The Metabolic Impact of Nonalcoholic Fatty Liver Disease on Cognitive Dysfunction: A Comprehensive Clinical and Pathophysiological Review.

Nonalcoholic fatty liver disease (NAFLD) exponentially affects the global healthcare burden, and it is currently gaining increasing interest in relation to its potential impact on central nervous system (CNS) diseases, especially concerning cognitive deterioration and dementias. Overall, scientific research nowadays extends to different levels, exploring NAFLD's putative proinflammatory mechanism of such dysmetabolic conditions, spreading out from the liver to a multisystemic involvement. The aim of this review is to analyze the most recent scientific literature on cognitive involvement in NAFLD, as well as understand its underlying potential background processes, i.e., neuroinflammation, the role of microbiota in the brain-liver-gut axis, hyperammonemia neurotoxicity, insulin resistance, free fatty acids, and vitamins.

The Gut-Liver-Brain Axis: From the Head to the Feet.

The gut-liver-brain axis, a multifaceted network of communication, intricately connects the enteric, hepatic, and central nervous systems [...].

Gut Microbes Meet Machine Learning: The Next Step towards Advancing Our Understanding of the Gut Microbiome in Health and Disease.

The human gut microbiome plays a crucial role in human health and has been a focus of increasing research in recent years. Omics-based methods, such as metagenomics, metatranscriptomics, and metabolomics, are commonly used to study the gut microbiome because they provide high-throughput and high-resolution data. The vast amount of data generated by these methods has led to the development of computational methods for data processing and analysis, with machine learning becoming a powerful and widely used tool in this field. Despite the promising results of machine learning-based approaches for analyzing the association between microbiota and disease, there are several unmet challenges. Small sample sizes, disproportionate label distribution, inconsistent experimental protocols, or a lack of access to relevant metadata can all contribute to a lack of reproducibility and translational application into everyday clinical practice. These pitfalls can lead to false models, resulting in misinterpretation biases for microbe-disease correlations. Recent efforts to address these challenges include the construction of human gut microbiota data repositories, improved data transparency guidelines, and more accessible machine learning frameworks; implementation of these efforts has facilitated a shift in the field from observational association studies to experimental causal inference and clinical intervention.

Small Vessel Disease: Ancient Description, Novel Biomarkers.

Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood-brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.

Bilirubin Prevents the TH+ Dopaminergic Neuron Loss in a Parkinson's Disease Model by Acting on TNF-α.

Parkinson's disease (PD), the fastest-growing movement disorder, is still challenged by the unavailability of disease-modifying therapy. Mildly elevated levels of unconjugated bilirubin (UCB, PubChem CID 5280352) have been shown to be protective against several extra-CNS diseases, and the effect is attributed to its well-known anti-oxidant and anti-inflammatory capability. We explored the neuroprotective effect of low concentrations of UCB (from 0.5 to 4 µM) in our PD model based on organotypic brain cultures of substantia nigra (OBCs-SN) challenged with a low dose of rotenone (Rot). UCB at 0.5 and 1 µM fully protects against the loss of TH+ (dopaminergic) neurons (DOPAn). The alteration in oxidative stress is involved in TH+ positive neuron demise induced by Rot, but is not the key player in UCB-conferred protection. On the contrary, inflammation, specifically tumor necrosis factor alpha (TNF-α), was found to be the key to UCB protection against DOPAn sufferance. Further work will be needed to introduce the use of UCB into clinical settings, but determining that TNF-α plays a key role in PD may be crucial in designing therapeutic options.

Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation.

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called "gut-liver-brain axis" involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with "neuroCD".

Bilirubin: A Promising Therapy for Parkinson's Disease.

Following the increase in life expectancy, the prevalence of Parkinson's disease (PD) as the most common movement disorder is expected to rise. Despite the incredibly huge efforts in research to find the definitive biomarker, to date, the diagnosis of PD still relies mainly upon clinical symptoms. A wide range of treatments is available for PD, mainly alleviating the clinical symptoms. However, none of these current therapies can stop or even slow down the disease evolution. Hence, disease-modifying treatment is still a paramount unmet medical need. On the other side, bilirubin and its enzymatic machinery and precursors have offered potential benefits by targeting multiple mechanisms in chronic diseases, including PD. Nevertheless, only limited discussions are available in the context of neurological conditions, particularly in PD. Therefore, in this review, we profoundly discuss this topic to understand bilirubin's therapeutical potential in PD.

Homocysteine in Neurology: A Possible Contributing Factor to Small Vessel Disease.

Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.

Behavior in subcortical vascular dementia with sight pathologies: visual hallucinations as a consequence of precocious gait imbalance and institutionalization.

BACKGROUND: Subcortical vascular dementia (sVAD) is considered the most frequent dementia in old population, and it is due to a small vessel disease. It has a very specific nosography, where the dominant factors are dysexecutive functions, depression, and apathy. Very few studies described visual hallucinations in sVAD, apart from in the final stages of it. METHODS: This study recruited 577 patients with a diagnosis of sVAD associated with major ocular pathologies and 1118 patients with sVAD without any significant ocular pathology: Patients were followed up for 24 months. We studied the influence of ocular pathologies in precocious visual hallucinations, on behavior disorder (aggressiveness), and gait disorders (instability, fells). We registered the necessity of neuropsychiatric therapies, incidence of hospitalization, and institutionalization. RESULTS: What emerges from our study is that the ocular comorbidities might change the behavior profile of dementia, provoking behavioral alterations, and the need for therapies with adverse effects. As far as old age is a complicated status of life, many factors can modify its development. The possible contribution of multiple biological events cannot be neglected, particularly the underlying influence of chronic diseases as well as the geriatric conditions, per se, might compromise the cognitive functions and the pathological conditions. Ocular pathology as a superimposing event in sVAD might worse the outcome. A correct and rapid identification of critical patients might be relevant for the dynamic life events in these patients and their caregivers.

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

The arteriosclerosis-dependent alteration of brain perfusion is one of the major determinants in small vessel disease, since small vessels have a pivotal role in the brain's autoregulation. Nevertheless, as far as we know, endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia that is related to small vessel disease (SVD), also being defined as subcortical vascular dementia (sVAD), as well as microglia activation, chronic hypoxia and hypoperfusion, vessel-tone dysregulation, altered astrocytes, and pericytes functioning blood-brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence (or a first event, too) is the macroscopic alteration of the neurovascular coupling. Here, we examined the possible mechanisms that lead a healthy aging process towards subcortical dementia. We remarked that SVD and white matter abnormalities related to age could be accelerated and potentiated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors, which are, to the best of our knowledge, mostly unknown. Metabolic demands, active neurovascular coupling, correct glymphatic process, and adequate oxidative and inflammatory responses could be bulwarks in defense of the correct aging process; their impairments lead to a potentially catastrophic and non-reversible condition.

An Iatrogenic Model of Brain Small-Vessel Disease: Post-Radiation Encephalopathy.

We studied 114 primitive cerebral neoplasia, that were surgically treated, and underwent radiotherapy (RT), and compared their results to those obtained by 190 patients diagnosed with subcortical vascular dementia (sVAD). Patients with any form of primitive cerebral neoplasia underwent whole-brain radiotherapy. All the tumor patients had regional field partial brain RT, which encompassed each tumor, with an average margin of 2.6 cm from the initial target tumor volume. We observed in our patients who have been exposed to a higher dose of RT (30-65 Gy) a cognitive and behavior decline similar to that observed in sVAD, with the frontal dysexecutive syndrome, apathy, and gait alterations, but with a more rapid onset and with an overwhelming effect. Multiple mechanisms are likely to be involved in radiation-induced cognitive impairment. The active site of RT brain damage is the white matter areas, particularly the internal capsule, basal ganglia, caudate, hippocampus, and subventricular zone. In all cases, radiation damage inside the brain mainly focuses on the cortical-subcortical frontal loops, which integrate and process the flow of information from the cortical areas, where executive functions are "elaborated" and prepared, towards the thalamus, subthalamus, and cerebellum, where they are continuously refined and executed. The active mechanisms that RT drives are similar to those observed in cerebral small vessel disease (SVD), leading to sVAD. The RT's primary targets, outside the tumor mass, are the blood-brain barrier (BBB), the small vessels, and putative mechanisms that can be taken into account are oxidative stress and neuro-inflammation, strongly associated with the alteration of NMDA receptor subunit composition.

From Brain to Heart: Possible Role of Amyloid-ß in Ischemic Heart Disease and Ischemia-Reperfusion Injury.

Ischemic heart disease (IHD) is among the leading causes of death in developed countries. Its pathological origin is traced back to coronary atherosclerosis, a lipid-driven immuno-inflammatory disease of the arteries that leads to multifocal plaque development. The primary clinical manifestation of IHD is acute myocardial infarction (AMI),) whose prognosis is ameliorated with optimal timing of revascularization. Paradoxically, myocardium re-perfusion can be detrimental because of ischemia-reperfusion injury (IRI), an oxidative-driven process that damages other organs. Amyloid-ß (Aß) plays a physiological role in the central nervous system (CNS). Alterations in its synthesis, concentration and clearance have been connected to several pathologies, such as Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Aß has been suggested to play a role in the pathogenesis of IHD and cerebral IRI. The purpose of this review is to summarize what is known about the pathological role of Aß in the CNS; starting from this evidence, we will illustrate the role played by Aß in the development of coronary atherosclerosis and its possible implications in the pathophysiology of IHD and myocardial IRI. Better elucidation of Aß's contribution to the molecular pathways underlying IHD and IRI could be of great help in developing new therapeutic strategies.

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage.

Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.

Non-alcoholic fatty liver disease and neurological defects.

INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) can be considered one of the most common causes of liver disease in our days and is regarded as one of the newest vascular risk factors for cerebrovascular and other neurological diseases. MATERIALS AND METHODS: We studied a group of neurological outpatients, divided into two homogenous groups based on the presence or absence of NAFLD. RESULTS AND CONCLUSIONS: We testified an independent relationship between NAFLD and common vascular risk factors (age, sex, educational level, BMI, cholesterol and lipid assessment, Hb1ac). At the same time, we ascertained an independent relationship between NAFLD and more recently recognized vascular risk factors, such as lack of folate, vitamin B12 and vitamin D-OH25, and increased levels of homocysteine. Finally, we have documented that NAFLD showed worse executive and frontal functions, and behavioral changes, such as depressive mood and anxiety, and apathy.

B Vitamins and Fatty Acids: What Do They Share with Small Vessel Disease-Related Dementia?

Many studies have been written on vitamin supplementation, fatty acid, and dementia, but results are still under debate, and no definite conclusion has yet been drawn. Nevertheless, a significant amount of lab evidence confirms that vitamins of the B group are tightly related to gene control for endothelium protection, act as antioxidants, play a co-enzymatic role in the most critical biochemical reactions inside the brain, and cooperate with many other elements, such as choline, for the synthesis of polyunsaturated phosphatidylcholine, through S-adenosyl-methionine (SAM) methyl donation. B-vitamins have anti-inflammatory properties and act in protective roles against neurodegenerative mechanisms, for example, through modulation of the glutamate currents and a reduction of the calcium currents. In addition, they also have extraordinary antioxidant properties. However, laboratory data are far from clinical practice. Many studies have tried to apply these results in everyday clinical activity, but results have been discouraging and far from a possible resolution of the associated mysteries, like those represented by Alzheimer's disease (AD) or small vessel disease dementia. Above all, two significant problems emerge from the research: No consensus exists on general diagnostic criteria-MCI or AD? Which diagnostic criteria should be applied for small vessel disease-related dementia? In addition, no general schema exists for determining a possible correct time of implementation to have effective results. Here we present an up-to-date review of the literature on such topics, shedding some light on the possible interaction of vitamins and phosphatidylcholine, and their role in brain metabolism and catabolism. Further studies should take into account all of these questions, with well-designed and world-homogeneous trials.

The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice.

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) can be responsible of different systemic and neurological disease. Actually, HHcy has been considered as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and HHcy has been reported in many neurologic disorders including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. HHcy is typically defined as levels >15 micromol/L. Treatment of hyperhomocysteinemia with folic acid and B vitamins seems to be effective in the prevention of the development of atherosclerosis, CVD, and strokes. However, data from literature show controversial results regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum (ER) stress have been considered to play an important role in the pathogenesis of several diseases including atherosclerosis and stroke. The aim of our research is to review the possible role of HHcy in neurodegenerative disease and stroke and to understand its pathogenesis.

Earliest Mechanisms of Dopaminergic Neurons Sufferance in a Novel Slow Progressing Ex Vivo Model of Parkinson Disease in Rat Organotypic Cultures of Substantia Nigra.

The current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understanding of the early events causing the decline of dopaminergic neurons (DOPAn). To overcome this problem, slow progressively degenerating models of PD allowing the study of the pre-clinical phase are crucial. We recreated in a short ex vivo time scale (96 h) all the features of human PD (needing dozens of years) by challenging organotypic culture of rat substantia nigra with low doses of rotenone. Thus, taking advantage of the existent knowledge, the model was used to perform a time-dependent comparative study of the principal possible causative molecular mechanisms undergoing DOPAn demise. Alteration in the redox state and inflammation started at 3 h, preceding the reduction in DOPAn number (pre-diagnosis phase). The number of DOPAn declined to levels compatible with diagnosis only at 12 h. The decline was accompanied by a persistent inflammation and redox imbalance. Significant microglia activation, apoptosis, a reduction in dopamine vesicle transporters, and the ubiquitination of misfolded protein clearance pathways were late (96 h, consequential) events. The work suggests inflammation and redox imbalance as simultaneous early mechanisms undergoing DOPAn sufferance, to be targeted for a causative treatment aimed to stop/delay PD.

Hepatitis C-related cryoglobulinemic neuropathy: potential role of oxcarbazepine for pain control.

BACKGROUND: Peripheral neuropathy is one most common, limiting and invalidating neurological symptom in subjects with hepatitis C virus and mixed cryoglobulinemia. Notably, the medical therapy proposed to eradicate HCV, can frequently exacerbate the painful neuropathy. Therefore, neuropathy therapies are insufficient and inadequate, and comprise immunosuppressive drugs, such as steroid or cyclosporine, intravenous immunoglobulin or plasma exchange. These have shown variable success in case reports, with a presumably temporary effect, but with major side effects. METHODS: We assessed the effects of oxcarbazepine treatment in 67 cases of cryoglobulinemia related neuropathy, who did not respond to either steroid or Gabapentin, or Pregabalin. Oxcarbazepine was chosen based on the promising preliminary results. RESULTS: Patients treated with Oxcarbazepine showed a rapid, discrete and persistent relief of polyneuropathic signs, without consistent side effects, and with a limited interaction with concomitant drugs. CONCLUSIONS: These data favor the use of oxcarbazepine as a useful tool in the management of neuropathic pain associated with Hepatitis-C cryoglobulin neuropathy.

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact.

It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurological pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease-modifying strategies, the role of different risk factors should be investigated in neurology, as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.

Focus on neuro-Behçet's disease: A review.

Behçet's disease (BD) is a multisystemic vasculitis disorder of almost unknown etiology, which involves small and large vessels and affects both veins and arteries. BD is characterized by recurrent oral aphthae (the main and most recurrent symptoms), genital ulcers, variable skin lesions, arthritis, uveitis, and thrombophlebitis. Other reported symptoms concern the involvement of the gastrointestinal and the central nervous system. Neuro-Behçet's disease (NBD) is one of the main causes of long-term morbidity and mortality, making its prompt recognition and treatment fundamental to attaining a better outcome. As pointed out by Kalra et al., there are definite consensus statements for BD, but less data are available for NBD. A multidisciplinary team of rheumatologists, dermatologists, ophthalmologists, neurologists, cardiovascular surgeons, and gastroenterologists, often led by rheumatologists, participate in the management of patients with BD and NBD.