**3. MoyaMoya syndrome in adults (aMMD)**

Adult MMD patients usually complain of experiencing difficulties in the normal development of their work, typically due to subtle cognitive deficits, but sometimes because of an apparent intellectual disability [53], including occasionally reported

cases of progressive dementia associated [54]. Growing interest in patients' neurocognitive profiles can be observed in the scientific literature published in recent years, including those with no neuroradiological evidence of a marked ictus [55–57]. The most recent works suggest that the cognitive impairment in adult MMD is the result of ischemic stroke, but the presence and extent of cognitive decline in asymptomatic patients (those who do not show evidence of ictus, but show some cognitive impairment due to subtle hypoperfusion sustained over years) is an aspect that requires exploration [58]. Some authors have highlighted the absence of a methodological consensus regarding neuropsychological evaluation in MMD as a limitation to definite conclusions [55, 56, 59]. In this sense, the COSMO-JAPAN multicentric prospective study, with 60 adult MMD patients [60] proposed a protocol for cognitive evaluation based on the WAIS-III (intelligence) and WMS-R (memory) tests together with an instrument to measure executive function, such as the FAB (Frontal Assessment Battery), the WCST (Wisconsin Card Classification Test), the Stroop test, the Verbal Fluency Test (FAS) or the TMT A/B (Trail Making Test), and including behavioural scales such as the BDI II (Beck depression scale), the STAI (state-trait anxiety scale), the FrSBe (Frontal behaviour scale), and the WHOQOL26 (a quality of life questionnaire). The results obtained in this study indicated an evident impairment of executive functions, which showedgood correlation with functional neuroimaging data, as a result of vascular involvement (hemodynamic ischemia measured with SPECT at rest) of the anteromedial branches of the anterior cerebral arteries, even in the absence of overt stroke. Functional neuroimaging data has helped to clarify brain-symptomatology relations in MMD. Nakagawara et al. [61] indicated that, even if infarction has not yet occurred, brain dysfunction is associated with persistent hemodynamic compromise in the medial frontal lobes that can be visualized by means of [123I] iomazenil (IMZ) single-photon emission C.T. (SPECT). They highlighted the tremendous potential of this technique as a tool for diagnosing cognitive impairment in adult patients with MMD in whom extensive abnormalities are not revealed by computed tomography (CT) or magnetic resonance imaging (MRI) [61].

In this way, the characterization of the cognitive profile of MMD patients has been the focus of much research in recent years. However, the literature has always indicated that the incidence and severity of cognitive alterations are highly variable among adult patients. In 2008, Karzmark et al. published a survey intended to document more comprehensively the nature of cognitive impairment in moyamoya disease by assessing a larger number of adult cases [57] with a neuropsychological assessment test battery. They demonstrated that the highest rate of impairment corresponded with executive functioning and the lowest rates with memory and perception [62]. Cognitive impairment was present in 31% of the patients, and was severe in 11%. The authors claimedthat MMD can impair cognition in adults, but that the effect is not as severe as in pediatric cases (not the case according to the meta-analyses by Kronenburg et al., which we will address later, which show that the proportion of adult patients with impaired cognitive function matches that of children) [44]. Festa et al. demonstrated that approximately two-thirds of their adult patients (in a pool of 29 patients) exhibited neurocognitive dysfunction [55]. Moreover, a large proportion performed 2 S.D. below the mean on various tests measuring different cognitive domains (29% in processing speed, 31% in verbal memory, 26% in verbal fluency, 25% in executive function). Manual strength and dexterity were also affected in many patients, with impairment detected in 36–58%. The authors suggested that a mechanism of diffuse small vessel disease, perhaps caused by chronic hypoperfusion, could explain the pattern of deficits. Karzmark et al. evaluated another sample of 20 adult MMD patients and observed 67% of them exhibited small T2 hyperintensities in the cerebral subcortical white matter
