Virtual hospital and artificial intelligence: a first step towards the application of an innovative health system for the care of rare cerebrovascular diseases.

The development of virtual care options, including virtual hospital platforms, is rapidly changing the healthcare, mostly in the pandemic period, due to difficulties in in-person consultations. For this purpose, in 2020, a neurological Virtual Hospital (NOVHO) pilot study has been implemented, in order to experiment a multidisciplinary second opinion evaluation system for neurological diseases. Cerebrovascular diseases represent a preponderant part of neurological disorders. However, more than 30% of strokes remain of undetermined source, and rare CVD (rCVD) are often misdiagnosed. The lack of data on phenotype and clinical course of rCVD patients makes the diagnosis and the development of therapies challenging. Since the diagnosis and care of rCVDs require adequate expertise and instrumental tools, their management is mostly allocated to a few experienced hospitals, making difficult equity in access to care. Therefore, strategies for virtual consultations are increasingly applied with some advantage for patient management also in peripheral areas. Moreover, health data are becoming increasingly complex and require new technologies to be managed. The use of Artificial Intelligence is beginning to be applied to the healthcare system and together with the Internet of Things will enable the creation of virtual models with predictive abilities, bringing healthcare one step closer to personalized medicine. Herein, we will report on the preliminary results of the NOVHO project and present the methodology of a new project aimed at developing an innovative multidisciplinary and multicentre virtual care model, specific for rCVD (NOVHO-rCVD), which combines the virtual hospital approach and the deep-learning machine system.

Migraine and rare neurological disorders.

Although migraine is generally considered an idiopathic and isolated neurological condition, it may also represent the presenting symptom of several uncommon heritable and acquired neurological diseases contributing to the recognition of such conditions. Migraine may indeed present with atypical characteristics or prolonged duration and may be associated with specific neuroradiological findings that may help in identifying the underlying condition. However, features of migraine in rare diseases are usually little known because of the lack of systematic studies. The aim of this paper is to provide clinicians with an updated review on specific clinical and neuroradiological features of migraine in uncommon neurological diseases that may be helpful to their diagnosis and treatment. Therefore, the early diagnosis of these uncommon diseases is crucial for patients' clinical management and for the implementation of therapeutic approaches aimed at targeting the underlying disease pathogenic mechanisms. Thus, when investigating patients affected by migraine, physicians should always be aware about rare causes of migraine that if misdiagnosed could seriously impact patients' outcome. Given these relevant implications, future studies specifically assessing features of migraine in uncommon diseases are mandatory.

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aß) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.

Correction: Sciacca, F. L., et al. Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome. Int. J. Mol. Sci. 2018, 19, 3675.

The authors wish to make the corrections to this paper [...].

Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome.

Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal "moyamoya" vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes) including several heritable conditions such as Down syndrome, neurofibromatosis type 1 and other genomic defects. Although the mechanism that links MA to these genetic syndromes is still unclear, it is believed that the involved genes may contribute to the disease susceptibility. Herein, we describe the case of a 43 years old woman with bilateral MA and peculiar facial characteristics, having a 484-kb microduplication of the chromosomal region 15q13.3 and a previously unreported 786 kb microdeletion in 18q21.32. This patient may have a newly-recognized genetic syndrome associated with MA. Although the relationship between these genetic variants and MA is unclear, our report would contribute to widening the genetic scenario of MA, in which not only genic mutation, but also genome unbalances are possible candidate susceptibility factors.

Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells.

Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.

Does Body Memory Exist? A Review of Models, Approaches and Recent Findings Useful for Neurorehabilitation.

Over the past twenty years, scientific research on body representations has grown significantly, with Body Memory (BM) emerging as a prominent area of interest in neurorehabilitation. Compared to other body representations, BM stands out as one of the most obscure due to the multifaceted nature of the concept of "memory" itself, which includes various aspects (such as implicit vs. explicit, conscious vs. unconscious). The concept of body memory originates from the field of phenomenology and has been developed by research groups studying embodied cognition. In this narrative review, we aim to present compelling evidence from recent studies that explore various definitions and explanatory models of BM. Additionally, we will provide a comprehensive overview of the empirical settings used to examine BM. The results can be categorized into two main areas: (i) how the body influences our memories, and (ii) how memories, in their broadest sense, could generate and/or influence metarepresentations-the ability to reflect on or make inferences about one's own cognitive representations or those of others. We present studies that emphasize the significance of BM in experimental settings involving patients with neurological and psychiatric disorders, ultimately analyzing these findings from an ontogenic perspective.

An Overview of the Bodily Awareness Representation and Interoception: Insights and Progress in the Field of Neurorehabilitation Research.

In the last two decades, the scientific literature on so-called body representations has been increasing, and the notion of body awareness (BA) is particularly interesting for neurorehabilitation. In this article, we present results derived from recent studies on this representation, considering the different definitions and explicative models proposed as well as the empirical settings used to test it, providing an extensive overview of these issues. This article discusses the challenge of understanding how we integrate the sensory experiences of proprioception (knowing where our body is in space) and interoception (sensing internal bodily sensations, like hunger of thirst) with our perception of self. This is a difficult problem to analyze because our awareness of our body is inherently linked to our perspective, since the body is the means through which we interact with the world. Presenting the different viewpoints offered by recent theories on this concern, we highlighted that the neurorehabilitation and psychiatric settings offer two important fields useful for the study of BA because in them it is possible to analyze bodily representations by inducing/observing a controlled discrepancy between dysfunctional content and sensory inputs.

CSF and Plasma Biomarkers in Patients With Iatrogenic Cerebral Amyloid Angiopathy.

OBJECTIVES: Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. ß-Amyloid (Aß) accumulation evidenced by amyloid PET positivity or CSF Aß decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aß and tau in iCAA and sCAA cohorts. METHODS: Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aß40, Aß42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. RESULTS: 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aß40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aß42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aß40 (p = 0.08, 95% CI 181-222), Aß42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aß40, 95% CI 153-193; Aß42, 95% CI 6-7 and total tau, 95% CI 2-4). DISCUSSION: Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aß and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.

Visual neglect as a disconnection syndrome? A confirmatory case report.

Visual neglect has classically been associated with right hemisphere injury in parietal, frontal, or temporal cortex, in the basal ganglia or in the thalamus. More recently, visual neglect has been associated with injury extended into fronto-parietal white matter tracts. However, in most published cases white and gray matter injuries were associated. We present the anatomo-clinical study of a patient presenting with severe acute left visual neglect due to ischemic infarct limited to the right cerebral hemisphere white matter. Magnetic resonance diffusion tensor imaging tractography was instrumental to accurately localize the injury to the right arcuate fasciculus that is a component of the large-scale networks controlling visuo-spatial attention. These results add to a growing appreciation that neglect may result from disruption of a distributed attentional network.

An Overview of the Body Schema and Body Image: Theoretical Models, Methodological Settings and Pitfalls for Rehabilitation of Persons with Neurological Disorders.

Given the widespread debate on the definition of the terms "Body Schema" and "Body Image", this article presents a broad overview of the studies that have investigated the nature of these types of body representations, especially focusing on the innovative information about these two representations that could be useful for the rehabilitation of patients with different neurological disorders with motor deficits (especially those affecting the upper limbs). In particular, we analyzed (i) the different definitions and explicative models proposed, (ii) the empirical settings used to test them and (iii) the clinical and rehabilitative implications derived from the application of interventions on specific case reports. The growing number of neurological diseases with motor impairment in the general population has required the development of new rehabilitation techniques and a new phenomenological paradigm placing body schema as fundamental and intrinsic parts for action in space. In this narrative review, the focus was placed on evidence from the application of innovative rehabilitation techniques and case reports involving the upper limbs, as body parts particularly involved in finalistic voluntary actions in everyday life, discussing body representations and their functional role.

The Octopus Trap of Takotsubo and Stroke: Genetics, Biomarkers and Clinical Management.

Takotsubo cardiomyopathy (TC) is a reversible cardiomyopathy mimicking an acute coronary syndrome, usually observed in response to acute stress situations. The association between acute ischemic stroke and TC is already known, since it has been previously reported that ischemic stroke can be both a consequence and a potential cause of TC. However, the precise pathophysiological mechanism linking the two conditions is still poorly understood. The aim of our review is to expand insights regarding the genetic susceptibility and available specific biomarkers of TC and to investigate the clinical profile and outcomes of patients with TC and stroke. Since evidence and trials on TC and stroke are currently lacking, this paper aims to fill a substantial gap in the literature about the relationship between these pathologies.

Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism.

Cell-based therapy could be a valid option to treat myocardial infarct (MI). Adipose-derived stromal cells (ADStCs) have demonstrated tissue regenerative potential including cardiomyogenesis. Omentum is an extremely rich source of visceral fat and its accumulation seems to correlate with cardiovascular diseases. We investigated the capacity of human fat Omentum-derived StCs (FOStCs) to affect heart function upon acute infarct in pigs induced by permanent ligation of the anterior interventricular artery (IVA). We demonstrated for the first time that the local injection of 50x10(6) of FOStCs ameliorates the functional parameters of post-infarct heart. Most importantly, histology of FOStCs treated hearts demonstrated a substantial improvement of cardiomyogenesis. In culture, FOStCs produced an impressive number and amount of angiogenic factors and cytokines. Moreover, the conditioned medium of FOStCs (FOStCs-CM) stimulates in vitro cardiac endothelial cells (ECs) proliferation and vascular morphogenesis and inhibits monocytes, EC activation and cardiomyocyte apoptosis. Since FOStCs in vivo did not trans-differentiate into cardiomyocyte-like cells, we conclude that FOStCs efficacy was presumably mediated by a potent paracrine mechanism involving molecules that concomitantly improved angiogenesis, reduced inflammation and prevented cardiomyocytes death. Our results highlight for the first time the important role that human FOStCs may have in cardiac regeneration.

Clinical Management of Moyamoya Patients.

Moyamoya angiopathy (MMA) is a peculiar cerebrovascular condition characterized by progressive steno-occlusion of the terminal part of the internal carotid arteries (ICAs) and their proximal branches, associated with the development of a network of fragile collateral vessels at the base of the brain. The diagnosis is essentially made by radiological angiographic techniques. MMA is often idiopathic (moyamoya disease-MMD); conversely, it can be associated with acquired or hereditary conditions (moyamoya Syndrome-MMS); however, the pathophysiology underlying either MMD or MMS has not been fully elucidated to date, and this poor knowledge reflects uncertainties and heterogeneity in patient management. MMD and MMS also have similar clinical expressions, including, above all, ischemic and hemorrhagic strokes, then headaches, seizures, cognitive impairment, and movement disorders. The available treatment strategies are currently shared between idiopathic MMD and MMS, including pharmacological and surgical stroke prevention treatments and symptomatic drugs. No pharmacological treatment able to reverse the progressive disappearance of the ICAs has been found to date in both idiopathic and syndromic cases. Antithrombotic agents are usually prescribed in ischemic MMA, although the coexisting hemorrhagic risk should be considered. Surgical revascularization techniques, which are currently the best available treatment in symptomatic MMA, are associated with good long-term outcomes and reduced ischemic and hemorrhagic risks. Given the lack of dedicated randomized clinical trials, current treatment is mainly based on observational studies and physicians' and surgeons' expertise.

PGE2 Is Crucial for the Generation of FAST Whole- Tumor-Antigens Loaded Dendritic Cells Suitable for Immunotherapy in Glioblastoma.

Dendritic cells (DC) are the most potent antigen-presenting cells, strongly inducers of T cell-mediated immune responses and, as such, broadly used as vaccine adjuvant in experimental clinical settings. DC are widely generated from human monocytes following in vitro protocols which require 5-7 days of differentiation with GM-CSF and IL-4 followed by 2-3 days of activation/maturation. In attempts to shorten the vaccine's production, Fast-DC protocols have been developed. Here we reported a Fast-DC method in compliance with good manufacturing practices for the production of autologous mature dendritic cells loaded with antigens derived from whole tumor lysate, suitable for the immunotherapy in glioblastoma patients. The feasibility of generating Fast-DC pulsed with whole tumor lysate was assessed using a series of small-scale cultures performed in parallel with clinical grade large scale standard method preparations. Our results demonstrate that this Fast protocol is effective only in the presence of PGE2 in the maturation cocktail to guarantee that Fast-DC cells exhibit a mature phenotype and fulfill all requirements for in vivo use in immunotherapy approaches. Fast-DC generated following this protocol were equally potent to standard DC in inducing Ag-specific T cell proliferation in vitro. Generation of Fast-DC not only reduces labor, cost, and time required for in vitro clinical grade DC development, but can also minimizes inter-preparations variability and the risk of contamination.

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

Differential effects on angiogenesis of two antimalarial compounds, dihydroartemisinin and artemisone: implications for embryotoxicity.

Artemisinin derivatives are highly effective and well-tolerated antimalarial drugs that now form the basis of antimalarial combination therapies recommended by the World Health Organization. Although not yet reported to be a problem in clinical use, neurotoxicity and embryotoxicity are displayed by the compound class in in vitro and in vivo experimental models, in particular by dihydroartemisinin, the main metabolite of all current clinical artemisinins. Embryotoxicity appears to be connected with defective angiogenesis and vasculogenesis in certain stages of embryo development. This may prevent the use of artemisinin derivatives in malaria during pregnancy, when both mother and fetus are at high risk of death. Artemisone is a novel 10-alkylamino derivative which is not metabolised to dihydroartemisinin. It was selected as a clinical drug candidate on the basis of its high efficacy against Plasmodium falciparum in vitro and its lack of detectable neurotoxicity in both in vitro and in vivo screens. Here we describe the results of a comparative study of the anti-angiogenic properties of both artemisone and dihydroartemisinin in different model systems. We evaluated the proliferation of human endothelial cells and their migration on a fibronectin matrix, the sprouting of new vessels from rat aorta sections grown in collagen and the production of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF) and interleukin-8 (CXCL-8). The data show that artemisone is significantly less anti-angiogenic than dihydroartemisinin in all the experimental models, suggesting that it will be safer to use than the current clinical artemisinins during pregnancy.

CADASIL: Treatment and Management Options.

OPINION STATEMENT: CADASIL is a life-threatening and disabling disease. Despite the progress achieved so far, no therapies able to limit the disease progression have been found and only empiric treatments can be employed to relieve the main disease symptoms. Further in vivo studies as well as data aggregation and multi-centre controlled clinical trials are needed to confirm the emerging findings in order to identify evidence-based therapies for CADASIL.

Period3 gene in disorder of consciousness: The role of neuroimaging in understanding the relationship between genotype and sleep. A brief communication.

BACKGROUND: Several methodologies including neuroimaging and sleep evaluation are being developed to complement the clinical bedside examinations in patients with disorder of consciousness (DOC). Recently, we demonstrated a possible association between Period3 (Per3) variable number tandem repeat (VNTR) polymorphism and functional impairment of DOC patients, speculating a possible role of this gene in sleep regulation. AIM: To assess whether the degree of structural and metabolic damage of the main brain areas involved in the sleep generation and homeostasis may influence the different outcome of DOC patients carrying the Per35/5 genotype in comparison to Per34/4 ones. METHODS: For the present study, we reviewed 44 DOC patients from the Coma Research Centre of the Fondazione IRCCS Istituto Neurologico "C. Besta" of Milan. All patients underwent to polysomnographic sleep evaluation, cerebral structural magnetic resonance imaging (MRI) and 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) analysis. RESULTS: Our DOC patients presented a moderate anatomical (median score 2) and metabolic damage (median value 2.36 SUVmean) of the sleep areas at both MRI and FDG-PET evaluation. Total sleep time seemed to be higher in 5/5 genotype DOC patients (median value Per35/5, 221min, range 126-323min; median value Per34/4, 167min, range 36-477min; and median value Per34/5, 187min, range 29-422min). However, the MRI scores and FDG-PET values of whole brain, overall sleep areas, hypothalamus, midbrain and thalamus did not differ by genotype distribution. CONCLUSION: Although limited by the small sample size, our data might support the idea that Per3 genetic predisposition in DOC patients could affect impairment and residual cognitive functions through sleep homeostasis independently from structural and/or metabolic integrity of sleep areas.

Fabry Disease: Recognition, Diagnosis, and Treatment of Neurological Features.

OPINION STATEMENT: Fabry disease is an X-linked, lysosomal storage disorder caused by a mutation in the GLA gene leading to a deficiency in alpha-galactosidase A enzyme (α-Gal A) activity, which in turn results in accumulation of globotriaosylceramide in the vascular endothelium and smooth muscle cells of different organs, including kidney and heart, finally leading to impairment or failure of organ function. The central and peripheral nervous systems are also affected leading to neurological manifestations such as cerebrovascular diseases, small fiber neuropathy (SFN), and dysautonomic disorders that may be the presenting clinical features in a proportion of patients. This review offers a complete update of all neurological aspects of Fabry disease and therapeutic options. The rarity of disease, as well as the incomplete knowledge regarding natural history, pathogenic mechanisms, and the uncertain efficacy of available therapies, make imperative the acquisition of standardized data on natural disease course. These data are fundamental for the development of new treatments better able to access the central nervous system, to bypass the neutralizing antibodies and to improve the heart and kidney function.