the selected studies using a rigorous approach. The data will be described quantitatively using frequency and trend analysis methods, and heterogeneity between the included studies will be assessed using the I2 test. The risk of bias will be summarized using the most recent prediction model risk of bias assessment tool. Be sure to include relevant statistics here, such as sample sizes, response rates, P values or Confidence Intervals. Be specific (by stating the value) rather than general (eg, "there were differences between the groups"). This protocol will map out the construction of a systematic review that will identify and synthesize the advances in movement analysis of people with ALS through sEMG, using data extracted from articles.

Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS. METHODS: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939. RESULTS: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival. DISCUSSION: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.

Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Altered spreading of fast aperiodic brain waves relates to disease duration in Amyotrophic Lateral Sclerosis.

OBJECTIVE: To test the hypothesis that patients affected by Amyotrophic Lateral Sclerosis (ALS) show an altered spatio-temporal spreading of neuronal avalanches in the brain, and that this may related to the clinical picture. METHODS: We obtained the source-reconstructed magnetoencephalography (MEG) signals from thirty-six ALS patients and forty-two healthy controls. Then, we used the construct of the avalanche transition matrix (ATM) and the corresponding network parameter nodal strength to quantify the changes in each region, since this parameter provides key information about which brain regions are mostly involved in the spreading avalanches. RESULTS: ALS patients presented higher values of the nodal strength in both cortical and sub-cortical brain areas. This parameter correlated directly with disease duration. CONCLUSIONS: In this work, we provide a deeper characterization of neuronal avalanches propagation in ALS, describing their spatio-temporal trajectories and identifying the brain regions most likely to be involved in the process. This makes it possible to recognize the brain areas that take part in the pathogenic mechanisms of ALS. Furthermore, the nodal strength of the involved regions correlates directly with disease duration. SIGNIFICANCE: Our results corroborate the clinical relevance of aperiodic, fast large-scale brain activity as a biomarker of microscopic changes induced by neurophysiological processes.

Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study.

BACKGROUND: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS. METHODS: Patients with ALS wore an accelerometer on the hip for 3-7 days, every 2-3 months during a multi-year observation period. An accelerometer-derived outcome, the Vertical Movement Index (VMI), was calculated, together with predicted disease progression rates, and jointly analysed with overall survival. The clinical utility of VMI was evaluated using comparisons to patient-reported functionality, while the impact of various monitoring schemes on empirical power was explored through simulations. FINDINGS: In total, 97 patients (70.1% male) wore the accelerometer for 1995 days, for a total of 27,701 h. The VMI was highly discriminatory for predicted disease progression rates, revealing faster rates of decline in patients with a worse predicted prognosis compared to those with a better predicted prognosis (p < 0.0001). The VMI was strongly associated with the hazard for death (HR 0.20, 95% CI: 0.09-0.44, p < 0.0001), where a decrease of 0.19-0.41 unit was associated with reduced ambulatory status. Recommendations for future studies using accelerometery are provided. INTERPRETATION: The results serve as motivation to incorporate accelerometer-derived outcomes in clinical trials, which is essential for further validation of these markers to meaningful endpoints. FUNDING: Stichting ALS Nederland (TRICALS-Reactive-II).

Motor band sign is specific for amyotrophic lateral sclerosis and corresponds to motor symptoms.

OBJECTIVE: Magnetic resonance imaging can detect neurodegenerative iron accumulation in the motor cortex, called the motor band sign. This study aims to evaluate its sensitivity/specificity and correlations to symptomatology, biomarkers, and clinical outcome in amyotrophic lateral sclerosis. METHODS: This prospective study consecutively enrolled 114 persons with amyotrophic lateral sclerosis and 79 mimics referred to Karolinska University Hospital, and also 31 healthy controls. All underwent 3-Tesla brain susceptibility-weighted imaging. Three raters independently assessed motor cortex susceptibility with total and regional motor band scores. Survival was evaluated at a median of 34.2 months after the imaging. RESULTS: The motor band sign identified amyotrophic lateral sclerosis with a sensitivity of 59.6% and a specificity of 91.1% versus mimics and 96.8% versus controls. Higher motor band scores were more common with genetic risk factors (p = 0.032), especially with C9orf72 mutation, and were associated with higher neurofilament light levels (std. ß 0.22, p = 0.019). Regional scores correlated strongly with focal symptoms (medial region vs. gross motor dysfunction, std. ß -0.64, p = 0.001; intermediate region vs. fine motor dysfunction, std. ß -0.51, p = 0.031; lateral region vs. bulbar symptoms std. ß -0.71, p < 0.001). There were no associations with cognition, progression rate, or survival. INTERPRETATION: In a real-life clinical setting, the motor band sign has high specificity but relatively low sensitivity for identifying amyotrophic lateral sclerosis. Associations with genetic risk factors, neurofilament levels and somatotopic correspondence to focal motor weakness suggest that the motor band sign could be a suitable biomarker for diagnostics and clinical trials in amyotrophic lateral sclerosis.

Biomarkers for Managing Neurodegenerative Diseases.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).