LONgitudinal and Integrated Evaluation of Biomarkers in reLation to phenotYpe in ALS (LONELYALS)

December 17, 2025 updated by: Istituto Auxologico Italiano

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, leading to paralysis and death. Despite its uniformly fatal outcome, ALS shows marked clinical heterogeneity with respect to phenotype, progression rate, cognitive involvement, and survival. This heterogeneity limits prognostic accuracy and complicates patient stratification in both clinical practice and research settings.

Neurochemical biomarkers have emerged as promising tools to improve diagnosis, prognostication, and understanding of ALS pathophysiology. Among them, neurofilament light chain (NfL) represents the most established biomarker, reflecting axonal degeneration. Additional biomarkers, including glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau181), and Alzheimer's disease-related markers (Aβ42 and Aβ40), may provide complementary information regarding astroglial activation, motor neuron subtype involvement, and cognitive-behavioral features. However, the phenotypic correlates, longitudinal trajectories, and biological determinants of these biomarkers in ALS are not yet fully understood.

The LONELYALS study is an ongoing, monocentric, observational cohort study with a case-control component, designed to investigate the relationships between ALS phenotype and a comprehensive panel of cerebrospinal fluid (CSF) and blood biomarkers. The study will enroll 140 adult patients with ALS and collect longitudinal clinical, neuropsychological, biological, and laboratory data over a follow-up period of up to 36 months. By integrating biomarker measurements with detailed phenotypic characterization, the study aims to clarify biomarker origins, determinants, and prognostic value, and to identify novel CSF biomarkers relevant to ALS.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons and leading to muscle weakness, paralysis, and premature death. Although ALS is uniformly fatal, it is characterized by substantial clinical and biological heterogeneity, including differences in site of onset, rate of disease progression, cognitive and behavioral involvement, and survival. This heterogeneity poses major challenges for prognostication, patient counseling, and the design and interpretation of clinical trials.

In recent years, neurochemical biomarkers have gained increasing relevance in ALS research. Neurofilaments, particularly neurofilament light chain (NfL), are currently the most widely studied biomarkers and are considered indicators of axonal degeneration. Elevated NfL levels in cerebrospinal fluid (CSF) and blood have been consistently observed in ALS and are associated with disease severity and survival. However, several key questions remain unresolved, including the relative contribution of upper versus lower motor neuron degeneration to NfL release, the extent to which NfL reflects disease aggressiveness versus anatomical disease burden, and the factors influencing its distribution between CSF and blood.

Other biomarkers may capture complementary aspects of ALS pathophysiology. Glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been reported to be increased in ALS and may be related to extra-motor and cognitive features. Phosphorylated tau (p-tau181), widely used as a biomarker of Alzheimer's disease, has recently been proposed as a potential ALS biomarker, possibly reflecting lower motor neuron degeneration. In addition, classic Alzheimer's disease biomarkers such as Aβ42 and Aβ40 may provide insights into cognitive impairment and overlapping neurodegenerative mechanisms in ALS. The relationships among these biomarkers, their longitudinal evolution, and their associations with clinical phenotype and disease progression remain insufficiently characterized.

The LONELYALS study (LONgitudinal and integrated Evaluation of biomarkers in reLation to phenotYpe in ALS) is an ongoing, monocentric, observational clinical-epidemiological study focusing on biological material. The study adopts a prospective cohort design with a case-control component and is conducted at a single specialized ALS center. A total of 140 adult patients with ALS, aged 18 to 90 years, are being enrolled and followed longitudinally for up to 36 months. Patients are recruited during inpatient admissions, and all participants provide biological samples and clinical data according to standardized procedures.

The study involves the collection and analysis of CSF and blood samples, including genetic material, alongside comprehensive clinical, neurological, and neuropsychological assessments. Biomarkers of interest include established and emerging neurochemical markers related to axonal degeneration, astroglial activation, tau pathology, and amyloid metabolism. Longitudinal sampling allows evaluation of biomarker trajectories over time and their relationship with disease progression.

The primary objectives of the study are to explore the associations between baseline biomarker levels and ALS phenotype, to assess the relationships between CSF and blood biomarker concentrations, and to evaluate the prognostic value of biomarkers with respect to longitudinal clinical evolution. Additional aims include investigating the influence of physiological and pathophysiological factors-such as age, sex, body mass index, and renal function-on biomarker levels; exploring interrelationships among different biomarkers; and identifying novel CSF biomarkers relevant to ALS.

By integrating longitudinal biomarker data with detailed phenotypic characterization, the LONELYALS study seeks to improve understanding of ALS pathophysiology and heterogeneity. The results are expected to support biomarker-based patient stratification, facilitate more accurate prognostication, and contribute to the development of personalized clinical management strategies. In the longer term, improved biomarker characterization may also enhance patient selection and outcome assessment in future interventional trials.

Study Type

Interventional

Enrollment (Estimated)

140

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
    • Lombardy
      • Milan, Lombardy, Italy, 20149
        • Recruiting
        • Istituto Auxologico Italiano IRCCS
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria ALS patients:

  • diagnosis of Amyotrophic Lateral Sclerosis (ALS);
  • age ≥18 y;
  • feasibility of lumbar puncture (LP);
  • informed consent.

Exclusion Criteria ALS patients:

  • severe medical comorbidities;
  • recent traumatic, inflammatory, vascular, or neoplastic Central Nervous System disease; contraindications to LP.

Inclusion Criteria Controls:

  • age ≥18 y;
  • individuals undergoing LP for neurological symptoms;
  • no evidence of nervous system pathology;
  • informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: ALS Patients
Patients with Amyotrophic Lateral Sclerosis
Diagnostic test: Lumbar Puncture for analysis of Cerebrospinal Fluid
Lumbar Puncture for analysis of Cerebrospinal Fluid for subsequent discovery and validation of a novel biomarker
Diagnostic test: Deep Phenotyping
Clinical, neurophysiological, neuroradiological, neuropsychological phenotyping and respiratory investigation
Diagnostic test: Routine blood chemistry analysis and genetic analysis
Plasma sampling and genetic analysis
Other: Controls
Individuals undergoing Lumbar Puncture for neurological symptoms but finally having no evidence of nervous system pathology
Diagnostic test: Lumbar Puncture for analysis of Cerebrospinal Fluid
Lumbar Puncture for analysis of Cerebrospinal Fluid for subsequent discovery and validation of a novel biomarker

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical - ALSFRS-R score
Time Frame: At enrolment, at 6 months, at 12 months
At enrolment, at 6 months, at 12 months
Clinical - Penn UMN Score
Time Frame: At enrolment, at 6 months, at 12 months
At enrolment, at 6 months, at 12 months
Clinical - LMN score
Time Frame: At enrolment, at 6 months, at 12 months
At enrolment, at 6 months, at 12 months
Neuropsychological phenotyping
Time Frame: At enrollment
Score at Montreal Cognitive Assessment
At enrollment
Neurophysiological - Limb denervation score (EMG)
Time Frame: At enrollment
At enrollment
Neurophysiological - CMCT (central motor conduction time) (TMS, transcranial magnetic stimulation)
Time Frame: At enrolment
At enrolment
Arterial blood gas analysis - PaO2
Time Frame: At enrollment
At enrollment
Arterial blood gas analysis - PaCO2
Time Frame: At enrolment
At enrolment
Neuroradiological phenotyping
Time Frame: At enrollment
Presence or absence of T2-FLAIR hyperintensity of the corticospinal tracts
At enrollment
Neurochemical - Plasma NFL
Time Frame: An enrolment, at 6 months, at 12 months
An enrolment, at 6 months, at 12 months
Outcome measure for controls
Time Frame: At enrolment
Exclusion of ALS or other neurodegenerative diseases
At enrolment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Auxologico Italiano

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 17, 2025

Primary Completion (Estimated)

December 15, 2027

Study Completion (Estimated)

December 15, 2027

Study Registration Dates

First Submitted

December 17, 2025

First Submitted That Met QC Criteria

December 17, 2025

First Posted (Actual)

December 31, 2025

Study Record Updates

Last Update Posted (Actual)

December 31, 2025

Last Update Submitted That Met QC Criteria

December 17, 2025

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 23A307

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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