Wernicke Korsakoff Encephalopathy

Consideration for Wernicke encephalopathy should be given to patients with any evidence of long-term alco- hol abuse or malnutrition and any of the following: acute confusion, decreased conscious level, ataxia, ophthalmo- plegia, memory disturbance, hypothermia with hypoten- sion, and delirium tremens. Wernicke encephalopathy should be considered when any patient with long-term malnutrition presents with confusion or altered metal sta- tus. Signi cant overlap exists between Wernicke enceph- alopathy and Korsako psychosis, in which patients ex- perience delayed and potentially irreversible anterograde and retrograde amnesia. For this reason, the two entities have been described together as Wernicke-Korsako syn- drome. Bariatric surgery, human immunode ciency virus, hyperemesis gravidarum, and other disorders associated with grossly impaired nutritional status have been asso- ciated with Wernicke-Korsako syndrome. Additionally, infantile thiamine de ciency with manifestations of Wer- nicke syndrome has been reported in infants fed formula that was de cient in thiamine. Implementation therapy, with thiamine is a fun- damental approach for the treatment of WE: it must be avoided the administration of ev glucose, which may cause a precipitation of thiamine defects. No therapy has been validated for the treatment of Korsako amnestic syndrome. erefore, the clinicians should avoid any po- tential precipitating factor in speci c patients, more at risk to develop Wernicke-Korsako syndrome

Gait Pathway in Subcortical Vascular Dementia and in Alzheimer’s Disease

Gait impairment, worse equilibrium scores and falls are associated with leukoaraiosis, as widely recognised [1-6]. In Binswanger\u2019s disease with a severe leukoaraiosis gait disorders are clearly evident while patients with mild periventricular changes may present subclinical forms of gait disorders, as proposed by some authors (see data in [7]). Gait disorders in the elderly are particularly relevant, since they can influence the loss of functional independence and death [8]. As anticipated, cerebral small vessel disease (both white matter lesions and lacunar infarcts) correlates with gait parameters: stride length and a lower gait velocity [8]. Most importantly, subcortical vascular lesions seem to increase the possibility of falls, even if clear evidences are still lacking [9-11]. Walking difficulties in Alzheimer\u2019s disease are well described [12]: patients show slow and irregular steps, difficulties in turning and avoiding obstacles [13, 14]. These disturbances have been described also in patients free from extrapyramidal, ataxic, paretic signs, and clinically relevant musculoskeletal impairments [12, 14]. Moreover, Alzheimer\u2019s disease patients have a worse balance [12, 14, 15] and a higher risk of falls compared with matched controls [16, 17]. The prevalence of gait abnormalities varies widely across the studies (from 8.7% [18] to over 90% [19]); this can be explained because of different inclusion criteria and/or assessment procedures. These observations have been confirmed by studies demonstrating that patients with Alzheimer\u2019s disease walk more slowly compared to healthy controls [12] and these gait problems have been interpreted as manifestations of the extrapyramidal deficits (well-known to affect 12\u201328% of Alzheimer patients), or as side effects of drug treatment (e.g. neuroleptic agents) [20]. Since a overt walking problems and trunk movement alterations can be seen also in absence of extrapyramidal signs, it has been proposed that some Alzheimer\u2019s disease patients may present \u201cfrontal gait disorder\u201d, a syndrome coterminous with gait apraxia [21, 15]. The lack of a standardised instrument to assess gait has been implicated as a possible cause for the low frequency of reports on the topic. Since the walking assessment cannot discriminate between walking disorders caused by gait apraxia and other neurological causes of walking difficulty, there has been the necessity to exclude alternative causes of walking abnormalities in Alzheimer\u2019s disease (overt extrapyramidal impairments or other concurrent neurological diseases); in order to assess gait capacity, a new test has been proposed and a large proportion of the sample (40%) scored below cut off, even if the percentage of severely impaired was smaller. Although the possibility of right\u2013left confusion, working memory deficits, and problems with verbal comprehension was minimised by demonstrating the items, the complexity of some of them might have contributed to inflating the proportion of patients performing poorly. Even though, the presence of associated vascular pathology in a few patients also cannot account for the outcome. Neuroradiological signs of white matter changes were reported in three of the 24 patients (22.5%) in the Della Sala et al.\u2019s study [12], who scored below cut off in the assessment of walking skills. Therefore, in a well-defined population suffering from subcortical vascular dementia and Alzheimer\u2019s disease (standing from a neurological, clinical, and radiological criteria), we tried to explore gait, balance and equilibrium alterations, and a behavioral complex symptom, such as apathy, even considering precipitant factors, such as concomitant pathologies and consequent therapies. We now present an extension of the work, with a speculation on what we observed for a two-year follow-up

Transport and Metabolism at Blood–Brain Interfaces and in Neural Cells: Relevance to Bilirubin-Induced Encephalopathy

Bilirubin, the end-product of heme catabolism, circulates in non-pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood–brain interfaces (BBIs) into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, BBIs act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of BBIs in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood–brain and blood–cerebrospinal fluid barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic unconjugated hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as the potential role of transporters such as ABCC1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed

Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment

The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2-13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity

Nonalcoholic Fatty Liver Disease and Altered Neuropsychological Functions in Patients with Subcortical Vascular Dementia

NAFLD is the most common cause of abnormality in liver function tests. NAFLD is considered a potential cardiovascular risk factor and is linked to cardiovascular risk factors such as obesity, hypertension, type 2 diabetes, and dyslipidemia. Few previous studies have investigated whether NAFLD could be independently associated with cognitive impairment. The current study aims to find a possible role of NAFLD in the development of subcortical vascular dementia (sVaD). We considered NAFLD as a possible independent vascular risk factor or, considering its metabolic role, associated with other commonly accepted sVaD risk factors, i.e., lack of folate, vitamin B12, and vitamin D-OH25, and increased levels of homocysteine. We studied 319 patients diagnosed with sVaD. All patients underwent an abdominal ultrasound examination to classify steatosis into four levels (1—none up to 4—severe). sVaD patients were divided into two groups according to the presence or absence of NAFLD. Our results demonstrated a strong correlation between NAFLD and sVaD. Patients with the two comorbidities had worse neuropsychological outcomes and a worse metabolic profile. We also found a robust relationship between NAFLD and severe vitamin B12, folate, vitamin D hypovitaminosis, and higher hyperhomocysteinemia levels. This way, it is evident that NAFLD contributes to a more severe metabolic pathway. However, the strong relationship with the three parameters (B12, folate and vitamin D, and homocysteinemia) suggests that NAFLD can contribute to a proinflammatory condition

Thalamus and language: What do we know from vascular and degenerative pathologies

Language is a complex cognitive task that is essential in our daily life. For decades, researchers have tried to understand the different role of cortical and subcortical areas in cerebral language representations and language processing. Language-related cortical zones are richly interconnected with other cortical regions (particularly via myelinated fibre tracts), but they also participate in subcortical feedback loops within the basal ganglia (caudate nucleus and putamen) and thalamus. The most relevant thalamic functions are the control and adaptation of cortico-cortical connectivity and bandwidth for information exchange. Despite having the knowledge of thalamic and basal ganglionic involvement in linguistic operations, the specific functions of these subcortical structures remain rather controversial. The aim of this study is to better understand the role of thalamus in language network, exploring the functional configuration of basal network components. The language specificity of subcortical supporting activity and the associated clinical features in thalamic involvement are also highlighted. \ua9 2018 Neurology India, Neurological Society of India

Vitamin D, homocysteine, and folate in subcortical vascular dementia and alzheimer dementia

Dementia is a worldwide health problem which affects millions of patients; Alzheimer's disease (AD) and subcortical vascular dementia (sVAD) are the two most frequent forms of its presentation. As no definite therapeutic options have been discovered, different risk factors for cognitive impairment have been searched for potential therapies. This report focuses on the possible evidence that vitamin D deficiency and hyper-homocysteinemia can be considered as two important factors for the development or the progression of neurodegenerative or vascular pathologies. To this end, we assessed: the difference in vascular risk factors and vitamin D-OH25 levels among groups of sVAD, AD, and healthy age-matched controls; the association of folate, B12, homocysteine, and vitamin D with sVAD/AD and whether a deficiency of vitamin D and an increment in homocysteine levels may be related to neurodegenerative or vessel damages. The commonly-considered vascular risk factors were collected in 543 patients and compared with those obtained from a healthy old volunteer population. ANOVA group comparison showed that vitamin D deficiency was present in demented cases, as well as low levels of folate and high levels of homocysteine, more pronounced in sVAD cases. The statistical models we employed, with regression models built, and adjustments for biochemical, demographic and neuropsychiatric scores, confirmed the association between the three measures (folate decrease, hyperhomocysteinemia and vitamin D decrease) and dementia, more pronounced in sVAD than in AD

Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat

Background: Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood–brain barrier and the choroidal blood–CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood–brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia.// Methods: Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [14C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes.// Results: In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood–brain and blood–CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide.// Conclusion: The data highlight developmental specificities of the blood–brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice./

An animal model for the juvenile non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

11Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches.openopenMarin, Veronica; Rosso, Natalia; Dal Ben, Matteo; Raseni, Alan; Boschelle, Manuela; Degrassi, Cristina; Nemeckova, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, SilviaMarin, Veronica; Rosso, NATALIA CAROLINA; DAL BEN, Matteo; Raseni, Alan; Boschelle, Manuela; Degrassi, Cristina; Nemeckova, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, Silvi

Severe neonatal hyperbilirubinemia and the brain: the old but still evolving story

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