Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations:a scoping review

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients.Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury,but relatively less is known about the effect in pediatric populations.The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibito rs as a potential a djuvant treatment fo r neurocognitive decline in pediatric patients with traumatic brain injury.Investigators queried PubMed to identify literature published from database inception thro ugh June 2023 desc ribing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions.Based on preselected search criteria,340 unique papers we re selected for title and abstra ct screening.Thirty-two reco rds were reviewed in full after eliminating preclinical studies and pape rs outside the scope of the project.In adult traumatic brain injury,we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tole rated and shows both objective and patient-reported efficacy for reducing cognitive impairment.In children,3 pape rs report on 5 children recovering from traumatic brain injury,showing limited efficacy.An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group.Given its promise for efficacy in adults with traumatic brain injury and tole rability in pediatric patients,we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

Fish-on-Chips:unveiling neural processing of chemicals in small animals through precise fluidic control

Precise chemical cue presentation alongside advanced brainwide imaging techniques is important to the study of chemosensory processing in animals.Nevertheless,the dynamic nature of chemical-carrying media,such as water or air,poses a significant challenge for delivering highly-controlled chemical flow to an animal subject.Moreover,contact-based cue manipulation and delivery easily shift the position of the animal subject,which is often undesirable for high-quality brain imaging.Additionally,more advanced interfacing tools that align with the diverse range of body part sizes of an animal,ranging from micrometer-scale neurons to meter-long limbs,are much needed.This is particularly crucial when dealing with dimensions that are beyond the reach of conventional experimental tools.

(Phospho)creatine:the reserve and merry-go-round of brain energetics

Creatine transporter(CrT)-deficiency,the most common form of the cerebral creatine deficiency syndromes,causes cognition impairments and severe reduction of the brain creatine(Cr)and phosphocreatine(PCr)levels,and responds poorly to oral Cr supplement as a treatment option.The ca uses of cognitive impairments in CrT-deficient children remain unclear.We recently use gene-targeting to create a mouse model of CrT-deficiency to assess the impacts of Cr/PCr deficiency on brain energetics and stress-adaptation responses(Chen et al.,2021).

CD137L,a driver of harmful inflammation in the nervous system

CD137 (TNFRSF9,4-1BB) is a member of the tumor necrosis factor (TNF) receptor family and a potent costimulatory molecule.High levels of CD137 are expressed on T cells upon activation.CD137 signaling in T cells,either by cognate interaction with antigen-presenting cells (APC)or by agonistic anti-CD137 antibodies,strongly enhances proliferation,interferon-y secretion,and cytolytic activity of T cells.Thus,CD137 signaling is a main driver of cellular,type 1 helper T cells (Th1)and type 1 cytolytic T cells (Tc1) polarised immune responses.

Is medical management useful in Moyamoya disease?

Moyamoya disease(MMD),characterized by progressive internal carotid artery stenosis and collateral vessel formation,prompts cerebral perfusion complications and is stratified into idiopathic and Moyamoya syndrome subtypes.A multifa-ceted approach toward MMD management addresses cerebral infarctions through revascularization surgery and adjunctive medical therapy,while also navigating risks such as intracranial hemorrhage and cerebral infarction resulting from arte-rial stenosis and fragile collateral vessels.Addressing antithrombotic management reveals a potential role for treatments like antiplatelet agents and anticoagulants,despite the ambiguous contribution of thrombosis to MMD-related infarctions and the critical balance between preventing ischemic events and averting hemo-rrhagic complications.Transcranial doppler has proven useful in thromboembolic detection,despite persisting challenges concerning the efficacy and safety of an-tithrombotic treatments.Furthermore,antihypertensive interventions aim to ma-nage blood pressure meticulously,especially during intracerebral hemorrhage,with recommendations and protocols varying based on the patient’s hypertension status.Additionally,lipid-lowering therapeutic strategies,particularly employing statins,are appraised for their possible beneficial role in MMD management,even as comprehensive data from disease-specific clinical trials remains elusive.Com-prehensive guidelines and protocols to navigate the multifaceted therapeutic ave-nues for MMD,while maintaining a delicate balance between efficacy and safety,warrant further meticulous research and development.This protocol manuscript seeks to elucidate the various aspects and challenges imbued in managing and navigating through the complex landscape of MMD treatment.

Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease

Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid p accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS 1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS 1 /1 RS2-mediated signaling in the central nervous system and cognitive decline.

Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation:Mechanisms and implications for psychopathology

Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid(DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In nonhuman primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with longstanding deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder(ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies.

Towards reperfusion-centric preclinical stroke research:outside the box of “reperfusion injury”

Stroke is a major health issue of increasing significance for any society with an aging population. Globally, stroke is the second-leading cause of death with approximately 5.9 million fatal events in 2010, equivalent to 11.1% of all deaths. Yet, despite years of preclinical research on neuroprotection and a multitude of clinical trials, tissue plas- minogen activator （tPA）-mediated recanalization remains the mainstay of acute ischemic stroke therapy, whereas tPA thrombolysis rarely provides benefits in the mechanical occlusion-based stroke models. This split between the bench and bedside raised the concern over the clinical ap- plicability of neuroprotection in acute ischemic stroke. In this perspective commentary, we call for attention to the differences between mechanical-occlusion and thrombo- embolic stroke models in cerebral hemodynamics （Figure 1A, B）, the implications of these differences in view of progressive pathobiology of ischemic stroke （Figure 1C）, and the need and strategies towards reperfusion-centric preclinical stroke research.

Assessment of autonomic function in untreated adult coeliac disease

AIM: Some recent studies showed that alteration of upper-gut motility in coeliac disease may be related to dysfunction of autonomic nervous system. The aim of our study was to investigate whether autonomic nervous system was altered in untreated and unselected coeliac disease patients.METHODS: We studied 8 untreated and consecutive coeliac disease patients (2 males and 6 females, age range 37±14.5 years). Histological evaluation of duodenal mucosa, anti-gliadin antibodies (AGA), antiendomysial antibodies (EMA) and anti-tTG antibodies and sorbitol H2 breath test were performed in all patients. Extrinsic autonomic neuropathy was assessed by the standardized measurement of cardiovascular reflexes (lying-to-standing,Valsalva manoeuvre, deep breathing, sustained handgrip).The results obtained were compared with a healthy,asymptomatic control group (6 males and 7females, age range 42.3±13.5 years).RESULTS: Coeliac patients exhibited a lower increase of PAS as a response to isometric effort, a reduction of spectral power LF as a response to clinostatic position,but without statistical significance. Also they showed a lower tolerance to orthostatic position, associated with a latent disequilibrium of sympathetic-vagal balance, a relative prevalence of parasympathetic component of the autonomic function. However, these results were not statistically significant when compared with control group(P = n.s.). And they were unchanged after 6 and 12 mo of gluten-free diet.CONCLUSION: This study failed to confirm a significant correlation between autonomic dysfunction and coeliac disease, yet we could not exclude a role of autonomic dysfunction in the genesis of systemic symptoms in some coeliacs.

Effect of Abnormal Posture on Quality of Life in Patients with Parkinson’s Disease

Background: Relationship between abnormal posture and QOL of Parkinson's disease is not clear. Objectives: To clarify the association between quality of life (QOL) and abnormal posture in patients with Parkinson’s disease (PD) and examine which QOL dimensions are involved. Methods: This study retrospectively examined PD patients (n = 57) who had undergone outpatient rehabilitation between January and March 2014. Evaluation items were Modified Hoehn Yahr (H-Y) stage, Unified Parkinson’s Disease Rating Scale (UPDRS)-Part III score, Timed Up and Go test (TUG, 3-m walking) result, Parkinson’s Disease Questionnaire (PDQ)-39 score, and the angle of forward and lateral trunk flexion in the standing position. Statistical analysis was performed to reveal the relationship between the total PDQ-39 score and individual evaluation items and which QOL dimensions were affected by abnormal posture due to forward or lateral flexion. Results: A total of 38 PD patients (17 men, 21 women;mean age, 73.2 ± 8.6 years) were enrolled. Among the evaluation items, lateral flexion angle showed a significant correlation with the total PDQ-39 score (r = 0.422, P = 0.008). PDQ-39 dimensions showing an association with forward flexion were activities of daily living (ADL) (P = 0.002) and communication (P = 0.007), whereas ADL (P = 0.004), communication (P = 0.021), and social support (P = 0.029) were associated with lateral flexion. Mobility was not associated with forward or lateral flexion. Conclusion: The present findings revealed a correlation between lateral flexion and QOL in PD patients. Among the PDQ-39 dimensions, ADL and communication were associated with abnormal posture.

Pure Salivatory Seizures Secondary to a Subtle Malformation of the Right Parietal Cortex

Background: Salivatory seizures are a singularly rare condition, which can occur both in idiopathic and symptomatic epilepsies. Objectives: To describe and discuss the case of an adolescent patient with sleep-triggered “pure” salivatory seizures associated with a subtle cortical malformation of the right parietal cortex. Case report: Herein, we report a 17-year-old female who started to present salivatory paroxysms, which occasionally secondarily generalized, shortly after falling asleep, at the age of eight years. Video-electroencephalographic monitoring with scalp electrodes failed to show any epileptiform activity during the several recorded clinical events. Brain MRI and curvilinear reconstruction revealed, in the three orthogonal planes, a subtle cortical thickening, limited to a single gyrus in the right parietal cortex, suggestive of a focal cortical malformation. After antiepileptic drug therapy was optimized, the patient became seizure-free. Conclusion: An epilepsy diagnosis should be pursued in patients presenting isolated, paroxysmal hypersalivation, despite possible negative scalp EEG studies.

Needs of exploring the burden of recent onset seizures due to neurocysticercosis and challenges in southeast Asia focusing on scenario in Malaysia

Seizures due to neurocysticercosis(NCC) is a neglected human-to-human transmitted disorder and an emerging problem worldwide.A substantial portion of recent onset seizures is known to be attributed to NCC in Taenia solium(T.solium) endemic areas where populations which neither raise pigs nor eat pig meat are also at risk.High prevalence of NCC causing epilepsy has been reported in the underdeveloped areas of Southeast Asia(SEA) however,only fragmentary information on its incidence is available in countries like Malaysia.In Malaysia T.solium infection was previously thought to be infrequent due to Muslim population majority and the religious prohibition of consuming pork,but it is not totally absent There is an evident lack of knowledge and awareness of the actual burden,routes of transmission,and the impact of NCC in this region.The problem is assumed to be more prevalent particularly in cities because of the frequent inflow of possibly T.solium infected individuals or carriers among those who migrate from neighboring endemic countries to Malaysia.The issue of imported cases that are likely to be emerging in Malaysia is highlighted here.An accurate quantification of regional burdens of epilepsy due to NCC in Malaysia is warranted considering the disease emergence in its neighboring countries.It is suggested that the importance of NCC be recognized through quantification of its burden,and also to collect epidemiological data for its subsequent elimination in line of World Health Organization's mission for control of cysticercosis as a neglected tropical disease.In this review the need as well as a strategy for neurc-care center screening of epilepsy cases,and various issues with possible explanations are discussed.It is also proposed that NCC be declared as a reportable disease which is one of the eradicable public health problems in SEA.

Circulating factors present in the sera of naturally skinny people may influence cell commitment and adipocyte differentiation of mesenchymal stromal cells

BACKGROUND Research on physiopathology of obesity may receive new hints from studies on skinny people(SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements.AIM To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells(MSCs).METHODS We isolated MSCs from bone marrow of healthy donors with both normal body mass index(BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people(NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation.RESULTS SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation.CONCLUSION Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.

PROPERTIES OF VOLTAGE-GATED SODIUM CHANNELS IN DEVELOPING AUDITORY NEURONS OF THE MOUSE IN VITRO

Objective. To investigate the properties of voltage-gated sodium (Na+) channels in developing auditoryneurons during early postnatal stages in the mammalian central nervous system.Methods. Using the whole-cell voltage-clamp technique, we have studied changes in the electrophysi-ological properties of Na+ channels in the principal neurons of the medial nucleus of the trapezoid body (MNTB).Results. We found that MNTB neurons already express functional Na+ channels at postnatal day 1 (P1),and that channel density begins to increase at P5 when the neurons receive synaptic innervation andreach its maximum (～3 fold) at P11 when functional hearing onsets. These changes were paralleled byan age-dependent acceleration in both inactivation and recovery from inactivation. In contrast, there wasvery little alteration in the voltage-dependence of inactivation.Conclusion. These profound changes in the properties of voltage-gated Na+ channels may increase theexcitability of MNTB neurons and enhance their phase-locking fidelity and capacity during high-frequencysynaptic transmission.

An Unusual Cause of Irritability in a Single Ventricle Patient after Bidirectional Glenn Shunt

The differential diagnosis for irritability in children is broad.In patients with congenital heart disease,one must strongly consider cardiac etiologies such as low cardiac output or elevated central venous pressure(CVP).In patients with single-ventricle physiology,the second stage of palliation includes bidirectional Glenn,which involves anastomosis of the superior vena cava to the pulmonary artery resulting in volume offloading of the single systemic ventricle.Typically,early in the post-operative period,patients may experience a headache due to the acute increase in CVP,and symptoms improve over time.Idiopathic intracranial hypertension(IIH),also known as pseudotumor cerebri,is a rare neurologic disorder in children,characterized by raised intracranial pressure(ICP)in the absence of brain parenchymal lesions or cerebrospinal fluid(CSF)abnormalities.While the pathogenesis of IIH is unknown,early recognition and treatment of IIH are important to prevent permanent vision loss.There are only rare reports of IIH in patients with Fontan circulation.To our knowledge,we report the first case of IIH in a 2-year-old female after bidirectional Glenn.

Electrophysiology as a tool to unravel the origin of pancreatic pain

Intense abdominal pain is the most common symptom in chronic pancreatitis, but the underlying mechanisms are not completely understood and pain management remains a significant clinical challenge.The focus of pain origin in chronic pancreatitis traditionally has been on the pancreatic gland, assuming pain to originate in the pancreas or its surrounding organs. However, research in the last decade points to abnormal central nervous system pain processing.For this reason, electroencephalography has been receiving increasing attention. In contrast to imaging methods such as functional magnetic resonance and positron emission tomography, electroencephalogram has excellent temporal resolution making it possible to investigate central processing of pain on a millisecond time scale. Moreover, continuously advancing methodology made it possible to explore brain sources responsible for generation of evoked potentialsand hence to study brain reorganization due to pain in chronic pancreatitis. The aim of this review is to give an overview of the current methods and findings in electroencephalography as a tool to unravel the origin of pancreatic pain.

A case of Bickerstaff brainstem encephalitis successfully treated with intravenous immunoglobulin and methylprednisolone after unsuccessful immunoadsorption plasmapheresis

Bickerstaff brainstem encephalitis (BBE) is a rare post-infectious neurological syndrome for which an effective treatment strategy has not been established. Here, we report a case of a 71-year-old male who suffered from an upper respiratory tract infection, and 7 days later, developed numbness of the bilateral upper and lower limbs, unsteady gait and dysarthria. Brain magnetic resonance imaging was normal, nerve conduction study and cerebral spinal fluid analysis were nonspecific. Based on the clinical features, we tentatively diagnosed Guillain-Barré syndrome and started immunoadsorption plasmapheresis. However, consciousness progressively declined to coma level within 10 days. Electroencephalogram showed diffuse slowing, and auditory evoked brainstem response (ABR) demonstrated absence of waves II, III and V. Serum anti-GQ1b IgG autoantibody and anti-GM1b IgG autoantibody were negative. Subsequently, we diagnosed BBE, and clinical symptoms resolved after treatment with intravenous immunoglobulin and methyllprednisolone. On day 62, neurological symptoms were remarkably alleviated with an improvement in ABR. Our observations suggest that immunoadsorption plasmapheresis should be used only when anti-ganglioside antibodies are detected. Combination therapy with intravenous immunoglobulin and methylprednisolone or plasma exchange?is recommended as initial therapy.

Central and peripheral neurological involvement in monoclonal gammopathies of undetermined significance

Several studies have suggested a pathogenetic role of paraproteinaemias in PNS damage. Over the few last years, the presence of symptomatic or subclinical PNS lesions in CNS diseases like multiple sclerosis has been described. On the other hand, CNS demyelinating lesions and cervical atrophy have been re- ported in patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Very few cases of MGUS associated with CNS disease alone or with both CNS and PNS disease have been re- ported. Since 1999, we have been studying 16 patients (8 M, 8 F), with a mean age 60.2 ± 13.4, affected by MGUS associated with symptomatic neurological central and/or peripheral diseases. Patients affected with lymphomas, lupus erithematosus and other immunological diseases were excluded. Involvement of both PNS and CNS was not associated to a particular type of paraproteinemia: monoclonal IgM were found in 8 patients;monoclonal IgG in 6 patients and mono- clonal IgA in 1 patient and Igl in 1 patient. High anti- nervous system autoantibodies were found in 10/16 patients and antiMAG antibodies were detected in patients with paraproteinemic demyelinating neuropathy (PDN). High reactivity anti-nervous system might support the hypothesis of a pathogenetic role of MGUS in these neurological diseases. Nevertheless, at present, we cannot exclude that there is only a circumstantial association between MGUS and neurological damages, particularly concerning CNS.

Impact of Motor Speech Intervention on Neural Activity in Children with Speech Sound Disorders: Use of Magnetoencephalography

We present the novel use of a neuroimaging technique, magnetoenceph-alography (MEG), for examining therapy-related changes in neural activity during a speech and a non-speech motor task in children with speech sound disorders (SSD). Nine children (mean age = 4.2 years) with SSD were scanned in the MEG before and after an eight-week course of intensive motor speech therapy. MEG tasks involved an oromotor and a syllable production task. MEG analyses identified significant post-therapy changes in brain regions related to oromotor control and speech production. Behavioral assessments showed significant improvements on measures of motor speech skills and articulation following intervention. This is the first demonstration of the ability of MEG to: 1) capture brain activations resulting from oromotor movements and simple syllable production in young children, and 2) capture brain changes related to speech therapy. As the findings from this study are promising, we discuss directions for the design of future studies to further examine specific neural dysfunctions in speech sound disorders.

Effects of Cholinesterase Inhibitors in Cognition on Parkinson’s Disease Dementia: A Systematic Review and Meta-Analysis

Introduction: Dementia is frequently associated with Parkinson’s disease, especially in later stages. Efficacy of cholinesterase inhibitors (ChI) in Alzheimer’s dementia is well established. However, treatment with ChI in Parkinson’s disease dementia (PDD) remains controversial. The objective of this systematic review and meta-analysis was to assess the effects of ChI in PDD. Methods: A comprehensive literature search was performed in MEDLINE, EMBASE and Cochrane library up to March 2014 using the descriptors “Parkinson’s disease”, “dementia in Parkinson’s disease”, “cognition”, “acetylcholinesterase inhibitors”, “cholinesterase inhibitors”, “anticholinesterase agents”, “rivastigmine”, “donepezil” and “galantamine” (Pubmed search strategy). All randomized, doubleblinded, placebo-controlled trials that met the eligibility criteria and assessed the effects of ChI in PDD were considered for analysis. There were no restrictions regarding paper language. Summary effect-sizes were presented as standardized mean differences (SMD) and the pooled analysis was performed with a fixed-effects model. Outcomes considered for analysis were the Mini Mental Status Exam (MMSE) score and the cognition scale for evaluation of dementia ADAS-Cog. The degree of heterogeneity between included studies was assessed through the I2 test. Results: After a comprehensive search, 175 references were retrieved. From these, five randomized trials involving 946PDD subjects were included in the review. Four studies used donepezil and only one study used rivastigmine. The pooled analysis of five studies that assessed the effects of ChI in MMSE total score showed a SMD of 0.24 (CI 95% 0.11 - 0.38). Three studies considered the effects of ChI on Adas-Cog and the pooled results showed a SMD of 0.21 (CI 95% 0.07 - 0.35). There was no significant heterogeneity between the studies. Conclusions: The results of this systematic review and meta- analysis suggest that ChI improves cognitive impairment in PDD subjects. Despite statistically significant, the translation of these results into relevant clinical improvement should be taken with caution, as the studies did not address what would be considered a clinically significant result.