The goal of this observational study is to investigate the frequency and the possible pathogenic role of neuronal synaptic antibodies (NSAb) in patients with cognitive impairment (CI). The main questions it aims to answer are:

1. the frequency and associated features of NSAb in patients with CI and the usefulness of a clinical score in improving autoimmune dementia (AID) diagnosis;
2. the clinical significance of NSAb in patients with CI not fulfilling the autoimmune encephalitis (AE) criteria and serum NSAb (NSAb-pos-CI);
3. the impact of blood-brain-barrier (BBB) dysfunction on their pathogenicity.

AE can mimic dementia and, contrarily to neurodegenerative dementia syndromes, affected patients can improve with timely immunotherapies. Consensus-based diagnostic criteria for AE help to select patients for antibody testing. However, encephalitis signs can be absent, particularly in the elderly, and AE can present with slowly progressing CI mimicking classical neurodegenerative diseases, misleading the diagnostic process. Data on the prevalence of NSAb and AE in unselected patients with CI are sparse and mostly affected by retrospective design, small cohorts, and antibody assay shortcomings. There is an urgent need to define the frequency of NSAb and AE in CI patients and elucidate the associated clinical, laboratory and imaging features. Filling these gaps is the first aim of this project. This will allow the early identification and the best management of patients with AID. On the other hand, a proportion of CI patients have NSAb and do not fit the AE criteria (NSAb-pos-CI).

These NSAb are often in the serum, and not in the Cerebrospinal Fluid (CSF), or belong to the Immunoglobulin A/M (Ig A/M) subclasses, as opposite to the AE-associated Immunoglobulin G (IgG) subclass, thus triggering questions about their clinical and therapeutic implications. As NSAb can be found at low titers in the serum of healthy controls, a hypothesis explaining their pathogenicity relies on dysfunctions of the BBB, in a context of indolent inflammation, that might allow the antibodies to reach the Central Nervous System (CNS). Alternatively, NSAb may not be directly pathogenic and could even be secondary to an ongoing neurodegenerative process. However, even in this context, known and unknown NSAb, could still contribute to the clinical phenotype, modulating the disease progression or the presence of additional clinical features (i.e. psychiatric symptoms). Understanding if these serum NSAb, along with other factors such as inflammation and BBB alterations, have a role in modifying the disease trajectory, i.e. accelerating the neurodegeneration and CI progression, is the other main goal. This project will represent a chance to clarify the role of NSAb in NSAb-pos-CI and potentially help to identify a subgroup of patients with specific phenotypes, who could benefit from immunotherapies. The identification of such patients will allow their best clinical management.

Inclusion Criteria:

• both sexes
• adult (aged between 40 and 90 years)
• patients with a diagnosis of new-onset neurocognitive disorders (major and minor), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, with onset within the previous 24 months

Exclusion Criteria:

- presence of a history of seizures within 4 weeks from onset.

patients with a diagnosis of new-onset neurocognitive disorders (major and minor)