Direct Central Nervous System Research Articles

Investigation of Antibody Pharmacokinetics in the Brain Following Intra-CNS Administration and Development of PBPK Model to Characterize the Data.

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders.

Bioavailable central nervous system disease-modifying therapies for multiple sclerosis.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

Pre-clinical delivery of gene therapy products to the cerebrospinal fluid: challenges and considerations for clinical translation.

While the majority of gene therapy studies in neurological indications have focused on direct gene transfer to the central nervous system (CNS), there is growing interest in the delivery of therapeutics using the cerebrospinal fluid (CSF) as a conduit. Historically, direct CNS routes-of-administration (RoAs) have relied on tissue dynamics, displacement of interstitial fluid, and regional specificity to achieve focal delivery into regions of interest, such as the brain. While intraparenchymal delivery minimizes peripheral organ exposure, one perceived drawback is the relative invasiveness of this approach to drug delivery. In this mini review, we examine the CSF as an alternative RoA to target CNS tissue and discuss considerations associated with the safety of performing such procedures, biodistribution of therapeutics following single administration, and translation of findings given differences between small and large animals. These factors will help delineate key considerations for translating data obtained from animal studies into clinical settings that may be useful in the treatment of neurological conditions.

Toxicologic Pathology Forum: Opinion on Interpretive Challenges for Procedure-Related Effects Associated With Direct Central Nervous System Delivery of Oligonucleotides to Rodents, Dogs, and Nonhuman Primates.

Direct delivery of therapeutics to the central nervous system (CNS) greatly expands opportunities to treat neurological diseases but is technically challenging. This opinion outlines principal technical aspects of direct CNS delivery via intracerebroventricular (ICV) or intrathecal (IT) injection to common nonclinical test species (rodents, dogs, and nonhuman primates) and describes procedure-related clinical and histopathological effects that confound interpretation of test article-related effects. Direct dosing is by ICV injection in mice due to their small body size, while other species are dosed IT in the lumbar cistern. The most frequent procedure-related functional effects are transient absence of lower spinal reflexes after IT injection or death soon after ICV dosing. Common procedure-related microscopic findings in all species include leukocyte infiltrates in CNS meninges or perivascular (Virchow-Robin) spaces; nerve fiber degeneration in the spinal cord white matter (especially dorsal and lateral tracts compressed by dosing needles or indwelling catheters), spinal nerve roots, and sciatic nerve; meningeal fibrosis at or near IT injection sites; hemorrhage; and gliosis. Findings typically are minimal to occasionally mild. Findings tend to be more severe and/or have a higher incidence in the spinal cord segments and spinal nerve roots at or close to the site of administration.

Neuroimaging Spectrum in COVID-19 Infection: A Single-Center Experience.

Background and Purpose The ongoing coronavirus disease 2019 (COVID-19) pandemic is a multisystemic disease and involvement of the nervous system is well established. The neurological and neuroimaging features of the disease have been extensively evaluated. Our study aimed to elucidate the neuroradiological findings in COVID-19 infected patients admitted to our institute during the first and second waves of the pandemic in India. Methods This was a single-center retrospective study of all COVID-19 positive patients who underwent neuroimaging between March 2020 and May 2021. The presenting neurological complaints, the imaging findings in computed tomography (CT) imaging, and/or magnetic resonance imaging (MRI) were recorded. They recorded the findings in the subheadings of ischemic stroke, hemorrhagic stroke, parainfectious demyelination, acute encephalitis syndrome, and changes of global hypoxic changes. Patients with age-related, chronic, and incidental findings were excluded. Results The study comprised of 180 COVID-19 positive patients who underwent neuroimaging. CT scan was performed for 169 patients, MRI for 28, and a combination of both CT and MRI was performed for 17 patients. Seventy percent of patients were males, and median age was 61.5 years (interquartile range: 48.25-70.75). Out of the 180 patients, 66 patients had nonspecific findings that could not be attributed to COVID-19 infection. In the remaining 114 patients, 77 (42.7%) had ischemic findings, while 22 (12.2%) had hemorrhagic stroke. Hypoxic ischemic changes were noted in five patients. The rest of the patients had a spectrum of changes including, cerebellitis (3), tumefactive demyelination (1), COVID-19-associated encephalitis (1), hemorrhagic acute demyelinating encephalomyelitis (1), transverse myelitis (1), cytotoxic lesions of corpus callosum (1), Guillain-Barre syndrome (1), and COVID-19-associated microhemorrhages (1). Conclusion Neurological manifestations of COVID-19 infection are not uncommon, and our understanding of this topic is expanding. A complex interplay of neurotropism and direct central nervous system invasion, immune activation and cytokine storm, vasculitis, and parainfectious processes are implicated in the pathophysiology. While the most common imaging finding was ischemic stroke, followed by hemorrhagic stroke, a diverse range of parainfectious findings was also noted in our study.

Central nervous system involvement in multiple myeloma: Experience from a tertiary cancer center and review of literature

Background: Multiple myeloma (MM) results from clonal expansion of immunoglobulin secreting, heavy chain class-switched, terminally differentiated B-lymphocytes (plasma cells), resulting in radiologic or biochemical evidence of end-organ damage. Though neurological manifestations (peripheral neuropathies, spinal radiculopathies, cranial nerve palsies, and metabolic encephalopathies) can occur during the disease course, direct central nervous system (CNS) infiltration by malignant plasma cells (CNS-MM) is very rare (~1%) and has a dismal prognosis (survival of <6 months). Methodology: Clinico-laboratory profile and outcome of CNS-MM patients diagnosed and treated at a tertiary cancer care hospital were retrospectively analyzed. Results: On scrutinizing 500 consecutive myeloma case records, 4 patients with CNS-MM were identified. All these patients were diagnosed during myeloma relapse, and all had deceased within 1 week and 12 months of developing CNS infiltration. Our experience with CNS-MM patients is similar to the experiences documented across major world literature. Conclusion: Our manuscript reinforces that CNS-MM should be considered in any myeloma patient presenting with unexplainable CNS manifestations. As there are no prospective studies to recommend optimal treatment strategies, CNS-MM still remains a dismal complication of myeloma.

Diagnosing, Imaging and Successfully Treating a Debilitating Case of Bing-Neel Syndrome: A Multidisciplinary Feat

Waldenstroms Macroglobulinaemia (WM) is a rare B-cell lymphoma representing ~2% of all haematological malignancies. While most neurological complications of WM are secondary to the overproduction of Immunoglobulin M (IgM), Bing-Neel Syndrome (BNS) is an extremely rare direct Central Nervous System (CNS) infiltration by malignant Lymphoplasmocytic Lymphoma (LPL) cells. Limited information on BNS exists in the literature with sparse case reports and case series. Here we present a diagnostically challenging BNS case successfully treated with systemic chemoimmunotherapy and ibrutinib, with remarkable clinical response.

Endothelial glycocalyx-associated molecules as potential serological markers for sepsis-associated encephalopathy: A systematic review and meta-analysis.

Sepsis-associated encephalopathy (SAE) is characterized by a diffuse cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system infection. The endothelial glycocalyx is a dynamic mesh containing heparan sulfate linked to proteoglycans and glycoproteins, including selectins and vascular/intercellular adhesion molecules (V/I-CAMs), which protects the endothelium while mediating mechano-signal transduction between the blood and vascular wall. During severe inflammatory states, components of the glycocalyx are shed into the circulation and can be detected in soluble forms. Currently, SAE remains a diagnosis of exclusion and limited information is available on the utility of glycocalyx-associated molecules as biomarkers for SAE. We set out to synthesize all available evidence on the association between circulating molecules released from the endothelial glycocalyx surface during sepsis and sepsis-associated encephalopathy. MEDLINE (PubMed) and EMBASE were searched since inception until May 2, 2022 to identify eligible studies. Any comparative observational study: i) evaluating the association between sepsis and cognitive decline and ii) providing information on level of circulating glycocalyx-associated molecules was eligible for inclusion. Four case-control studies with 160 patients met the inclusion criteria. Meta-analysis of biomarkers ICAM-1 (SMD 0.41; 95% CI 0.05-0.76; p = 0.03; I2 = 50%) and VCAM-1 (SMD 0.55; 95% CI 0.12-0.98; p = 0.01; I2 = 82%) revealed higher pooled mean concentration in patients with SAE compared to the patients with sepsis alone. Single studies reported elevated levels of P-selectin (MD 0.80; 95% CI -17.77-19.37), E-selectin (MD 96.40; 95% Cl 37.90-154.90), heparan sulfate NS2S (MD 19.41; 95% CI 13.37-25.46), and heparan sulfate NS+NS2S+NS6S (MD 67.00; 95% CI 31.00-103.00) in patients with SAE compared to the patients with sepsis alone. Plasma glycocalyx-associated molecules are elevated in SAE and may be useful for early identification of cognitive decline in sepsis patients.

Monkeypox-Associated Central Nervous System Disease: A Case Series and Review.

Monkeypox virus (MPXV) disease has been declared a public health emergency by the World Health Organization, creating an urgent need for neurologists to be able to recognize, diagnosis, and treat MPXV-associated neurologic disease. Three cases of MPXV-associated central nervous system (CNS) disease occurring during the 2022 outbreak, and their associated imaging findings are presented, with 2 cases previously published in a limited capacity in a public health bulletin. Three previously healthy immunocompetent gay men in their 30s developed a febrile illness followed by progressive neurologic symptoms with presence of a vesiculopustular rash. MPXV nucleic acid was detected by polymerase chain reaction (PCR) from skin lesions of 2 patients, with the third patient having indeterminate testing but an epidemiologic link to a confirmed MPXV disease case. Cerebrospinal fluid demonstrated a lymphocytic pleocytosis, elevated protein, and negative MPXV-specific PCR. In 2 patients, magnetic resonance imaging of the brain and spine demonstrated partially enhancing, longitudinally extensive central spinal cord lesions with multifocal subcortical, basal ganglia, thalamic, cerebellar, and/or brainstem lesions. The third patient had thalamic and basal ganglia lesions. All patients received 14 days of tecovirimat, and 2 patients also received multiple forms of immunotherapy, including intravenous immunoglobulin, pulsed high-dose steroids, plasmapheresis, and/or rituximab. Good neurologic recovery was observed in all cases. MPXV can be associated with CNS disease. It is unclear whether this is from a parainfectious immune-mediated injury or direct CNS viral invasion. ANN NEUROL 2023;93:893-905.

Exploring the Major Triggers of Seizures Due to Drug Overdose and Their Corresponding Countermeasures

Seizures in the context of drug overdose present a complex challenge, primarily arising from central nervous system (CNS) stimulation, electrolyte imbalances, reduced seizure thresholds, drug interactions, hepatic impairment, and direct CNS toxicity. Commonly implicated substances include stimulants like amphetamines, cocaine, and ecstasy, as well as prescription medications like opioids and benzodiazepines. Management strategies include the use of benzodiazepines to reduce neuronal activity, fluid resuscitation, electrolyte replacement therapy, and specific interventions for drug interactions and hepatic impairment. The clinical manifestations of drug-induced seizures are diverse, including convulsions, altered consciousness, autonomic dysfunction, focal neurological deficits, and in severe cases, status epilepticus. These manifestations require swift and targeted clinical interventions to minimize patient morbidity and mortality. This comprehensive review addresses the significant public health concern of drug overdose-related seizures, focusing on the triggers and appropriate countermeasures. The management of drug overdose-induced seizures is a nuanced and multifaceted process. It demands a coordinated effort from healthcare professionals, integrating prevention strategies, patientcentered care, and continuous monitoring to ensure effective management and long-term recovery.

Review of Neurofilaments as Biomarkers in Sepsis-Associated Encephalopathy.

Sepsis is a common and fatal disease, especially in critically ill patients. Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction with acute altered consciousness, permanent cognitive impairment, and even coma, accompanied by sepsis, without direct central nervous system infection. When managing SAE, early identification and quantification of axonal damage facilitate faster and more accurate diagnosis and prognosis. Although no specific markers for SAE have been identified, several biomarkers have been proposed. Neurofilament light chain (NFL) is a highly expressed cytoskeletal component of neurofilament (NF) proteins that can be found in blood and cerebrospinal fluid (CSF) after exposure to axonal injury. NFs can be used as diagnostic and prognostic biomarkers for sepsis-related brain injury. Phosphorylation of NFs contributes to the maturation and stabilization of cytoskeletal structures, especially axons, and facilitates axonal transport, including mitochondrial transport and energy transport. The stability of NF proteins can be assessed by monitoring the expression of NF genes. Furthermore, phosphorylation levels of NFs can be monitored to determine mitochondrial axonal transport associated with cellular energy metabolism at distal axons to assess progression during SAE treatment. This paper provides new insights into the biological characteristics, detection techniques, and scientific achievements of NFs, and discusses the underlying mechanisms and future research directions of NFs in SAE.

Effect of SARS-CoV-2 infection in neonates or in pregnancy on developmental outcomes at 21–24 months (SINEPOST): study protocol for a prospective cohort study

IntroductionExposure to SARS-CoV-2 during pregnancy or in the neonatal period may impact fetal or neonatal brain development either through direct central nervous system infection or indirectly through the adverse effects...

Clearing the Fog: a Systematic Review on Cognitive Dysfunction in COVID-19

[Objective] The systematic review aims to examine the association between COVID-19 and cognitive dysfunction, including the link between the severity of COVID-19 and the occurrence of cognitive impairment and the potential pathophysiological mechanisms related to brain fog among COVID-19 patients. [Methods] PubMed, Oxford University Press, ProQuest Health and Medical Complete, ScienceDirect, Ovid, HERDIN, Google Scholar, and Cochrane Library databases were accessed to retrieve literature using the PRISMA guidelines. [Results] After critical appraisal, 13 full journal articles were included in the study. The studies showed the most frequent cognitive impairment are attention, memory, and executive function in COVID-19 patients. Compared with healthy controls in three out of four studies, cognitive impairment was only evident in COVID-19 patients. Furthermore, two studies showed no correlation between brain fog and depression, and five studies showed a link between the severity of COVID-19 infection and cognitive impairment. Cases ranging from mild to severe illness presented manifestations of brain fog. However, a disparity in the evidence of the pathophysiology of COVID-19 and cognitive dysfunction exists, prompting the need to investigate further. Additionally, recent studies provide insufficient evidence for direct central nervous system invasion, and there are emerging studies that contrast the presumed pathogenesis of neurological complications from neuroinflammation. [Conclusion] There is an association between COVID-19 and cognitive dysfunction. Manifestation of cognitive dysfunction is present regardless of illness severity. Moreover, there are existing pathophysiological mechanisms of the Coronavirus that lead to cognitive dysfunction in COVID-19 patients; however, additional studies are required to substantiate such mechanisms further. [PROSPERO registration number] CRD42022325669.

Analysis of COVID-19-related psychiatric disorders: clinical manifestations and therapeutic considerations

During the COVID-19 pandemic, neuropsychiatric disorders have been diagnosed both in the acute phase, and in the aftermath of this disease. Inpatients, as well as outpatients recently diagnosed with mild, moderate or severe forms of Coronavirus infection have reported neuropsychiatric manifestations with variable duration, symptoms that could be directly or indirectly related to the viral pathogenic agent. Patients who are recovering from the acute phase of COVID-19 also may exhibit various psychopathological manifestations, during the so-called “post-COVID-19 syndrome” or “long COVID-19 syndrome”. Explanations regarding the onset of this type of clinical manifestations and the SARS-CoV-2 infection are extremely diverse, ranging from biological factors (e.g., direct central nervous system viral activity, cerebral hypo-oxygenation, high level of inflammatory response) to psycho-social stressors (e.g., isolation, fear of death, anxiety related to possible somatic complications or sequelae). Objectives: The primary objective of this article was to analyze psychiatric manifestations in patients with acute COVID-19 disease and in patients during post-COVID-19 phase. The secondary objective was to propose a conceptual framework for the evaluation and treatment of these patients. Methods: Patients included in this analysis were screened positive for COVID-19 infection in the last 6 months before their first psychiatric examination. These patients were further evaluated to detect any personal history of psychiatric disorders, somatic comorbidities, or significant concomitant pharmacological treatments. Specific scales for the measurement of symptoms severity and functional impairment were administered in all patients. Results: Five patients were included in this analysis, one during the acute phase of COVID-19 infection, and four patients were evaluated after the complete remission of this disease. Hyperactive delirium, mild neurocognitive disorder, major depressive episode, panic disorder with agoraphobia, or acute psychotic disorder were the main diagnoses in these patients. All patients received adequate treatment and they were monitored using psychological scales until symptoms remission or stabilisation. Conclusions: Psychosocial stressors, neurobiological changes, systemic inflammatory reaction, and individual vulnerability factors may contribute to a diathesis-stress model for psychiatric disorders onset within the acute phase or after the remission of acute manifestations in COVID-19-diagnosed patients

SARS-CoV-2 infection and seizures: the perfect storm.

Seizures have been increasingly identified as a neurologic manifestation of coronavirus disease 2019 (COVID-19) infection. They may be symptomatic due to systemic infections, as a result of direct central nervous system (CNS) invasion, or occur in response to inflammatory reactions to the virus. It is possible that proinflammatory molecules released in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to hyperexcitability and epileptogenesis, similar to infections caused by other neurotrophic viruses. Cerebral spinal fluid (CSF) in patients with COVID-19 and seizures is negative for SARS-CoV-2 (PCR) in the majority of patients, but has been found to be positive for proinflammatory molecules like IL-6, IL-8, and anti-neuronal autoantibodies. Electroencephalogram (EEG) in COVID-19 patients are nonspecific. However, in the encephalopathic and critically ill subpopulation, EEG is essential in detecting nonconvulsive seizures and status epilepticus which is associated with increased overall mortality in COVID-19 patients. Thus, as encephalopathy is often the only CNS symptom evidenced in patients with nonconvulsive seizures, more judicious use of continuous EEG in encephalopathic COVID-19 patients should be considered. This would facilitate earlier detection and treatment of seizures in this population, which would ultimately improve outcomes. Further research into the onset and potential for development of seizures and epilepsy in patients with COVID-19 is needed.

COVID- 19 Following Acute Psychosis: Case series report

IntroductionCoronavirus disease (COVID-19) could result in various medical consequences. Clinical manifestations are diverse and range from asymptomatic or mild, fever-like symptoms, to more severe and life-threatening complications. Although the clinical presentation was initially dominated by respiratory symptoms, psychiatric symptoms and sequelae have been reported in COVID- 19 patients and convalescents.ObjectivesTo describe four clinical case reports of patients admitted to the inpatient unit of Psychiatric Hospital Sarajevo (PHS) with acute onset of psychosis in the recovery stage of COVID-19.Methods In this case series we report cases of 4 patients, all female, mean age 53.25 years, hospitalized in PHS during the third wave of the COVID-19 pandemic. All developed psychotic symptoms in the recovery phase of COVID-19. None had a previous history of psychiatric disturbances of any kind. All patients were diagnosed with brief psychotic disorder (BPD), according to DSM 5 criteria for BPD.ResultsCOVID-19 affects various organ systems, including the brain, with variable symptoms based on disease severity. Psychotic features have been observed as well. The pathophysiology and direct biological effects of the disease are not fully understood. COVID-19 patients and convalescents can develop psychotic symptoms as a consequence of multiple concurrent factors. Several proposed mechanisms include direct central nervous system infiltration, cytokine network dysregulation, peripheral immune cell transmigration, and post-infectious autoimmunity [1], treatments used to manage the infection, and psychosocial stress.ConclusionsClinicians need to be aware of possible psychotic manifestations in COVID-19 patients and survivors. Long-term follow-up is warranted to provide efficient patient care.DisclosureNo significant relationships.

Cerebrospinal fluid analysis of pregnant women at early stages of COVID-19

ObjectiveTo determine the presence or absence of SARS-CoV-2 in the cerebrospinal fluid of pregnant women at early stages of COVID-19. Materials and methodsWe conducted a prospective observational study with pregnant women undergoing cesarean section and real-time polymerase chain reaction to SARS-CoV-2 was performed in the cerebrospinal fluid in the early stages of COVID-19. ResultsFourteen pregnant women, whose COVID-19 symptoms started between four to 18 days prior to delivery, were included. Eleven of the women reported anosmia, dysgeusia, and headaches and there were two fatal cases. SARS-Cov-2 was not present in the cerebrospinal fluid of these COVID-19 patients with early neurological symptoms, even in severe cases. ConclusionOur study suggests that peripheric cell damage and parainfectious phenomena may predominate over direct central nervous system injury in the pathophysiology of COVID-19 related early neurological symptoms on pregnant women.

Neurophysiological Aspects in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome.

Patients with coronavirus disease 2019 (COVID-19) often develop acute respiratory failure and acute respiratory distress syndrome (ARDS) that requires intensive care unit (ICU) hospitalization and invasive mechanical ventilation, associated with a high mortality rate. In addition, many patients fail early weaning attempts, further increasing ICU length of stay and mortality. COVID-19 related ARDS can be complicated by neurological involvement with mechanisms of direct central nervous system (CNS) infection and with overlapping para-infective mechanisms of the peripheral nervous system (PNS). We aimed to evaluate the possible involvement of the brainstem and PNS in patients with COVID-19 related ARDS and difficulty in weaning from mechanical ventilation. We evaluated electroencephalogram (EEG), brainstem auditory evoked potentials (BAEPs), electroneurography of the four limbs and the phrenic nerve in 10 patients with respiratory insufficiency due to SARS-CoV-2. All were admitted to intensive care unit and were facing prolonged weaning from mechanical ventilation. All ten patients showed a mild diffuse non-specific slowing of brain electrical activity on the EEG. Four patients had an acute motor axonal neuropathy with absent or reduced amplitude phrenic nerve CMAP while four patients showed impairment of the BAEPs. A patient with peripheral nerve impairment suggestive of Guillain-Barré syndrome (GBS) underwent an intravenous immunoglobulin (IVIg) cycle that led to an improvement in the weaning process and progressive motor improvement. The inclusion of a comprehensive neurological evaluation in COVID-19 patients in ICU facilitated the early identification and effective management of Nervous System involvement.

Sixth Nerve Palsy in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Sixth Nerve Palsy in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes.

ContextSodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects.ObjectiveWe investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes.MethodsThis was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment.ResultsAfter 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala.ConclusionThe early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.