Epilepsy in Neurodegenerative Diseases: Related Drugs and Molecular Pathways

Alzheimer’s disease; Huntington’s disease; Parkinson’s diseaseEnfermedad de Alzheimer; Enfermedad de Huntington; Enfermedad de ParkinsonMalaltia d'Alzheimer; Malaltia de Huntington; Malaltia de ParkinsonEpilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca2+ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases.A.C. acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). Authors acknowledge the support of the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated into the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER “Una manera de hacer Europa”) grant PI17/01474 awarded to M.B. Boada, grant PI19/00335 awarded to M.M. and the European Social Fund (ESF “Investing in your future”) for the Sara Borrell Contract (CD19/00232) to SA-L; M.E. acknowledges the support of the Spanish Ministry of Economy and Competitiveness under the project SAF2017-84283-R, and CIBERNED under project CB06/05/0024. E.B.S. acknowledges the support of the Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020). A.R. acknowledges the support of CIBERNED (Instituto de Salud Carlos III (ISCIII)), the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, ADAPTED Grant Nº 115975, from EXIT project, EU Euronanomed3 Program JCT2017 Grant Nº AC17/00100, from PREADAPT project. Joint Program for Neurodegenerative Diseases (JPND) Grant No. AC19/00097, and from grants PI13/02434, PI16/01861 BA19/00020, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by Instituto de Salud Carlos III (ISCIII)- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”), by Fundación bancaria “La Caixa” and Grífols SA (GR@ACE project)

Epilepsy in neurodegenerative diseases: related drugs and molecular pathways

Epilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca2+ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimers disease, Parkinsons disease, Huntingtons disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases.Acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). Authors acknowledge the support of the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated into the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER “Una manera de hacer Europa”) grant PI17/01474 awarded to M.B. Boada and grant PI19/00335 awarded to M.M.; M.E. acknowledges the support of the Spanish Ministry of Economy and Competitiveness under the project SAF2017- 84283-R, and CIBERNED under project CB06/05/0024. E.B.S. acknowledges the support of the Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020). A.R. acknowledges the support of CIBERNED (Instituto de Salud Carlos III (ISCIII)), the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, ADAPTED Grant Nº 115975, from EXIT project, EU Euronanomed3 Program JCT2017 Grant Nº AC17/00100, from PREADAPT project. Joint Program for Neurodegenerative Diseases (JPND) Grant No. AC19/00097, and from grants PI13/02434, PI16/01861 BA19/00020, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by Instituto de Salud Carlos III (ISCIII)- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”), by Fundación bancaria “La Caixa” and Grífols SA (GR@ACE project)info:eu-repo/semantics/publishedVersio

Epilepsy in Neurodegenerative Diseases: Related Drugs and Molecular Pathways

Epilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca2+ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases. Keywords: Alzheimer's disease; Huntington's disease; Parkinson's disease; epilepsy; multiple sclerosis; neurodegenerative diseases

Structural and Functional Brain Correlates of Cognitive Impairment in Euthymic Patients with Bipolar Disorder

Introduction Cognitive impairment in the euthymic phase is a well-established finding in bipolar disorder. However, its brain structural and/or functional correlates are uncertain. Methods Thirty-three euthymic bipolar patients with preserved memory and executive function and 28 euthymic bipolar patients with significant memory and/or executive impairment, as defined using two test batteries, the Rivermead Behavioural Memory Test (RBMT) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS), plus 28 healthy controls underwent structural MRI using voxel-based morphometry (VBM). Twenty-seven of the cognitively preserved patients, 23 of the cognitively impaired patients and 28 controls also underwent fMRI during performance of the n-back working memory task. Results No clusters of grey or white matter volume difference were found between the two patient groups. During n-back performance, the cognitively impaired patients showed hypoactiva- tion compared to the cognitively preserved patients in a circumscribed region in the right dorsolateral prefrontal cortex. Both patient groups showed failure of de-activation in the medial frontal cortex compared to the healthy controls. Conclusions Cognitive impairment in euthymic bipolar patients appears from this study to be unrelated to structural brain abnormality, but there was some evidence for an association with altered prefrontal function

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

What we learn about bipolar disorder from large-scale neuroimaging:Findings and future directions from the ENIGMA Bipolar Disorder Working Group

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinsons disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Widespread white matter microstructural abnormalities in bipolar disorder: Evidence from mega- and meta-analyses across 3,033 individuals

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org

In vivo hippocampal subfield volumes in bipolar disorder—A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD