CASPR2, contactin-associated protein-like 2. between antibody-mediated and neurodegenerative disorders; (b) the occurrence of antibodies against neuronal surface antigens in patients with neurodegenerative disorders and their possible role in the disease course; and (c) the long-term cognitive and neuroradiological changes associated with autoimmune encephalitis, as well as the biomarkers that can help to predict the cognitive outcome. Finally, we review the clinical and pathological features of IgLON5 antibodies-related encephalitis, a unique model of the relationship between antibodies and neurodegeneration. Keywords: neuronal surface antigens, antibodies, neurodegeneration, autoimmune encephalitis, biomarkers 1. Introduction Autoimmune encephalitis (AE) represents a group of brain disorders characterised by the subacute onset of diverse neurological and neuropsychiatric symptoms due to a pathologic immune response directed against self-antigens expressed in the central Rabbit Polyclonal to CBLN2 nervous system. AE is often associated with antibodies against neuronal surface antigens (NSA-Ab) [1,2]. Due to the wide and different expression of the various antigenic targets, clinical manifestations IDO-IN-4 are variable and include diverse combinations of cognitive dysfunction, psychiatric and behavioural disturbances, movement disorders, seizures, sleep disorders and dysautonomia, among others (Table 1) [2]. Many NSA-Ab-related syndromes are associated with cognitive impairment and sometimes this is the first and prevalent manifestation, challenging the diagnosis. This is particularly true in the elderly, as encephalitic signs can be absent [3], and the disease can progress slowly, mimicking a primary neurodegenerative disorder. On the other hand, the idea that autoantibodies could be involved in dementia is old [4,5,6] and several targets have been investigated over time including neuronal receptors and glial protein (for review see [7]). Antibodies against several neuronal proteins involved in different neurodegenerative diseases (i.e., amyloid (A), tau and alpha-synuclein) occur in both healthy subjects and in pathological conditions and they could have either a physiological role in preventing the accumulation of pathological proteins or exert additional damage [8]. Antibodies against neuronal proteins might therefore be part of the homeostatic immunity, emerging for example secondarily to the physiological turnover of neurons outside the CNS, such as in the enteric nervous system [9]. After the discovery of NMDAR-Ab in patients with NMNDAR encephalitis [10], the presence of these antibodies was investigated in a few cohorts of patients with neurodegenerative disorders [11,12,13]. Oppositely to what is generally observed in patients with NSA-Ab-related AE, these antibodies are often found only in the serum in patients without encephalitic signs IDO-IN-4 IDO-IN-4 and often belong to the IgA/IgM subclasses (instead of IgG) [11,12,13,14,15], and therefore their role is not yet clear. In this context, NSA-Ab could be bystanders of a degenerative process or play a pathogenic function, if not primary at least secondary, acting as modifiers of the clinical phenotype and of the disease course. Indeed, NSA-Ab have the potential to cause secondary neurodegeneration even in typical AE, with mechanisms that have not yet been fully elucidated. Table 1 The main clinical features and pathogenic mechanisms of NSA-Ab. = 296) and controls (= 295), the association between NMDAR IgA/IgM antibodies and the presence and severity of cognitive impairment in PD was not confirmed. Moreover, unexpectedly, the frequency of NMDAR IgA/IgM antibodies was lower in PD (13%) than in controls (22%), and positively correlated with age in the latter [90]. Although the appearance of antibodies in neurodegenerative disorders is likely to be secondary, a role in modulating the phenotype has not been systemically investigated. Doss et al. [12] found no association between NMDAR-Abs and neuropsychiatric features in patients with dementia, whereas these antibodies have been associated with minimal symptomatic response to cholinesterase inhibitor treatment, more pronounced cognitive decline and overall poorer prognosis in patients IDO-IN-4 with.