Despite the improvements in life expectancy, neurodegenerative diseases (NDGs) have become the most dreaded disorders of older people. Aged brains show characteristic changes that are linked to neurodegeneration raising the question of whether these hallmarks represent the harbingers of NDGs. Lifestyle factors including, in particular physical exercise, have given particular attention to factors associated to movement issue as ones of the major factors in modulating the risk of developing NDGs, emphasizing the interest in the muscle-brain axis. Indeed, one of the crucial systems severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, and the neuromuscular junction (NMJ) represents the critical region at the level of which the two entities communicate.

Even if controversy exists on whether pathological events beginning at the NMJ precede or follow loss of motor units, some recent data highlight as NGDs (e.g. Amyotrophic Lateral Sclerosis, Alzheimer's Disease, and Parkinson's Disease) and Aging share some common pathologic features such as the loss of fast-twich fiber, a decreased number of synaptic vesicles and sarcopenia giving evidence supports the notion that NMJ dismantlement can occur independently from motor neuron degeneration and may represent an early pathogenic signature of muscle-nerve communication defects.

The M-Brain project is an observational, analytical case-control study that will apply a new approach to interpret data underling the NMJ dismantlement in NDGs patients by comparing their clinical and biological information with data obtained from people who have had a so called "good aging" and those who have had a "bad aging".

The study will collect data useful to identify potential predisposing or risk factors for the subsequent development of a NDGs or able to predict the phenotype traiectories of selected pathologies with differerent movement levels. The combination of a muscular and neurological phenotyping and a biological characterization combining biomarkers, miRNA and extracellular vesicle (EV) assessments will allow to better identify the determinants of muscle-brain cross-talk that can then be used as potential indicators for the definition of critical morphological and functional components involved in aging and some NGDs. The project then will aim to identify phenotyope trajectories of patients giving particular attention to the brain-muscle axis and movement issues in order to provide information useful for future clinical strategies able to minimaze risk/predisponent Factors.

Inclusion Criteria:

for Good aging group:

• Subjects aged 60 years or older
• Frailty Index below the pathological cut-off (>0.25)
• Absence of general cognitive impairment (MMSE > 24 points)
• Absence of a diagnosis of sarcopenia

for Bad aging group:

• Patients aged over 60 years

• Exclusive presence of one of the following diagnoses:

  1. Definite, probable, or probable laboratory-supported Amyotrophic Lateral Sclerosis (ALS), either sporadic or familial, according to the revised El Escorial Criteria for ALS diagnosis.
  2. Parkinson's disease (PD) according to the MDS Clinical Diagnostic Criteria for Parkinson's Disease (Postuma et al., Mov Disord., 2015 Oct; 30(12): 1591-1601).
  3. Alzheimer's disease (AD), possible or probable, according to international diagnostic guidelines.
  4. Diagnosis of severe acquired brain injury according to the Italian Guidelines for the Care of Patients in Vegetative State and Minimally Conscious State 2011 (approved by the Unified Conference on May 5, 2011 - Ministry of Health, Italy), with the presence of Sarcopenia.
  5. Presence of Mild Cognitive Impairment (MCI), subjective memory complaint, or deficit in a single cognitive domain, according to international criteria and in absence of established neurological diseases and sarcopenia.
  6. Presence of Sarcopenia as defined by the EWGSOP2 Sarcopenia Consensus, in the absence of cognitive deficits and established neurological diseases.

Exclusion Criteria:

• Inability to provide informed consent.
• Presence of severe and/or acute comorbidities (e.g., uncontrolled diabetes, heart failure, or a diagnosis of oncological disease), as determined by the research team.
• Evidence of other previous neurological or psychiatric disorders involving the cognitive domain.
• Uncontrolled or complicated systemic diseases or history of traumatic brain injury.
• For subjects with Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), individuals with a history of epilepsy will also be excluded.

Patients to be enrolled in the study will be those admitted at the hospitals involved in the project. Healthy volunteers may be recruited among patients' relatives or among hospital staff who are not involved in the study.