Disease-modifying Effects Research Articles

Beyond seizure freedom: Dissecting long-term seizure control after surgical resection for drug-resistant epilepsy.

This study was undertaken to better understand the long-term palliative and disease-modifying effects of surgical resection beyond seizure freedom, including frequency reduction and both late recurrence and remission, in patients with drug-resistant epilepsy. This retrospective database-driven cohort study included all patients with >9 years of follow-up at a single high-volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug-resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were (1) reduction in frequency of disabling seizures (at 6months, each year up to 9 years postoperatively, and at last follow-up), (2) achievement of seizure remission (>6months, >1year, and longest duration), and (3) seizure freedom at last follow-up. We included 251 patients; 234 (93.2%) achieved 6months and 232 (92.4%) experienced 1year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. A total of 182 (72.5%) patients were seizure-free at last follow-up (defined as >1year without seizures), with a median 11.9 years since remission. For patients not completely seizure-free, the mean seizure frequency reduction at each time point was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by .58, and 53 (21.2%) patients were on no antiseizure medication at last follow-up. Nearly half (47.1%) of those seizure-free at last follow-up were not seizure-free immediately postoperatively. Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner.

Epilepsy and Alzheimer's Disease: Current Concepts and Treatment Perspective on Two Closely Related Pathologies.

The literature on epileptic seizures in Alzheimer's disease has significantly increased over the past decades. Remarkably, several studies suggest a bi-directional link between these two common neurological diseases, with either condition carrying a nearly 2-fold risk of contracting the other in comparison to healthy subjects. In this respect, evidence from both clinical and preclinical studies indicates that epileptogenesis and neurodegeneration possibly share common underlying mechanisms. However, the precise association between epileptogenesis and neurodegeneration still needs to be fully elucidated. Targeted intervention to reduce abnormal network hyperexcitability might constitute a therapeutic strategy to postpone the onset of later neurodegenerative changes and consequent cognitive decline by many years in patients. By virtue of this, an early diagnosis and treatment of seizures in patients with Alzheimer's disease should be pursued. To date, no guidelines are available for treating epileptic activity in this context, largely due to the paucity of studies sufficient to answer the related questions. Accordingly, clinical trials are mandatory, not only to inform clinicians about symptomatic management of seizures in Alzheimer's disease patients but also to detect if treatment with antiseizure medications could have disease-modifying effects. Moreover, it will be fundamental to expand the application of animal models of Alzheimer's disease to comorbid conditions, such as epilepsy both to reveal the mechanisms underlying seizure onset and to better define their role in cognitive decline. Such models could also be useful to identify pharmacological compounds having therapeutically effectiveness as well as reliable early biomarkers for seizures in Alzheimer's disease.

Genetically-informed prediction of short-term Parkinson’s disease progression

Parkinson’s disease (PD) treatments modify disease symptoms but have not been shown to slow progression, characterized by gradual and varied motor and non-motor changes overtime. Variation in PD progression hampers clinical research, resulting in long and expensive clinical trials prone to failure. Development of models for short-term PD progression prediction could be useful for shortening the time required to detect disease-modifying drug effects in clinical studies. PD progressors were defined by an increase in MDS-UPDRS scores at 12-, 24-, and 36-months post-baseline. Using only baseline features, PD progression was separately predicted across all timepoints and MDS-UPDRS subparts in independent, optimized, XGBoost models. These predictions plus baseline features were combined into a meta-predictor for 12-month MDS UPDRS Total progression. Data from the Parkinson’s Progression Markers Initiative (PPMI) were used for training with independent testing on the Parkinson’s Disease Biomarkers Program (PDBP) cohort. 12-month PD total progression was predicted with an F-measure 0.77, ROC AUC of 0.77, and PR AUC of 0.76 when tested on a hold-out PPMI set. When tested on PDBP we achieve a F-measure 0.75, ROC AUC of 0.74, and PR AUC of 0.73. Exclusion of genetic predictors led to the greatest loss in predictive accuracy; ROC AUC of 0.66, PR AUC of 0.66–0.68 for both PPMI and PDBP testing. Short-term PD progression can be predicted with a combination of survey-based, neuroimaging, physician examination, and genetic predictors. Dissection of the interplay between genetic risk, motor symptoms, non-motor symptoms, and longer-term expected rates of progression enable generalizable predictions.

New Multifunctional Agents for Potential Alzheimer's Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones.

Alzheimer's disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24-0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036-0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.

Sleep disturbances in neurological disease: A target for intervention.

Sleep is a biological function required for neurological and general health, but a significant and under-recognized proportion of the population has disturbed sleep. Here, we briefly overview the biology of sleep, sleep requirements over the lifespan, and common sleep disorders. We then turn our attention to five neurological diseases that significantly contribute to global disease burden and neurology practice makeup: epilepsy, headache, ischemic stroke, Parkinson's disease, and Alzheimer's disease. For each disease, we review evidence that sleep disturbances contribute to disease risk and severity and discuss existing data that addressing sleep disturbances may have disease-modifying effects. We provide recommendations derived from the literature and existing clinical guidelines to facilitate the evaluation and management of sleep disturbances within the context of each neurological disease. Finally, we synthesize identified needs and commonalities into future directions for the field and practical sleep-related recommendations for physicians caring for patients at risk for or currently suffering from neurological disease.

MPN-238 Single-Cell RNA Profiling of Myelofibrosis Patients Reveals Pelabresib-Induced Decrease of Megakaryocytic Progenitors and Normalization of CD4+ T Cells in Peripheral Blood.

Abnormal differentiation of the megakaryocytic lineage and overproduction of proinflammatory cytokines, resulting in bone marrow fibrosis, anemia, symptoms, extramedullary hematopoiesis, and often hepatosplenomegaly, are key characteristics of myelofibrosis. Bromodomain and extraterminal domain (BET) proteins play a significant role in the regulation of neoplastic myeloproliferation and proinflammatory cytokine production. Pelabresib (CPI-0610) is an investigational, oral, small-molecule BET inhibitor. Characterize cellular composition and transcriptional alterations in peripheral blood (PB) obtained from myelofibrosis patients enrolled in three arms (Arm 1: pelabresib monotherapy; Arm 2: pelabresib 'add-on' to ruxolitinib in patients with suboptimal ruxolitinib response; Arm 3: pelabresib with ruxolitinib in JAKi-naïve patients) of the ongoing MANIFEST Phase 2 study (NCT02158858). We performed single-cell RNA sequencing on 234,904 CD34+ HSPCs and 135,970 CD34- mature PB cells. Baseline and on-treatment samples were obtained from a random pool of 20 patients (Arm 1: n=5; Arm 2: n=8; Arm 3: n=7). Mobilized PB cells from healthy donors (HD) were used as controls (n=11). Analysis of CD34+ HSPCs at baseline demonstrated increased numbers of megakaryocytic, neutrophilic, and erythroid progenitors in myelofibrosis patients compared with HDs and a significant reduction of myeloid and B-cell lineage progenitors. Pelabresib as monotherapy and combined with ruxolitinib led to significant reduction of megakaryocytic, neutrophilic, and erythroid progenitors compared with baseline. Analysis of CD34- cells from myelofibrosis patients identified a significantly lower proportion of CD4+ T cells and increased numbers of erythroid cells at baseline versus HD. Individual patients exhibited reduction in natural killer cells and CD16+ monocytes as well as elevated megakaryocytic lineage cells. Pelabresib as monotherapy and combined with ruxolitinib increased the proportion of CD4+ T cells, and, importantly, reduced megakaryocytic lineage cells in both treatment-naïve and ruxolitinib-relapsed/refractory patients. In myelofibrosis patients at baseline, larger spleen volume was observed in patients with lower numbers of CD4+ T cells and increased numbers of megakaryocytic and myeloid CSF3R+ cells. Single-cell profiling of a subset of myelofibrosis patients in the MANIFEST study suggests that pelabresib alone and in combination with ruxolitinib induces improvement of the myeloid-lymphoid imbalance. This potential disease-modifying effect warrants further investigation.

Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain

In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology. Our results show that dosing animals twice per week with PQR530 resulted in intermittent, rather than sustained target engagement. Nevertheless, this pulse-like mTOR inhibition followed by longer intervals of re-activation was sufficient to reduce tau pathology in the cerebral cortex in P301S tau transgenic mice. This suggests that balanced therapeutic dosing of blood-brain-barrier permeable mTOR-inhibitors can result in a disease-modifying effect in AD and at the same time prevents toxic side effects due to prolonged over activation of autophagy.

Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo

Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rather ambiguous. This is partly due to poor stability and bioavailability of the H2S donors, requiring impractically large doses that are associated with dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which is able to pose as a sacrificial redox substrate for 3-mercaptopyruvate sulfurtransferase (3MST), one of the H2S biosynthetic enzymes in the brain. Sulfanegen is able to mitigate toxicity emanating from oxidative insults and the Aβ1-42 peptide by releasing H2S through the 3MST pathway. When administered to symptomatic transgenic mouse model of AD (APP/PS1; 7 and 12 months) and mice that were intracerebroventricularly administered with the Aβ1-42 peptide, sulfanegen was able to reverse oxidative and neuroinflammatory consequences of AD pathology by restoring 3MST function. Quantitative neuropathological analyses confirmed significant disease modifying effect of the compound on amyloid plaque burden and brain inflammatory markers. More importantly, sulfanegen treatment attenuated progressive neurodegeneration in these mice, as evident from the restoration of TH+ neurons in the locus coeruleus. This study demonstrates a previously unknown concept that supplementation of 3MST function in the brain may be a viable approach for the management of AD. Finally, brought into the spotlight is the potential of sulfanegen as a promising AD therapeutic for future drug development efforts.

Progression models for repeated measures: Estimating novel treatment effects in progressive diseases.

Mixed models for repeated measures (MMRMs) are ubiquitous when analyzing outcomes of clinical trials. However, the linearity of the fixed-effect structure in these models largely restrict their use to estimating treatment effects that are defined as linear combinations of effects on the outcome scale. In some situations, alternative quantifications of treatment effects may be more appropriate. In progressive diseases, for example, one may want to estimate if a drug has cumulative effects resulting in increasing efficacy over time or whether it slows the time progression of disease. This article introduces a class of nonlinear mixed-effects models called progression models for repeated measures (PMRMs) that, based on a continuous-time extension of the categorical-time parametrization of MMRMs, enables estimation of novel types of treatment effects, including measures of slowing or delay of the time progression of disease. Compared to conventional estimates of treatment effects where the unit matches that of the outcome scale (eg, 2 points benefit on a cognitive scale), the time-based treatment effects can offer better interpretability and clinical meaningfulness (eg, 6months delay in progression of cognitive decline). The PMRM class includes conventionally used MMRMs and related models for longitudinal data analysis, as well as variants of previously proposed disease progression models as special cases. The potential of the PMRM framework is illustrated using both simulated and historical data from clinical trials in Alzheimer's disease with different types of artificially simulated treatment effects. Compared to conventional models it is shown that PMRMs can offer substantially increased power to detect disease-modifying treatment effects where the benefit is increasing with treatment duration.

Midazolam Prevents the Adverse Outcome of Neonatal Asphyxia.

Birth asphyxia (BA) is the most frequent cause of neonatal death as well as central nervous system (CNS) injury. BA is often associated with neonatal seizures, which only poorly respond to anti-seizure medications and may contribute to the adverse neurodevelopmental outcome. Using a non-invasive rat model of BA, we have recently reported that the potent benzodiazepine, midazolam, prevents neonatal seizures in ~50% of rat pups. In addition to its anti-seizure effect, midazolam exerts anti-inflammatory actions, which is highly relevant for therapeutic intervention following BA. The 2 major aims of the present study were to examine (1) whether midazolam reduces the adverse outcome of BA, and (2) whether this effect is different in rats that did or did not exhibit neonatal seizures after drug treatment. Behavioral and cognitive tests were performed over 14months after asphyxia, followed by immunohistochemical analyses. All vehicle-treated rats had seizures after asphyxia and developed behavioral and cognitive abnormalities, neuroinflammation in gray and white matter, neurodegeneration in the hippocampus and thalamus, and hippocampal mossy fiber sprouting in subsequent months. Administration of midazolam (1 mg/kg i.p.) directly after asphyxia prevented post-asphyctic seizures in ~50% of the rats and resulted in the prevention or decrease of neuroinflammation and the behavioral, cognitive, and neurodegenerative consequences of asphyxia. Except for neurodegeneration in the thalamus, seizures did not seem to contribute to the adverse outcome of asphyxia. The disease-modifying effect of midazolam identified here strongly suggests that this drug provides a valuable option for improving the treatment and outcome of BA. ANN NEUROL 2023;93:226-243.

Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.

Mitofusin (MFN) 1 and MFN2 are dynamin GTPase family mitochondrial proteins that mediate mitochondrial fusion requiring MFN conformational shifts, formation of macromolecular complexes on and between mitochondria, and GTP hydrolysis. Damaging MFN2 mutations cause an untreatable, largely pediatric progressive peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 2A. We used small molecule allosteric mitofusin activators that promote MFN conformations favoring fusion to interrogate the effects of MFN2 conformation and GTPase activity on MFN2-mediated mitochondrial fusion and motility in vitro. We translated these findings in vivo by defining dose-dependent pharmacodynamic and disease-modifying effects of mitofusin activators in murine CMT2A. MFN2 catalytic GTPase activity and MFN2 conformational switching are essential for mitochondrial fusion, but the two processes are separate and dissociable. We report the first concentration-response relationships for mitofusin activators to stimulate mitochondrial transport through CMT2A neuronal axons, which is similar to their stimulation of mitochondrial fusion. In CMT2A mice, intermittent (daily short acting) and sustained (twice daily long acting) mitofusin activation were equally effective in reversing neuromuscular degeneration. Moreover, acute dose-dependent pharmacodynamic effects of mitofusin activators on mitochondrial transport through CMT2A neuronal axons anticipated those for long-term reversal of neurodegenerative phenotypes. A crossover study showed that CMT2A neuronal deficits recurred after mitofusin activators are discontinued, and revealed that CMT2A can be ameliorated by mitofusin activation even in old (>74 week) mice. These data add to our understanding of mitochondrial dysfunction induced by a CMT2A MFN2 GTPase mutation and provide additional information supporting the approach of pharmacological mitofusin activation in CMT2A. SIGNIFICANCE: This study interrogated the roles of MFN2 catalytic activity and allosteric activation on impaired mitochondrial fusion and neuronal transport as they impact an untreatable peripheral neuropathy caused by MFN2 mutations, Charcot-Marie-Tooth disease type 2A. The results mechanistically link mitochondrial fusion and motility to the relaxed MFN2 protein conformation and correction of mitochondrial abnormalities to in vivo reversal of neurodegeneration in murine CMT2A.

Time to rethink the reported disease-modifying treatment effects on cognitive outcomes: Methods and interpretative caveats.

Time to rethink the reported disease-modifying treatment effects on cognitive outcomes: Methods and interpretative caveats.

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

BackgroundActivation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc).MethodsThe effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed.ResultsProphylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117.ConclusionsMT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.

Neuropilin-2 Signaling Modulates Mossy Fiber Sprouting by Regulating Axon Collateral Formation Through CRMP2 in a Rat Model of Epilepsy

Programmed neural circuit formation constitutes the foundation for normal brain functions. Axon guidance cues play crucial roles in neural circuit establishment during development. Whether or how they contribute to maintaining the stability of networks in mature brains is seldom studied. Upon injury, neural rewiring could happen in adulthood, of which mossy fiber sprouting (MFS) is a canonical example. Here, we uncovered a novel role of axon guidance molecule family Sema3F/Npn-2 signaling in MFS and epileptogenesis in a rat model of epilepsy. Dentate gyrus-specific Npn-2 knockdown increased seizure activity in epileptic animals along with increased MFS. Hippocampal culture results suggested that Npn-2 signaling modulates MFS via regulating axon outgrowth and collateral formation. In addition, we discovered that Sema3F/Npn-2 signal through CRMP2 by regulating its phosphorylation in the process of MFS. Our work illustrated that Npn-2 signaling in adult epilepsy animals could potentially modulate seizure activity by controlling MFS. MFS constitutes the structural basis for abnormal electric discharge of neurons and recurrent seizures. Therapies targeting Npn-2 signaling could potentially have disease-modifying anti-epileptogenesis effects in epilepsy treatment.

The Gelatinase Inhibitor ACT-03 Reduces Gliosis in the Rapid Kindling Rat Model of Epilepsy, and Attenuates Inflammation and Loss of Barrier Integrity In Vitro.

Matrix metalloproteinases (MMPs) are endopeptidases responsible for the cleavage of intra- and extracellular proteins. Several brain MMPs have been implicated in neurological disorders including epilepsy. We recently showed that the novel gelatinase inhibitor ACT-03 has disease-modifying effects in models of epilepsy. Here, we studied its effects on neuroinflammation and blood–brain barrier (BBB) integrity. Using the rapid kindling rat model of epilepsy, we examined whether ACT-03 affected astro- and microgliosis in the brain using immunohistochemistry. Cellular and molecular alterations were further studied in vitro using human fetal astrocyte and brain endothelial cell (hCMEC/D3) cultures, with a focus on neuroinflammatory markers as well as on barrier permeability using an endothelial and astrocyte co-culture model. We observed less astro- and microgliosis in the brains of kindled animals treated with ACT-03 compared to control vehicle-treated animals. In vitro, ACT-03 treatment attenuated stimulation-induced mRNA expression of several pro-inflammatory factors in human fetal astrocytes and brain endothelial cells, as well as a loss of barrier integrity in endothelial and astrocyte co-cultures. Since ACT-03 has disease-modifying effects in epilepsy models, possibly via limiting gliosis, inflammation, and barrier integrity loss, it is of interest to further evaluate its effects in a clinical trial.

Severe type 2 diabetes (T2D) remission using a very low-calorie ketogenic diet (VLCKD).

SummaryThere is a close association between obesity and type 2 diabetes (T2D). The value of weight loss in the management of patients with T2D has long been known. Loss of 15% or more of body weight can have a disease-modifying effect in people with diabetes inducing remission in a large proportion of patients. Very low-carbohydrate ketogenic diets (VLCKDs) have been proposed as an appealing nutritional strategy for obesity management. The diet was shown to result in significant weight loss in the short, intermediate, and long terms and improvement in body composition parameters as well as glycemic and lipid profiles. The reported case is a 35-year-old man with obesity, dyslipidemia, and T2D for 5 years. Despite the use of five antidiabetic medications, including insulin, HbA1c was 10.1%. A VLCKD through a commercial multidisciplinary weight loss program (PnK method) was prescribed and all medications were discontinued. The method is based on high-biological-value protein preparations and has 5 steps, the first 3 steps (active stage) consist of a VLCKD (600–800 kcal/d) that is low in carbohydrates (<50 g daily from vegetables) and lipids. The amount of proteins ranged between 0.8 and 1.2 g/kg of ideal body weight. After only 3 months, the patient lost 20 kg with weight normalization and diabetes remission, and after 2 years of follow-up, the patient remained without the pathologies. Due to the rapid and significant weight loss, VLCKD emerges as a useful tool in T2D remission in patients with obesity.Learning pointsObesity and type 2 diabetes (T2D) are conditions that share key pathophysiological mechanisms.Loss of 15% or more of body weight can have a disease-modifying effect in people with T2D inducing remission in a large proportion of patients.Diabetes remission should be defined as a return of HbA1c to <6.5% and which persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.The very low-carbohydrate ketogenic diet (VLCKD) is a nutritional approach that has significant beneficial effects on anthropometric and metabolic parameters.Due to the rapid and significant weight loss, VLCKD emerges as a useful tool in T2D remission in patients with obesity.

Kinetic and structural studies on the inhibition of acetylcholinesterase and butyrylcholinesterase by a series of multitarget-directed galantamine-peptide derivatives

Complex neurological disorders, including Alzheimer's disease, are one of the major therapeutic areas to which multitarget drug discovery strategies have been applied in the last twenty years. Due to the complex multifactorial etiopathogenesis of Alzheimer's disease, it has been proposed that to be successful the pharmaceutical agents should act on multiple targets in order to restore the complex disease network and to provide disease modifying effects. Here we report on the synthesis and the anticholinergic activity profiles of seven multitarget anti-Alzheimer compounds designed by combining galantamine, a well-known acetylcholinesterase inhibitor, with different peptide fragments endowed with inhibitory activity against BACE-1. A complementary approach based on molecular docking simulations of the galantamine-peptide derivatives in the active sites of acetylcholinesterase and of the related butyrylcholinesterase, as well as on inhibition kinetics, by global fitting of the reaction progress curves, allowed to gain insights into the enzyme-inhibitor mechanism of interaction. The resulting structure-activity relationships pave the way towards the design of more effective pharmacodynamic/pharmacokinetic multitarget inhibitors.

Association between vascular risk factors and cognitive impairment in amyotrophic lateral sclerosis: a case-control study

Objective The disease-modifying effects of type 2 diabetes mellitus (T2DM), and hyperlipidemia on the risk and prognosis of amyotrophic lateral sclerosis (ALS) have gained significant attention. We aim to evaluate the association between common vascular risk factors and cognitive impairment in patients with ALS. Methods Patients with ALS were consecutively recruited between June 2012 and November 2019 from a tertiary referral center for ALS at the West China Hospital. Vascular risk factors (hypertension, T2DM, hyperlipidemia, overweight, and smoking) were confirmed based on clinical data. Cognitive function was evaluated by the Chinese version of Addenbrooke’s Cognitive Examination-revised. With careful confounder adjustment, multivariable logistic regression analysis was performed separately and accumulatively to determine the association between cognitive impairment and vascular risk factors in ALS. Results Of 870 patients, 266 (30.6%) had cognitive impairment. No cognitive burden from vascular risk factors was found in patients with ALS. On the contrary, we first observed that T2DM (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.25–0.98; p = 0.04) and hyperlipidemia (OR, 0.50; 95% CI, 0.26–0.97; p = 0.04) showed protective effects against cognitive decline in ALS, adjusted for age, sex, educational level, site of onset, Revised-ALS Functional Rating Scale score, predominant upper motor neuron phenotype, family history of ALS, and the remaining vascular risk factors. Sensitivity analyses of sex did not substantially reverse the risk estimates. Conclusions T2DM and hyperlipidemia decrease the risk of cognitive impairment in patients with ALS. The fitness hypothesis in ALS has been tested and expanded in our work.

Sodium selenate as a therapeutic for tauopathies: A hypothesis paper.

In a large proportion of individuals with fronto-temporal lobar degeneration (FTLD), the underlying pathology is associated with the misfolding and aggregation of the microtubule associated protein tau (FTLD-tau). With disease progression, widespread protein accumulation throughout cortical and subcortical brain regions may be responsible for neurodegeneration. One of the syndromes of FTLD is the behavioral variant of frontotemporal dementia (bvFTD), in which the underlying pathology is heterogenous, with half of the cases being related to FTLD-tau. Currently, there are no approved disease-modifying treatments for FTLD-tau, therefore representing a major unmet therapeutic need. These descriptive, preliminary findings of the phase 1 open-label trial provide data to support the potential of sodium selenate to halt the cognitive and behavioral decline, as well as to reduce tau levels in a small group of participants with bvFTD (N = 11). All participants were treated with sodium selenate over a period of 52 weeks. Cognition was assessed with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG, total scores), social cognition with the Revised Self-Monitoring Scale (RSMS, total scores), behavior with the Cambridge Behavioral Inventory (CBI), and carer burden with the Caregiver Buden Scale (CBS). Fluid biomarker measures include cerebrospinal fluid of total tau (t-tau), phosphorylated tau (p-tau181), NfL, p-tau181/t-tau, t-tau/Aβ1–42, and p-tau181/Aβ1–42 levels. After treatment at follow-up, cognition and behavior showed further negative change (based on a reliable change criterion cut-off of annual NUCOG decline) in the “progressors,” but not in the “non-progressors.” “Non-progressors” also showed elevated baseline CSF tau levels and no increase after treatment, indicating underlying tau pathology and a positive response to sodium selenate treatment. Significant changes in MRI were not observed. The findings provide useful information for future clinical trials to systematically assess the disease-modifying treatment effects of sodium selenate in randomized controlled designs for bvFTD and FTLD-tau pathologies.

Impact of Belimumab on Organ Damage in Systemic Lupus Erythematosus.

Organ damage is a key determinant of poor long-term prognosis and early death in patients with systemic lupus erythematosus (SLE). Prevention of damage is a key treatment goal of the 2019 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for SLE management. Belimumab is a monoclonal antibody that inhibits B lymphocyte stimulator (BLyS) and is the only therapy approved for both SLE and lupus nephritis. Here, we review the clinical trial and real-world data on the effects of belimumab on organ damage in adult patients with SLE. Across 4 phase III studies, belimumab in combination with background SLE therapy demonstrated consistent reductions in key drivers of organ damage including disease activity, risk of new severe flares, and glucocorticoid exposure compared to background therapy alone. Long-term belimumab use in SLE also reduced organ damage progression measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, as reported in open-label extension studies, and propensity score-matched comparative analyses to background therapy alone. Results from a clinical trial showed that in patients with active lupus nephritis, belimumab treatment improved renal response, reduced the risk of renal-related events, and impacted features related to kidney damage progression compared to background therapy alone. The decrease of organ damage accumulation observed with belimumab treatment in SLE, including lupus nephritis, suggest a disease-modifying effect.