Aging in Behçet's syndrome: an overlooked risk for late-life cognitive impairment.

Behçet’s syndrome (BS) or Behçet’s disease (BD) is a chronic multisystem inflammatory disorder characterized by a relapsing-remitting course and several clinical manifestations, including oral and genital ulcers, skin lesions, and involvement of ocular, vascular, articular, gastrointestinal, urogenital, pulmonary, and neurologic systems []. Although neurological involvement in neuro-Behçet syndrome (NBS) represents one of the most severe disease complications, increasing evidence suggests that cognitive impairment may occur in BS, even in BS individuals without over central nervous system (CNS) involvement [, , ], suggesting that clinical inflammatory mechanisms may contribute to cognitive decline. Currently, some studies have reported that cognitive dysfunction in BS and NBS affect attention, executive functions, memory, information processing speed and visuospatial abilities []. Importantly, different pathophysiological features, such as chronic systemic inflammation, endothelial dysfunction, thrombo-inflammation, vascular insufficiency and immune dysregulation [–], as well as psychiatric symptoms and immunosuppressive therapies may further contribute to cognitive decline in this population [–]. All these factors overlap with mechanisms known to contribute to age-related cognitive decline and dementia. Given the high mortality rate in younger persons [], older individuals are currently understudied and underrepresented in BS literature. In fact, current studies involve young or middle aged persons. Due to the potential overlap between the pathological factors of BS and those involved in healthy aging, early diagnosis and appropriate treatment are crucial to minimize long-term neurological complications and improve patient outcomes []. On the other hand, the potential long-term neurological and neuropsychological consequences of BS and NBS remain largely unknown. The absence of longitudinal studies investigating dementia risk and long term cognitive trajectories in the BS population are lacking. In this perspective paper we discuss cognitive deficits in BS, epidemiological, inflammatory, vascular and aging-related mechanisms potentially linking BS to progressive cognitive decline, underscoring the important need for longitudinal studies specifically focused on the older BS population. From an epidemiological perspective, cognitive impairment has been consistently reported in both BS and NBS, affecting individuals with and without overt neurological involvement []. Available studies report prevalence estimates ranging from approximately 35% to 50%, with deficits predominantly involving attention, executive functioning, memory, and processing speed [, , , ]. Neuroimaging findings may partially support these observations, as parenchymal NBS lesions involving the diencephalon, brainstem, and basal ganglia have been associated with deficits in attention, executive functioning, and psychomotor speed [, ]. In older patients, age-related white matter lesions, cortical atrophy, and microvascular damage may further overlap with BS-related abnormalities, potentially contributing to cognitive vulnerability and complicating neuroradiological interpretation. Current evidence also indicates that disease activity, vascular involvement, chronic systemic inflammation, and longer disease duration may increase the risk of neurocognitive dysfunction, although available studies remain heterogeneous and are largely based on relatively small cohorts. Despite the growing recognition of cognitive impairment in BS, robust epidemiological evidence regarding long-term dementia outcomes remains extremely limited. To date, no large population-based longitudinal studies have specifically quantified the incidence of all-cause dementia, vascular dementia, or Alzheimer’s disease in BS populations. Nevertheless, indirect evidence supporting CNS vulnerability derives from a nationwide Korean cohort study reporting an increased risk of Parkinson’s disease in BS individuals (adjusted hazard ratio 2.47; 95% CI 1.65–3.68) [], suggesting that chronic inflammation and vasculopathy in BS may contribute to broader neurodegenerative processes. Importantly, most currently available studies involve relatively young or middle-aged patients, whereas older adults (≥ 65 years) remain significantly underrepresented. This represents a major unmet research gap, as aging-related neurodegenerative and vascular mechanisms may synergistically interact with BS-related inflammation and endothelial dysfunction, potentially increasing susceptibility to late-life cognitive impairment and dementia. Although the exact etiology of BD has not yet been fully understood, current evidence suggests that the disease arises from aberrant innate and adaptive immune responses triggered by environmental factors in genetically predisposed individuals []. Genetic susceptibility factors, particularly HLA-B51 and polymorphisms involving IL-10, IL-23R, and ERAP1, together with infectiou