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Vanaja Thulasimani,1 Kogilavani Shanmugavadivel,1 Jaehyuk Cho,2 Sathishkumar Veerappampalayam Easwaramoorthy3 1Department of Artificial Intelligence, Kongu Engineering College, Perundurai, Tamilnadu, India; 2Department of Software Engineering and Division of Electronics and Information Engineering, Jeonbuk National University, Jeonju-Si, Republic of Korea; 3School of Engineering and Technology, Sunway University, Selangor, Darul Ehsan, MalaysiaCorrespondence: Jaehyuk Cho, Email chojh@jbnu.ac.krAbstract: Alzheimer’s Dementia (AD) is a progressive neurological disorder that affects memory and cognitive function, necessitating early detection for its effective management. This poses a significant challenge to global public health. The early and accurate detection of dementia is crucial for several reasons. First, timely detection facilitates early intervention and planning of treatment. Second, precise diagnostic methods are essential for distinguishing dementia from other cognitive disorders and medical conditions that may present with similar symptoms. Continuous analysis and improvements in detection methods have contributed to advancements in medical research. It helps to identify new biomarkers, refine existing diagnostic tools, and foster the development of innovative technologies, ultimately leading to more accurate and efficient diagnostic approaches for dementia. This paper presents a critical analysis of multimodal imaging datasets, learning algorithms, and optimisation techniques utilised in the context of Alzheimer’s dementia detection. The focus is on understanding the advancements and challenges in employing diverse imaging modalities, such as MRI (Magnetic Resonance Imaging), PET (Positron Emission Tomography), and EEG (ElectroEncephaloGram). This study evaluated various machine learning algorithms, deep learning models, transfer learning techniques, and generative adversarial networks for the effective analysis of multi-modality imaging data for dementia detection. In addition, a critical examination of optimisation techniques encompassing optimisation algorithms and hyperparameter tuning strategies for processing and analysing images is presented in this study to discern their influence on model performance and generalisation. Thorough examination and enhancement of methods for dementia detection are fundamental for addressing the healthcare challenges posed by dementia, facilitating timely interventions, improving diagnostic accuracy, and advancing research in neurodegenerative diseases.Keywords: Alzheimer’s Dementia, Machine learning, Deep Learning, Transfer Learning and Generative Adversarial Network

James W Wheless,1 Danielle A Becker,2 Selim R Benbadis,3 Vinay Puri,4 Proleta Datta,5 Dave Clarke,6 Deepa Panjeti-Moore,7 Enrique Carrazana,8,9 Adrian L Rabinowicz8,10 1Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Memphis, TN, USA; 2Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, USA; 3Comprehensive Epilepsy Program, University of South Florida & Tampa General Hospital, Tampa, FL, USA; 4Norton Children’s Neuroscience Institute, Affiliated with University of Louisville, Louisville, KY, USA; 5Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, OR, USA; 6Dell Children’s Comprehensive Pediatric Epilepsy Center, University of Texas at Austin, Austin, TX, USA; 7Epilepsy Program; Neurology Consultants of Dallas, Dallas, TX, USA; 8Clinical Development and Medical Affairs, Neurelis, Inc., San Diego, CA, USA; 9Department of Family Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA; 10Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USACorrespondence: James W Wheless, Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, 777 Washington Avenue, Suite 335, Memphis, TN, 38105, USA, Tel +1 901.287.5207, Fax +1 901.287.5325, Email jwheless@uthsc.eduAbstract: Some patients with epilepsy continue to have seizures despite daily treatment with antiseizure medications. This includes seizure clusters (also known as acute repetitive seizures), which are an increase in seizure frequency that is different from the usual seizure pattern for that patient. In the literature, the term “rescue” is used for pharmacologic treatment for seizure clusters, but clarity regarding timing or whether a caregiver or patient should wait until a moment of life-threatening urgency before administering the medication is lacking. Additionally, the concept of waiting 5 minutes to identify and initiate treatment of status epilepticus has been carried over to the treatment of seizure clusters, as well as the idea of waiting owing to safety concerns, without reevaluation in the context of the reported safety profiles for currently available as-needed therapies when administered as prescribed. Delaying treatment of seizure clusters may have negative outcomes, including injury, emergency room use, hospitalization, and progression to status epilepticus. Additionally, increased time for administration of benzodiazepines, the cornerstone therapies for seizure clusters, may lower the potency and effectiveness once administration takes place, because of physiologic changes. Thus, clarifying the importance of timing in the treatment terminology may be of benefit in the acute context. The term “immediate-use seizure medication” (ISM), meaning treatment that is administered as quickly as possible once a seizure cluster is recognized, may help to clarify the timing of as-needed treatment. This review examines the recognition and definitions of seizure clusters, the physiologic rationale for ISM for seizure clusters, and the effectiveness and safety of early treatment. Remaining knowledge gaps are also discussed. The findings of this review suggest that it may be time to revisit the terminology of “rescue”, which implies waiting to administer treatment for seizure clusters, as doing so is not supported by pathophysiologic, effectiveness, or safety data.Plain Language Summary: Some people with epilepsy have seizures even if they take daily medication for their seizures. If they have more seizures than usual in a day, this may be called a seizure cluster. Drugs used to treat clusters are often said to be “rescue” medicines. But the word “rescue” may imply that the medication should only be administered when serious danger is present. Additionally, possibly because of previous instructions, people may think they have to wait to see if the seizure lasts more than 5 minutes to give the medicine, or they may be concerned about how safe the medicine will be if they give it. This older approach needs to be revisited and replaced. Waiting to give medicine could make it more likely that a person could get hurt or require a hospital or emergency room visit or their seizure condition could worsen. Waiting also may allow for changes in the body that may make a medicine less effective once it is given. Because of this, it may be better to say these medicines are for “immediate use” rather than for “rescue”. That way, the people giving the medicine know that they should give it as soon as they see the patient needs it. This paper discusses how seizure clusters are described and what can happen if someone waits to give medicine versus giving it right away. The paper shows that waiting may not be needed.Keywords: benzodiazepine, early intervention, epilepsy, rescue therapy

Yixin Chen,1,* Zhuo Yang,2,* Bin Nian,3 Chenglin Yu,4 Dilimulat Maimaiti,5 Min Chai,1 Xinran Yang,1 Xiuxian Zang,1 Dahai Xu1 1Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130000, People’s Republic of China; 2Department of Emergency Intensive Care Unit of Jilin University, Changchun, Jilin, 130000, People’s Republic of China; 3Department of Ultrasonography, Yanbian University Hospital, Yanji, Jilin, People’s Republic of China; 4Department of Emergency Medicine, Yanbian University Hospital, Yanji, Jilin, 133000, People’s Republic of China; 5Department of Emergency Medicine, Seventh Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dahai Xu; Xiuxian Zang, Department of Emergency Medicine, The First Hospital of Jilin University, No. 1 Xinmin Street, Chaoyang District, Changchun, Jilin, 130000, People’s Republic of China, Tel +8615043032548 ; +8613596097922, Email xudahai0319@jlu.edu.cn; zangxx@jlu.edu.cnAbstract: Organophosphates (OPs) refers to a diverse group of phosphorus-containing organic compounds; they are widely used all over the world and have had an important beneficial impact on industrial and agricultural production and control of vector transmission. Exposure to OPs of different toxicities (high, moderate, slight, and low toxicity) can all have negative consequences on the nervous system, such as nausea, vomiting, muscle tremors, and convulsions. In severe cases, it can lead to respiratory failure or even death. Notably, OPs induce neuropathy in the nervous system through specific interactions with nicotinic or muscarinic receptors, phosphorylating acetylcholinesterase, or neuropathic target esterases. This review summarizes the possible toxicological mechanisms and their interplay underlying OP pesticide poisoning, including cholinesterase inhibition and non-cholinesterase mechanisms. It outlines the possible links between OP pesticide poisoning and neurological disorders, such as dementia, neurodevelopmental diseases, and Parkinson’s disease. Additionally, it explores OP interactions’ potential therapeutic implications that may help mitigate the deleterious impact of OPs on the nervous system.Keywords: organophosphate pesticides, neurotoxicity, acetylcholinesterase, neurodegenerative diseases

Martha Sajatovic,1 Monica Doring,2 Oliver J Lopena,2 Karen Johnston,2 Ibrahim Turkoz,3 Nia Josiah,4 Camilo Obando2 1University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 2Janssen Scientific Affairs, LLC, a Johnson & Johnson company, Titusville, NJ, USA; 3Janssen Research & Development, LLC, Titusville, NJ, USA; 4The University of Pennsylvania School of Nursing, Philadelphia, PA, USACorrespondence: Monica Doring, Janssen Scientific Affairs, LLC, a Johnson & Johnson company, 1125 Trenton Harbourton Road, Titusville, 08560, NJ, Email Mdoring1@its.jnj.comPurpose: A previous integrated patient-level analysis demonstrated a significant benefit of implementing once-monthly injectable paliperidone palmitate (PP1M) earlier in the treatment course for schizophrenia. Earlier therapeutic interventions during the first 3– 5 years after disease onset can positively impact long-term outcomes in schizophrenia. This present analysis evaluated the risk of relapse both overall and by different durations of illness (0– 3 years, > 3– 5 years, and > 5 years from diagnosis) in adult patients with schizophrenia who received PP1M or oral antipsychotics (OAPs).Patients and Methods: This analysis included integrated patient-level data from the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) and Prevention of Relapse with Oral Antipsychotics versus Injectable Paliperidone Palmitate (PROSIPAL) studies. Both studies assessed relapse as the primary outcome in patients treated either PP1M or OAPs.Results: Overall, the risk of relapse was reduced by 31% with PP1M compared to OAP (HR 0.69; 95% CI [0.56– 0.86], P < 0.001). Fewer relapses were observed with PP1M versus OAP in the 0– 3-year subgroup (15.8% and 21.7%, respectively), > 3– 5-year subgroup (19.6% and 29.9%, respectively), and > 5-year subgroup (41.7% and 51.6%, respectively). These results represent a reduction in risk of relapse by 33% for patients receiving PP1M versus OAP in the 0– 3-year subgroup (HR 0.67; 95% CI [0.44– 1.00], P = 0.050), 43% in the > 3– 5-year subgroup (HR 0.57; 95% CI [0.35– 0.93], P = 0.025), and 26% in the > 5-year subgroup (HR 0.74; 95% CI [0.55– 1.00], P = 0.049). Treatment-emergent adverse event rates were similar between treatment groups.Conclusion: This analysis indicates that PP1M provides significant benefits in reducing relapse rates compared to OAPs, regardless of the duration of illness. These findings emphasize the importance of initiating PP1M treatment early in the course of schizophrenia to achieve better long-term outcomes.Keywords: early intervention, critical period, long-acting injectable antipsychotics, PRIDE, PROSIPAL

This review focuses on the current advances in the field of therapeutic targets and treatments for stroke. Stroke is a major health problem worldwide, with significant impacts on morbidity and mortality, and a considerable burden on the medical and socio-economic systems. This review provides a comprehensive overview of the current state of knowledge on acute treatments and therapeutic targets. Current stroke treatments like recanalization therapies focus mainly on restoring blood flow to the brain, reducing cell death, and preventing further damage, but have limitations in terms of efficacy and long-term outcomes. Besides acute treatments (mobile stroke units, telerehabilitation) and acute therapeutic targets, the review focuses on longer-term therapeutic targets, such as neuroprotection and neuroregeneration. Neuroprotective strategies target the mechanisms underlying energy failure, cellular acidosis, mitochondrial dysfunction, endoplasmic reticulum stress, excitotoxicity, calcium channels dysregulation, oxidative stress, neuroinflammation, blood-brain barrier disruption, apoptosis, and ischemia-reperfusion injury. Neuroregenerative approaches include stem cell therapy, gene therapy, growth factors, and rehabilitation techniques that promote the rewiring of neuronal circuits in the brain. Non-pharmacological treatments like neurostimulation and bioengineering are also presented. Additionally, we highlight the challenges and future directions in translating these therapies into clinical practice. Overall, the treatment of ischemic stroke is a complex and multifaceted process that requires a combination of acute measures as well as longer-term strategies to promote brain repair and recovery. The treatment of ischemic stroke has made significant progress in recent years with the development of new treatments and ongoing research to improve outcomes for stroke patients. However, before these therapies can be successfully integrated into routine clinical practise, further research is needed to establish standardised protocols, overcome methodological limitations, and overcome clinical challenges. By further deepening our understanding of the pathophysiology of ischemic stroke and developing innovative treatments, we can improve outcomes and quality of life for stroke survivors.

Tao Yu,1,&ast; Wenzhi Pei,1 Xulai Zhang,1 Chenchen Deng2,&ast; 1Anhui Mental Health Center; Affiliated Psychological Hospital of Anhui Medical University; Hefei Fourth People’s Hospital, Hefei, Anhui, 230022, People’s Republic of China; 2Anhui Province Maternity & Child Health Hospital, Hefei, Anhui, 230022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xulai Zhang, Email 479800330@qq.comBackground: Thyroid dysfunction and frontal lobe gray matter volume (GMV) alterations are associated with violence in schizophrenia (SCZ); however, little is known about the relationship between thyroid dysfunction and frontal lobe GMV. This study aimed to evaluate whether thyroid hormone levels were associated with frontal lobe GMV in male patients with schizophrenia and violence.Methods: Fifty-five male patients with SCZ underwent triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) tests and structural magnetic resonance imaging (sMRI) scans. The sMRI data were processed using the FreeSurfer version 5.0. Multiple linear stepwise regression analysis was used to investigate the relationship between frontal lobe GMV and thyroid hormone levels in all patients.Results: Patients with SCZ and violence exhibited lower GMV of the left frontal pole and higher TSH levels than those without violence. After controlling for potential covariates, the frontal pole GMV was negatively associated with TSH levels in all participants.Conclusion: These findings expand our understanding of the influence of TSH on frontal pole GMV in patients with schizophrenia and violence.Keywords: thyroid, schizophrenia, violence, gray matter volume, MRI, structures

Shaoxia Wang,1– 3 Xiang Zhang,1 Yanru Ding,1 Yanrong Wang,2,4 Chujun Wu,2,4 Shihao Lu,1,2 Jianqun Fang2,4 1School of First Clinical, Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 2Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 3Ningxia Civil Affairs Department Minkang Hospital, Yinchuan, Ningxia, 750001, People’s Republic of China; 4Mental Health Center, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of ChinaCorrespondence: Jianqun Fang, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China, Email fjq7887215@163.comObjective: Vitamin B12 is crucial for neurological functions and linked to various psychiatric disorders. Given its importance, this study explores the impact of vitamin B12 deficiency on sleep quality in Obsessive-Compulsive Disorder (OCD) patients, while also examining folate and homocysteine levels to explore their potential interactions with OCD symptoms and sleep quality.Methods: This cross-sectional study included 52 patients with OCD and 42 healthy controls. Serum levels of vitamin B12, homocysteine, and folate were measured. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the severity of OCD symptoms and the quality of sleep, respectively. Correlations and mediating effects between these variables were also assessed.Results: Vitamin B12 levels were significantly lower in OCD patients compared to healthy controls, and scores for sleep disturbances were significantly higher in the OCD group. No significant differences were observed in the levels of folate and homocysteine between the groups. Correlation analysis indicated that lower levels of vitamin B12 were significantly associated with more severe OCD symptoms and poorer sleep quality. Further mediation analysis suggested that low levels of vitamin B12 partially mediated the relationship between OCD symptoms and sleep disturbances.Conclusion: Lower levels of vitamin B12 not only affect sleep quality but also partially mediate the impact of OCD symptoms on sleep disturbances. Future clinical attention to vitamin B12 deficiency is crucial for further assessing the relationship between OCD symptoms and sleep disorders.Keywords: obsessive-compulsive disorder, sleep disturbances, vitamin b12, mediating effects

Keira Herr,1 Michael Berk,2 Wei-Lieh Huang,3 Tadafumi Kato,4 Jung Goo Lee,5,6 Chong Guan Ng,7 Zhen Wang,8 Thomas David Webb,1 Mami Kasahara-Kiritani,9 Lawrence Phillip Vandervoort10 1Janssen Asia Pacific, Singapore; 2School of Medicine, Deakin University, Geelong, Victoria, Australia; 3Department of Psychiatry, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan; 4Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Tokyo, Japan; 5Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea; 6Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea; 7Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 8Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 9Janssen Pharmaceutical K.K., Tokyo, Japan; 10Oracle Life Sciences, SingaporeCorrespondence: Keira Herr, Janssen Asia Pacific, 2 Science Park Drive, Singapore Science Park 1, Ascent, &num;07-13, 118222, Singapore, Email keiraherr@gmail.comPurpose: To explore the prevalence of anhedonia (ANH) in major depressive disorder (MDD) and treatment expectation and satisfaction among patients with MDD and physicians in the Asia-Pacific region.Methods: This cross-sectional web-based survey was conducted in April-May 2023 among physicians and individuals aged ≥ 18 years with self-reported physician diagnosis of MDD (9-item Patient Health Questionnaire [PHQ-9] score ≥ 10) further stratified by anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS): MDD-ANH (SHAPS score > 2) and MDD non-ANH (SHAPS score ≤ 2). The study assessed the prevalence of anhedonia in MDD as well as the perspectives on the treatment of anhedonia in MDD in terms of expectations and satisfaction among patients and physicians.Results: The regional estimated prevalence of MDD was 16.1% where 52.5% of MDD respondents had ANH (SHAPS score ≥ 2). Depressed mood, mental changes, and changes in sleeping patterns prompted MDD-ANH (n = 1448) or MDD non-ANH (n = 836) respondents to seek medical consultation. Respondents with MDD-ANH (vs MDD non-ANH) reported significantly higher levels of depression and anhedonia, longer treatment duration, and preferred switching their existing medications over adding additional medications (all, p < 0.001). Over half of physicians (55.0%) were not treating anhedonia separately. Anhedonia-specific treatment goals seemed important to all respondents, while avoiding suicidal ideation was significantly important to physicians. MDD-ANH respondents reported in general the lowest level of satisfaction with treatment goals than MDD non-ANH and physician, with “improvements in sexual satisfaction” being the treatment goal with the lowest level of satisfaction.Conclusion: This first large-scale study conducted across the Asia-Pacific region provides a recent update on the prevalence of MDD and anhedonia in MDD and highlights unmet needs in the current therapeutic landscape for anhedonia in MDD, emphasizing the need for novel treatment.Keywords: anhedonia, apathy, depression, emotional blunting, epidemiology, prevalence, treatment goals

Abstract Objective The single‐center retrospective cohort study investigated underlying pathogenic mechanisms and clinical significance of patients with temporal lobe epilepsy and hippocampal sclerosis (TLE‐HS), in the presence/absence of gray–white matter abnormalities (usually called “blurring”; GMB) in ipsilateral temporopolar region (TPR) on MRI. Methods The study involved 105 patients with unilateral TLE‐HS (60 GMB+ and 45 GMB−) who underwent standard anterior temporal lobectomy, along with 61 healthy controls. Resected specimens were examined under light microscope. With combined T1‐weighted and DTI data, we quantitatively compared large‐scale morphometric features and exacted diffusion parameters of ipsilateral TPR‐related superficial and deep white matter (WM) by atlas‐based segmentation. Along‐tract analysis was added to detect heterogeneous microstructural alterations at various points along deep WM tracts, which were categorized into inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and temporal cingulum. Results Comparable seizure semiology and postoperative seizure outcome were found, while the GMB+ group had significantly higher rate of HS Type 1 and history of febrile seizures, contrasting with significantly lower proportion of interictal contralateral epileptiform discharges, HS Type 2, and increased wasteosomes in hippocampal specimens. Similar morphometric features but greater WM atrophy with more diffusion abnormalities of superficial WM was observed adjacent to ipsilateral TPR in the GMB+ group. Moreover, microstructural alterations resulting from temporopolar GMB were more localized in temporal cingulum while evenly and widely distributed along ILF and UF. Interpretation Temporopolar GMB could signify more severe and widespread microstructural damage of white matter rather than a focal cortical lesion in TLE‐HS, affecting selection of surgical procedures.

Abstract Methods This study assessed data from two cohorts of patients with alpha‐synucleinopathies (University of Brescia and University of Rome Tor‐Vergata cohorts). Consecutive participants with video‐polysomnography‐confirmed iRBD, Parkinson's disease (PD), dementia with Lewy bodies (DLB) and controls underwent neurological, clinical and 123I‐FP‐CIT SPECT imaging assessments. Individuals with iRBD were longitudinally monitored to collect clinical phenoconversion to PD or DLB. The main outcome was to identify whole brain 123 I‐FP‐CIT SPECT measures reflecting monoaminergic deficits in each clinical group as compared to controls. Results The cohort (n = 184) included 45 patients with iRBD, 47 PD, 42 DLB and 50 age‐matched controls. Individuals with iRBD were categorized as RBD‐DAT− (n = 32) and RBD‐DAT+ (n = 13), according to nigrostriatal assessment used in clinical practice. Compared to controls, RBD‐DAT− showed an early involvement of the left insula, which increased in RBD‐DAT+, and was present in patients with Parkinson's disease and dementia with Lewy bodies. Longitudinal cox regression analyses revealed a higher risk of phenoconversion in individuals with iRBD and insular monoaminergic deficits [HR = 3.387; CI 95%: 1.18–10.27]. Interpretation In this study, altered insular monoaminergic binding in iRBD was associated with phenoconversion to DLB or PD. These findings may provide a helpful stratification approach for future pharmacological or non‐pharmacological interventions.

Abstract Objective Neuromuscular evaluation increasingly employs muscle ultrasonography to determine muscle thickness, mean grayscale echointensity, and visual semiquantitative echotexture attenuation. However, these measures provide low sensitivity for detection of mild muscle abnormality. Exercise‐induced intramuscular blood flow is a physiologic phenomenon, which may be impaired in mildly affected muscles, particularly in dystrophinopathies, and may indicate functional muscle ischemia. We aimed to determine if muscle blood flow is reduced in patients with neuromuscular disorders and preserved muscle strength, and if it correlates with echointensity and digital echotexture measurements. Methods Peak exercise‐induced blood flow, echointensity, and echotexture were quantified in the elbow flexor muscles of 15 adult patients with Becker muscular dystrophy (BMD) and 13 patients with other muscular dystrophies (OMD). These were compared to 17 patients with Charcot–Marie–Tooth type 1 (CMT1) neuropathy and 21 healthy adults from a previous study. Results Muscle blood flow was reduced in all patient groups compared to controls, most prominently in BMD patients (p

Abstract Objective This study aims to elucidate the cognitive underpinnings of language abnormalities in Alzheimer's Disease (AD) using a computational cross‐linguistic approach and ultimately enhance the understanding and diagnostic accuracy of the disease. Methods Computational analyses were conducted on language samples of 156 English and 50 Persian speakers, comprising both AD patients and healthy controls, to extract language indicators of AD. Furthermore, we introduced a machine learning‐based metric, Language Informativeness Index (LII), to quantify empty speech. Results Despite considerable disparities in surface structures between the two languages, we observed consistency across language indicators of AD in both English and Persian. Notably, indicators of AD in English resulted in a classification accuracy of 90% in classifying AD in Persian. The substantial degree of transferability suggests that the language abnormalities of AD do not tightly link to the surface structures specific to English. Subsequently, we posited that these abnormalities stem from impairments in a more universal aspect of language production: the ability to generate informative messages independent of the language spoken. Consistent with this hypothesis, we found significant correlations between language indicators of AD and empty speech in both English and Persian. Interpretation The findings of this study suggest that language impairments in AD arise from a deficit in a universal aspect of message formation rather than from the breakdown of language‐specific morphosyntactic structures. Beyond enhancing our understanding of the psycholinguistic deficits of AD, our approach fosters the development of diagnostic tools across various languages, enhancing health equity and biocultural diversity.

Abstract Diffuse midline gliomas present a particularly intricate and challenging clinical scenario. This rare case involves a patient with comutant H3F3A and FGFR diffuse midline glioma with a clinical presentation of fulminant leptomeningitis. A 22‐year‐old male presented with fatal and fulminant diffuse leptomeningitis. Next‐generation sequencing of plasma and cerebrospinal circulating tumour DNA revealed diffuse midline gliomas with H3F3A and FGFR mutations. Methylome analysis of meningeal tissue collected during autopsy confirmed the diagnosis. Liquid biopsy plays a crucial role in the diagnosis of diffuse midline gliomas, mainly those with exclusively leptomeningeal presentations.

Abstract Objective Stroke is the leading cause of death and disability. Timely differentiation between ischemic stroke, hemorrhagic stroke, and stroke mimics is critical for tailored treatment and triage. To accelerate the identification of stroke's subtype, we propose to use the levels of circulating tPA as a biomarker. Methods Biostroke is an observational study performed at the Caen Hospital. We quantified tPA levels in 110 patients with ischemic strokes, 30 patients with hemorrhagic strokes, and 67 stroke mimic patients upon their arrival at the emergency. Two logistic regression models were formulated: one with parameters measurable in an ambulance (Model A) and one with parameters measurable at the hospital (Model H). These models were both tested with or without plasma tPA measurements. Our initial assessment involved evaluating the effectiveness of both models in distinguishing between hemorrhagic strokes, ischemic strokes, and stroke mimics within our study cohort. Results Plasmatic tPA levels exhibit significant distinctions between hemorrhagic, ischemic, and mimic stroke patients (1.8; 2.5; 2.4 ng/mL, respectively). The inclusion of tPA in model A significantly enhances the classification accuracy of hemorrhagic patients only, increasing identification from 0.67 (95% CI, 0.59 to 0.75) to 0.78 (95% CI, 0.7 to 0.85) (p = 0.0098). Similarly, in model H, classification accuracy of hemorrhagic patients significantly increased with the addition of tPA, rising from 0.75 (95% CI, 0.67 to 0.83) without tPA to 0.86 (95% CI, 0.81 to 0.91) with tPA (p = 0.024). Interpretations Our findings underscore the valuable role of tPA levels in distinguishing between stroke subtypes.

Abstract Objective To assess the prevalence, timing, and functional impact of neuropsychiatric symptoms in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to assess whether these neuropsychiatric symptoms are associated with magnetic resonance imaging (MRI) features of the patients. Methods Our study included a total of 78 patients with CADASIL. To assess neuropsychiatric symptoms, we evaluated the caregivers using the Neuropsychiatric Inventory (NPI). Patients were considered to have an irritability, depression, apathy, aggression, or anxiety disorder if they scored ≥1 in the NPI. Subsequently, we conducted a more detailed assessment of irritability, depression, apathy, aggression, and anxiety. Multivariate logistic regression was employed to analyze the relationships between neuropsychiatric symptoms and clinical/MRI features in the patients. Results Overall, 57.69% of patients with CADASIL experienced neuropsychiatric symptoms. Among these symptoms, irritability was the most prevalent (52.56%), followed by depression (19.23%), apathy (17.95%), aggression (7.69%), and anxiety (6.41%). The mean age of onset for irritability was the youngest, followed by anxiety, apathy, aggression, and depression. Among patients with both stroke/TIA and neuropsychiatric symptoms, 31.03% reported experiencing neuropsychiatric symptoms prior to stroke/TIA. Furthermore, both irritability and apathy had a negative impact on the patients' daily functioning. Additionally, there was a correlation between the presence of neuropsychiatric symptoms and the patients' MRI lesion burden. Interpretation Our study has discovered that neuropsychiatric symptoms are highly prevalent in patients with CADASIL and may occur before cerebrovascular events, suggesting that neuropsychiatric symptoms of CADASIL deserve more attention and earlier exploration.

Abstract Objective Strokes involving sensory pathways can result in contralesional pain syndromes often refractory to pharmacologic interventions. Scrambler therapy (ST) is a noninvasive electroanalgesia device used to treat pain caused by peripheral neuropathy; however, data are scarce regarding its use in conditions secondary to central nervous system pathology. We evaluate the efficacy of ST to treat poststroke pain. Methods Twenty patients with a history of prior stroke resulting in contralesional pain were randomized to receive ST or Sham as an adjunct to their stable medication regimen. Participants underwent 5 consecutive daily 40‐min sessions. The study was blinded to patient and assessor. Pain scores (0–10) were recorded at baseline, pre‐ and postsession, and 4 weeks after final treatment. Student's t‐tests compared differences in the mean change in pain score between groups immediately post‐treatment #5, and at 4‐weeks. The chi‐squared analysis compared the proportion of patients in each group with >50% pain reduction. Results Participants randomized to ST had a mean change in pain score of −3.73 (SD 2.85) postintervention and −2.57 (SD 2.07) at 4 weeks, while the Sham group had a mean change in score of −0.94 (SD 1.36) and −0.25 (SD 0.84) (p between groups = 0.012, 0.004, respectively). Significantly more participants treated with ST reported a >50% reduction in pain immediately postintervention compared to Sham (70% vs. 10%, p = 0.006), but not at follow‐up (30% vs. 10%, p = ns). Interpretation ST may effectively decrease poststroke pain compared to Sham. Larger studies are needed to evaluate confounders such as stroke location, time from stroke, and concomitant treatment with medications.

Abstract Objective Black American (BA) multiple sclerosis (MS) patients experience greater disability compared to White American (WA) patients. Here, we investigated the role of paramagnetic rim lesions (PRLs), a subset of chronic active lesions, on race‐related disability in MS. Methods We conducted a retrospective observational study comparing BA and WA MS patients. PRLs were identified through Quantitative Susceptibility Mapping (QSM) MRI. A causal mediation analysis explored the impact of PRLs on the relationship between race and disability, as measured by the Expanded Disability Status Scale (EDSS). Results The prevalence of PRLs in BA patients with MS was higher at 55% compared to WA patients at 39% (p = 0.022). A higher percentage of PRLs among all white matter lesions was observed with BA (8.01%) patients compared to WA (3.4%) patients (p = 0.003). In a regression analysis, controlling for significant patient‐level covariates and income‐level demographics, the percentage of PRLs was, on average, 4.61 points higher for BA patients than for WA patients (p = 0.003). In a separate regression analysis, accounting for covariates, BA patients exhibited significantly higher EDSS scores (p

Abstract It is unknown if cognition is impaired before clinical onset of paediatric acquired demyelinating syndromes. We conducted a matched cohort study using prospectively collected educational data in multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) patients (n = 60) and controls (pooled n = 449,553). Academic performance at ages 10–11 was impaired in MOGAD (−1.27 adjusted z‐score [95% CI: −1.81 to −0.73], P

Abstract Objective This study aimed to evaluate the diagnostic accuracy of dried blood spot (DBS) compared with conventional serum Aquaporin‐4‐IgG (AQP4‐IgG) testing. Methods Prospective multicenter diagnostic study was conducted between April 2018 and October 2023 across medical centers in the United States, Uganda, and the Republic of Guinea. Neuromyelitis optica spectrum disorder (NMOSD) patients and controls collected blood on filter paper cards along with concurrent serum samples. These samples underwent analysis using flow cytometric live‐cell‐based assays (CBA) and enzyme‐linked immunosorbent assay (ELISA) to determine AQP4 serostatus. The accuracy of AQP4‐IgG detection between DBS and serum (gold standard) was compared. Results Among 150 participants (47 cases, 103 controls), there was a strong correlation between DBS and serum samples (Spearman's correlation coefficient of 0.82). The AUC was 0.97 (95% CI: 0.92–0.99). AQP4‐IgG detection through DBS showed 87.0% sensitivity (95% CI: 0.74–0.95) and 100% specificity (95% CI: 0.96–1.00) using CBA, and 65.2% sensitivity (95% CI: 0.43–0.84) and 95.2% specificity (95% CI: 0.76–0.99) using ELISA. Serum ELISA demonstrated 69.6% sensitivity (95% CI: 0.47–0.87) and 98.4% specificity (95% CI: 0.91–0.99). The stability of DBS in detecting AQP4‐IgG persisted over 24 months for most cases. Interpretation The DBS represents a viable alternative for detecting AQP4‐IgG in resource‐limited settings to diagnose NMOSD, offering high sensitivity and specificity comparable to serum testing. Moreover, DBS has low shipping costs, is easy to administer, and is suitable for point‐of‐care testing.

Abstract Objective People with multiple sclerosis (MS) might experience symptoms that are usually underestimated. Dysphagia should be evaluated within the Expanded Disability Status Scale (EDSS), but clinicians often do not assess it properly. The objectives of this study are as follows: To assess the prevalence of dysphagia in patients with MS utilizing the Swallowing Disturbance Questionnaire (SDQ); to examine the correlation with the EDSS; to investigate the relationship between dysphagia and clinico‐demographic characteristics of MS. Methods In total, 177 MS patients underwent evaluations with EDSS, SDQ, cognitive functions, anxiety, depression, fatigue, and sleep quality tests. We compared clinico‐demographic data of patients with and without dysphagia and native‐EDSS to SDQ‐EDSS. Results Out of the 177 MS patients, 56% of individuals were identified having dysphagia according to the SDQ with 41 patients exhibiting mild dysphagia, 31 showing moderate dysphagia and 27 patients having severe dysphagia. Only 6 patients had dysphagia recorded in the EDSS. SDQ‐EDSS scores were significantly higher than native scores. Dysphagia was associated with depressive symptoms and sleep quality. Interpretation Dysphagia affects up to 56% of MS patients. The SDQ questionnaire is useful for identifying dysphagia, which can help in capturing disease progression and preventing complications like aspiration pneumonia. The SDQ‐EDSS was higher than the native‐EDSS, reflecting the poor ability of the native‐EDSS to evaluate certain symptoms such as dysphagia. The SDQ correlated with depressive symptoms, which are associated with a greater perception of MS symptoms, and poor sleep quality, which could be associated with the triggering of pathogenic mechanisms responsible for disease progression.

Abstract Objective: Lennox‐Gastaut syndrome (LGS) is a severe, childhood‐onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes. Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review. Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease‐modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving “drops,” but should incorporate additional patient‐centered outcomes, using emerging measures adapted to people with LGS. Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient‐centered clinical trials that are tailored to LGS pathophysiology and natural history.

Abstract Background Early diagnosis of large vessel occlusion (LVO) in acute stroke often requires CT angiography (CTA). Automated CT perfusion (CTP) software, which identifies blood flow abnormalities, enhances LVO diagnosis and patient selection for endovascular thrombectomy (EVT). This study evaluates the sensitivity of automated CTP images in detecting perfusion abnormalities in patients with acute ischemic stroke (AIS) and LVO or medium vessel occlusion (MeVO), compared to CTA. Methods We screened acute ischemic stroke patients presenting within 24 h who underwent CT, CTA, and CTP as per institutional protocol. RAPID AI software processed CTP images, while neuroradiologists reviewed CTA for intracranial arterial occlusions. Sensitivity, specificity, and accuracy of automated CTP maps in detecting occlusions were assessed. Results Of 790 screened patients, 31 were excluded due to lack of RAPID CTP data or poor‐quality scans, leaving 759 for analysis. The median age was 71 years (IQR: 61–81), with 47% female. Among them, 678 had AIS, and 81 had AIS ruled out. CTA identified arterial occlusion in 562 patients (74%), with corresponding CTP abnormalities in 537 patients (Tmax > 6 sec). In the 197 without occlusion, CTP was negative in 161. Automated CTP maps had a sensitivity of 95.55% (CI 95: 93.50–97.10%), specificity of 81.73% (CI 95: 75.61–86.86%), negative predictive value of 98.22% (CI 95: 97.39–98.79%), positive predictive value of 63.54% (CI 95: 56.46–70.09%), and overall accuracy of 85.18% (CI 95: 82.45–87.64%). Conclusions Automated CTP maps demonstrated high sensitivity and negative predictive value for LVOs and MeVOs, suggesting their usefulness as a rapid diagnostic tool, especially in settings without expert neuroradiologists.

Abstract FARS2‐associated hereditary spastic paraplegia, later onset spastic paraplegia type 77, is a rarely neurodegenerative disease. Here, we reported two affected siblings in an autosomal recessive spastic paraplegia family with a pseudo‐homozygous missense variant and Alu‐mediated exon 5 deletion in FARS2. Both patients gradually developed altered gaits and weakness in both lower limbs. In our literature review, spastic paraplegia type 77 shows high heterogeneity in clinical manifestations. Our study broadens the scope of pathogenic mechanisms of SPG77 resulting from compound heterozygous mutations in FARS2 and provides strong evidence that deletion in FARS2 due to recombination event mediated by Alu element.

Abstract Objective Paramagnetic rim lesions (PRLs) are a biomarker of chronic active lesions (CALs), and an important driver of neurological disability in multiple sclerosis (MS). The reason subtending some acute lesions evolvement into CALs is not known. Here we ask whether a relatively lower oxygen content is linked to CALs. Methods In this prospective cross‐sectional study, 64 people with multiple sclerosis (PwMS), clinically isolated syndrome and radiologically isolated syndrome underwent a 7.0 Tesla (7 T) brain magnetic resonance imaging (MRI). The scanning protocol included a T2‐w fluid‐attenuated inversion recovery (FLAIR), and a single echo gradient echo from which susceptibility‐weighted imaging (SWI) was derived. WM lesions were identified on the T2‐w‐FLAIR whilst PRLs were identified on the SWI sequence. T2‐lesions were classified as PRLs and rimless lesions (PRLs‐). We registered a universal vascular atlas to each subject's T2‐w‐FLAIR and classified each T2‐lesions according to its location into watershed‐ (ws), non‐watershed‐ (nws), and mixed‐lesion (m). Ws‐lesions were defined as lesions that were fully located in a region between the territories of two major arteries. Results Out of 1,975 T2‐lesions, 88 (4.5%) were PRLs. Ws‐regions had a higher number (p = 0.005) and proportion (p

Abstract Objective Isolated REM sleep behavior disorder (iRBD) is considered as the strongest predictor of Parkinson's disease (PD). Reliable and accurate biomarkers for iRBD detection and the prediction of phenoconversion are in urgent need. This study aimed to investigate whether α‐Synuclein (α‐Syn) species in plasma neuron‐derived extracellular vesicles (NDEVs) could differentiate between iRBD patients and healthy controls (HCs). Methods Nanoscale flow cytometry was used to detect α‐Syn‐containing NDEVs in plasma. Results A total of 54 iRBD patients and 53 HCs were recruited. The concentrations of total α‐Syn, α‐Syn aggregates, and phosphorylated α‐Syn at Ser129 (pS129)‐containing NDEVs in plasma of iRBD individuals were significantly higher than those in HCs (p

Abstract Twin girls born at 30 weeks' gestation with spinal muscular atrophy (SMA) received onsasemnogene‐abeparvovec (OA) at 3.5 weeks of life. They had no treatment‐related adverse events, normal acquisition of motor milestones, and normal neurological examination at 19 months. Genotyping revealed 0 copies of SMN1 and a single, hybrid SMN2 gene containing the positive genetic modifier c.835‐44A>G. This was associated with full‐length SMN2 blood mRNA expression levels similar to a 2 copy SMA infant. The observed favorable outcomes are likely due to the genetic modifier combined with early drug administration enabled by prematurity.

Abstract Objective This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non‐demented older adults. Methods Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow‐up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers. Results In main effect models, higher SCD was associated with more amyloidosis (p‐values 0.38). SCD score interacted with cognitive status (p 0.51) though SCD related to amyloid markers in the higher reading‐level group (p‐values

Abstract The evaluation of white matter lesions (WMLs) showing the central vein sign (CVS) and paramagnetic rim lesions (PRLs) has been suggested to enhance the diagnostic work‐up of adult multiple sclerosis (MS). We aimed to evaluate the fulfillment of different CVS criteria and the added value of PRLs in 22 pediatric MS patients. Eleven patients (50%) fulfilled the 40%‐rule threshold. Nineteen (86%) patients had ≥3 CVS+ WMLs or ≥1 PRL, whereas 17 (77%) had ≥6 CVS+ WMLs or ≥1 PRL. A simplified CVS‐based approach, with the combined evaluation of ≥1 PRL in patients with ≥6 CVS+ WMLs, may improve MS diagnosis in pediatric patients.

Abstract Objective To describe patient clinical characteristics associated with matched oligoclonal bands (OCB). Methods A retrospective review at the University of Utah examined patients with matched OCB from 2015 to 2020. Clinical data, diagnosis, and outcomes were collected. Patients were classified with either multiple sclerosis (MS), other inflammatory neurologic disorder (other‐IND), or noninflammatory neurologic disorder (NIND). Results Of 539 identified patients, 436 (53.4% female) were matched‐only, while 103 (43.7% female) were matched + unique. Patients with matched‐only bands were older (57.4 ± 16 vs. 52 ± 14.2, p

Abstract Objective Expand genetic screening for atypical Type I sialidosis (ST‐1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population. Methods We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation. Results A total of 31 patients from 23 unrelated families were genetically diagnosed with ST‐1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST‐1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic–clonic seizures. Mobility and independence varied greatly across the cohort. Cherry‐red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians. Interpretation ST‐1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry‐red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.

Abstract Objective To explore the relationship between 35 trace metals in scalp hair and the glioma risk as well as the potential mediating roles of 27 plasma inflammatory cytokines. Methods A case–control study involving 228 participants was performed in southeastern China. Trace metals in scalp hair were analyzed using inductively coupled plasma mass spectrometry, and multiplex cytokines were detected based on Luminex® technology. The least absolute shrinkage and selection operator (LASSO) regression in combination with four machine learning methods were used to select trace metals associated with gliomas. The joint exposure effect of trace metals was estimated using the generalized weighted quantile sum (gWQS) regression and quantile‐based g‐computation (qgcomp) algorithms. Results Both LASSO regression and random forest algorithms identified five trace metals (gadolinium [Gd], lithium [Li], thulium [Tm], thorium [Th], and molybdenum [Mo]) associated with gliomas. After adjustments for potential confounders, Gd (odds ratio [OR] = 2.84, 95% confidence interval [CI]: 1.89–4.43) and Li (OR = 1.77, 95% CI: 1.04–3.02) concentrations were positively associated with glioma risk, while Tm (OR = 0.36, 95% CI: 0.17–0.73) and Th (OR = 0.45, 95% CI: 0.28–0.71) exhibited inverse associations. Both gWQS and qgcomp algorithms showed Gd contributed most to the mixture effect. Moreover, there was a significant interaction between Gd and Tm or Th on glioma risk (p

Abstract Background Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer’s disease dementia (ADD), and vascular dementia (VaD). Methods Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed. Results The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability. Discussion Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment.

Abstract Background Females have a higher age-adjusted incidence of Alzheimer’s Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building cognitive reserve, particularly through stimulating avocational activities and occupational attainment presents a crucial, underexplored, dementia prevention approach for mid-life. It is currently unknown, however, whether modifiable lifestyle factors can protect against AD processes, from mid-life, differentially for females and males who carry inherited risk for late-life dementia. To address this gap, this study investigated the impact of biological sex and APOE4 carrier status on the relationship between stimulating activities, occupational attainment, and cognition in mid-life. Methods We leveraged the PREVENT–Dementia program, the world’s largest study investigating the origins and early diagnosis of dementia in mid-life at-risk individuals (N = 700; 40–59 years). Cognitive performance was measured using the Cognito Battery and the Visual Short Term Memory Binding task. Mid-life specific reserve contributors were assessed via the Lifetime of Experiences Questionnaire. Results Females had significantly better episodic and relational memory (p

Abstract Background The role of Vascular risk factors (VRFs) in the progression of Alzheimer’s Disease (AD) and cognitive decline remains to be elucidated, with previous studies resulting in conflicting findings. The possible impact of age-specific mechanisms of resilience/vulnerability is an under addressed issue. We evaluated the association of VRFs with markers of amyloid deposition, neurodegeneration, and blood-brain-barrier (BBB) permeability (Albumin quotient, Qalb), stratifying patients into early-onset ( 75, vLOAD), to evaluate the moderating effect of age of onset. Moreover, we explored the effects of VRFs on cognitive decline at one year follow-up (ΔMMSE). Methods For 368 patients with biologically confirmed AD, we computed eight risk factors in a composite measure of cumulative vascular risk (vascular score, VS). Stratifying patients according to age of onset, we regressed VS and main individual VRFs on p-tau/Aβ42, t-tau and Qalb, and used bootstrapped mediation analysis to test direct and indirect associations of VS with t-tau, using Qalb as mediator. In a subset of 105 patients, we performed multivariate backward regressions to assess the effects of sex, APOE, Qalb, VS, p-tau/Aβ42 and t-tau on ΔMMSE. Results VS was positively associated with CSF t-tau in more vulnerable groups burdened by more aggressive disease progression (EOAD: β = 0.256, p = 0.019) or aging (vLOAD: β = 0.007, p

Abstract This study aimed to identify potential markers that can predict Parkinson’s disease with mild cognitive impairment (PDMCI). We retrospectively collected general demographic data, clinically relevant scales, plasma samples, and neuroimaging data (T1-weighted magnetic resonance imaging (MRI) data as well as resting-state functional MRI [Rs-fMRI] data) from 173 individuals. Subsequently, based on the aforementioned multimodal indices, a support vector machine was employed to investigate the machine learning (ML) classification of PD patients with normal cognition (PDNC) and PDMCI. The performance of 29 classifiers was assessed based on various combinations of indicators. Results demonstrated that the optimal classifier in the validation set was composed by clinical + Rs-fMRI+ neurofilament light chain, exhibiting a mean Accuracy of 0.762, a mean area under curve of 0.840, a mean sensitivity of 0.745, along with a mean specificity of 0.783. The ML algorithm based on multimodal data demonstrated enhanced discriminative ability between PDNC and PDMCI patients.

Abstract Individual variability exists in parkinsonian motor symptoms despite a similar degree of nigrostriatal dopamine depletion in Parkinson’s disease (PD), called motor reserve. We enrolled 397 patients newly diagnosed with PD who underwent dual-phase 18F-FP-CIT PET upon initial assessment. Individual motor reserve was estimated based on initial parkinsonian motor symptoms and striatal dopamine transporter availability using a residual model. Patients with low motor reserve (the lowest quartile group, n = 100) exhibited decreased uptake in the occipital region compared to those with high motor reserve (the highest quartile group, n = 100) on early-phase 18F-FP-CIT PET images. Patients with high motor reserve had a lower risk of conversion to dementia than the those with low motor reserve, whereas the effect of PD groups on the risk of dementia conversion was not mediated by occipital hypoperfusion. These findings suggest that cerebral hypoperfusion in the occipital region is associated with low motor reserve in patients with PD.

Abstract Mitochondrial dysfunction plays an important role in Parkinson’s disease (PD), with mitochondrial DNA copy number (mtDNA-CN) emerging as a potential marker for mitochondrial health. We investigated the links between blood mtDNA-CN and PD severity and risk using the Accelerating Medicines Partnership program for Parkinson’s Disease dataset, replicating our results in the UK Biobank. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. We estimated blood cell composition using complete blood cell profile when available or RNA-sequencing data as a surrogate. After adjusting for blood cell composition, the associations between mtDNA-CN and PD risk and clinical symptoms became non-significant. Bidirectional Mendelian randomization analysis also found no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Hence peripheral inflammatory immune responses rather than mitochondrial dysfunction underpin these previously identified associations in PD.

Abstract Calcium ion (Ca2+) homeostasis is crucial for neuron function and neurotransmission. This study focused on the actions mediated by the CB1 receptor (CB1R), the most abundant G protein-coupled receptor (GPCR) in central nervous system (CNS) neurons, over by the AT1R, which is one of the few G protein-coupled CNS receptors able to regulate cytoplasmic Ca2+ levels. A functional interaction suggesting a direct association between these receptors was detected. AT1-CB1 receptor heteromers (AT1CB1Hets) were identified in HEK-293T cells by bioluminescence resonance energy transfer (BRET2). Functional interactions within the AT1-CB1 complex and their potential relevance in Parkinson’s disease (PD) were assessed. In situ proximity ligation assays (PLA) identified AT1CB1Hets in neurons, in which an important finding was that Ca2+ level increase upon AT1R activation was reduced in the presence of cannabinoids acting on CB1Rs. AT1CB1Het expression was quantified in samples from the 6-hydroxydopamine (6-OHDA) hemilesioned rat model of PD in which a lower expression of AT1CB1Hets was observed in striatal neurons from lesioned animals (versus non-lesioned). AT1CB1Het expression changed depending on both the lesion and the consequences of levodopa administration, i.e., dyskinesias versus lack of involuntary movements. A partial recovery in AT1CB1Het expression was detected in lesioned animals that developed levodopa-induced dyskinesias. These findings support the existence of a compensatory mechanism mediated by AT1CB1Hets that modulates susceptibility to levodopa-induced dyskinesias in PD. Therefore, cannabinoids may be useful in reducing calcium dyshomeostasis in dyskinesia.

Abstract Background “Frank autism,” recognizable through the first minutes of an interaction, describes a behavioral presentation of a subset of autistic individuals that is closely tied to social communication challenges, and may be linked to so-called “prototypical autism.” To date, there is no research on frank autism presentations of autistic adolescents and young adults, nor individuals diagnosed with autism spectrum disorder (ASD) in childhood who do not meet diagnostic criteria during or after adolescence (loss of autism diagnosis, LAD). In addition, there are currently no data on the factors that drive frank autism impressions in these adolescent groups. Methods This study quantifies initial impressions of autistic characteristics in 24 autistic, 24 LAD and 26 neurotypical (NT) individuals ages 12 to 39 years. Graduate student and expert clinicians completed five-minute impressions, rated confidence in their own impressions, and scored the atypicality of behaviors associated with impressions; impressions were compared with current gold-standard diagnostic outcomes. Results Overall, clinicians’ impressions within the first five minutes generally matched current gold-standard diagnostic status (clinical best estimate), were highly correlated with ADOS-2 CSS, and were driven primarily by prosodic and facial cues. However, this brief observation did not detect autism in all cases. While clinicians noted some subclinical atypicalities in the LAD group, impressions of the LAD and NT groups were similar. Limitations The brief observations in this study were conducted during clinical research, including some semi-structured assessments. While results suggest overall concordance between initial impressions and diagnoses following more thorough evaluation, findings may not generalize to less structured, informal contexts. In addition, our sample was demographically homogeneous and comprised only speaking autistic participants. They were also unmatched for sex, with more females in the non-autistic group. Future studies should recruit samples that are diverse in demographic variables and ability level to replicate these findings and explore their implications. Conclusions Results provide insights into the behavioral characteristics that contribute to the diagnosis of adolescents and young adults and may help inform diagnostic decision making in the wake of an increase in the demand for autism evaluations later than childhood. They also substantiate claims of an absence of apparent autistic characteristics in individuals who have lost the diagnosis.

Abstract The mechanisms through which systemic inflammation exerts its effect on the central nervous system (CNS) are still not completely understood. Exosomes are small (30 to 100 nm) membrane-bound extracellular vesicles released by most of the mammalian cells. Exosomes play a vital role in cell-to-cell communication. This includes regulation of inflammatory responses by shuttling mRNAs, miRNAs, and cytokines, both locally and systemically to the neighboring as well as distant cells to further modulate the transcriptional and/or translational states and affect the functional phenotype of those cells that have taken up these exosomes. The role of circulating blood exosomes leading to neuroinflammation during systemic inflammatory conditions was hereby characterized. Serum-derived exosomes from LPS-challenged mice (SDEL) were freshly isolated from the sera of the mice that were earlier treated with LPS and used to study the effects on neuroinflammation. Exosomes isolated from the sera of the mice injected with saline were used as a control. In-vitro studies showed that the SDEL upregulate pro-inflammatory cytokine gene expression in the murine cell lines of microglia (BV-2), astrocytes (C8-D1A), and cerebral microvascular endothelial cells (bEnd.3). To further study their effects in-vivo, SDEL were intravenously injected into normal adult mice. Elevated mRNA expression of pro-inflammatory cytokines was observed in the brains of SDEL recipient mice. Proteomic analysis of the SDEL confirmed the increased expression of inflammatory cytokines in them. Together, these results demonstrate and strengthen the novel role of peripheral circulating exosomes in causing neuroinflammation during systemic inflammatory conditions.

Abstract Background Intracranial atherosclerotic disease (ICAD) represents a leading cause of ischemic stroke worldwide, conferring increased risk of recurrent stroke and poor clinical outcomes among stroke survivors. Emerging evidence indicates a paradigm shift, pointing towards increasing detection rates of ICAD among White populations and an evolving epidemiological profile across racial and ethnic groups. The present review aims to provide a comprehensive overview of ICAD, focusing on its pathophysiology, diagnostic approach, and evolving epidemiological trends, including underlying mechanisms, advanced neuroimaging techniques for diagnostic evaluation, racial disparities in prevalence, and current and emerging management strategies. Main body Atherosclerotic plaque accumulation and progressive arterial stenosis of major intracranial arteries comprise the pathophysiological hallmark of ICAD. In clinical practice, the diagnosis of intracranial artery stenosis (ICAS) or high-grade ICAS is reached when luminal narrowing exceeds 50% and 70%, respectively. Advanced neuroimaging, including high-resolution vessel wall MRI (HRVW-MRI), has recently enabled ICAD detection before luminal stenosis occurs. While earlier studies disclosed significant racial disparities in ICAS prevalence, with higher rates among Asians, Hispanics, and Blacks, recent evidence reveals rising detection rates of ICAD among White populations. Genetic, environmental and epigenetic factors have been suggested to confer an increased susceptibility of certain ethnicities and races to ICAD. Nevertheless, with improved accessibility to advanced neuroimaging, ICAD is increasingly recognized as an underlying stroke etiology among White patients presenting with acute ischemic stroke and stroke of undetermined etiology. While conventional management of ICAS entails risk factor modification, pharmacotherapy, and endovascular treatment in selected high-risk patients, substantial progress remains to be made in the management of ICAD at its early, pre-stenotic stages. Conclusion ICAD remains a critical yet underappreciated risk factor for ischemic stroke across all populations, highlighting the need for increased awareness and improved diagnostic strategies. The emerging epidemiological profile of ICAD across racial groups necessitates a reassessment of risk factors, screening protocols and preventive strategies. Future research should focus on refining the diagnostic criteria and expanding the therapeutic options to cover the full spectrum of ICAD, with the aim of improving patient outcomes and reducing the global burden of intracranial atherosclerosis and stroke.

Abstract Background Diagnosing multiple sclerosis (MS) is challenging due to diverse symptoms and the absence of specific biomarkers. Concurrent autoimmune diseases (AID) or non-specific antibodies further complicate diagnosis, progression monitoring, and management. Data on AID prevalence in MS patients are sparse. This study aims to identify concurrent AIDs alongside MS. Methods In this retrospective single-center study, we analyzed patient records at our university hospital from 2010 to 2017, focusing on cases suspected of inflammatory demyelinating disease. The 2017 McDonald criteria were applied. Additionally, we measured neurofilament light (NfL) levels from available CSF samples in our biobank. Results We identified a total of 315 patients, of whom 66% were women. In total, 13.7% of all patients had concurrent AID, while 20.3% had isolated antibody findings without AID. The most common AID was autoimmune thyroiditis (8.9%), followed by chronic inflammatory skin diseases (1.6%), arthritis (1%), type 1 diabetes (1%), Sjögren’s syndrome (0.6%), and inflammatory bowel diseases (0.6%). Cardiolipin antibodies were the most frequent isolated antibody finding (8.6%). Our data showed that, from the perspective of the initial demyelinating event, neither comorbid AID nor isolated antibodies significantly influenced relapses or MS progression over a median follow-up of 9 months. Standard CSF parameters and NfL levels were similar between the groups at the time of MS diagnosis. Conclusion Our study shows that AIDs, particularly autoimmune thyroiditis, frequently occur at the onset of MS. The proportion of AIDs commonly treated with immunomodulatory therapy in our cohort was similar to that observed in the general population. Comorbid AID did not affect NfL levels, indicating similar disease activity. Future research should explore new AID emergence during the course of MS, especially considering the increased incidence of rheumatic diseases later in life.

Abstract Background Central Asia is known to face various ecological challenges that constitutes major risk factors for Parkinson’s disease (PD). This study examines the burden of PD in Central Asia, a region where data on neurological disorders is notably sparse. Methods Building on the latest Global Burden of Disease Study (GBD 2021), this study investigates the Years of Life Lost (YLLs), Years Lived with Disability (YLDs), and Disability-Adjusted Life Years (DALYs) associated with PD in Central Asia and its countries from 1990 to 2021. The authors calculated average annual percent change (AAPC) to analyze trends, and compared individual country estimates to global figures. Additionally, incorporating data from the World Bank, both Bayesian hierarchical and non-hierarchical frequentist regression models were employed to assess their impact on DALYs. Results The DALYs varied across the study period, primarily driven by YLLs. While YLLs showed a uniform trend, YLDs were mostly incremental. Kazakhstan had the highest estimates across all metrics and was the only country aligned with global patterns. Age- and sex-specific estimates revealed substantial variations, with notably high figures found in male subjects from Tajikistan. The YLLs, YLDs, and DALYs for Kazakhstan, Uzbekistan, and Turkmenistan saw a significant increase in AAPCs. In contrast, Kyrgyzstan and Tajikistan saw declines, likely attributable to civic conflict and inter-country differences in population structure. Further comparison of DALY trends revealed significant deviations for all countries from the global pattern. Conclusion This study showed an overall increase in PD burden from 1990 to 2021. These findings underscore the need for targeted strategies to reduce PD burden, with a particular focus on Kazakhstan. Integrating historical information is crucial for discussing the plausible mechanisms in studies sourced from the GBD.

Abstract Background Dynamic spasticity (DS) is a common complication post-spinal cord injury (SCI), marked by intermittent increases in muscle tone during postural transitions or movement. Despite its prevalence, high-quality research on DS incidence, risk factors, and underlying mechanisms in SCI patients remains limited. With the growing application of spinal cord stimulation (SCS) for spasticity control, the role of proprioception in DS development has garnered attention. Additionally, advances in diffusion tensor imaging (DTI) allow for the analysis of the reticulospinal tract’s (RST) role in postural control among SCI patients. However, the impact of microstructural changes in RST and proprioception on DS following SCI remains unclear. Objective To investigate the relationship between microstructural changes in the RST and proprioceptive circuits in SCI patients, exploring their association with DS and potential predictive factors that influence recovery. Methods This is a 12-month prospective cohort study. The neurophysiological and global functional status of the participants will be assessed. Primary outcomes include DTI indices of RST and proprioception, and spasticity assessment. Secondary outcomes include auditory startle reflex (ASR), H-reflex, shear wave velocity (SWV), overall functional status including spinal cord independence measure, gait analysis, modified Barthel Index, and the 36-item short form health survey. Data will be collected at 1, 3, 6, and 12 months after enrolment. Matched healthy controls will be measured during the same period after recruitment. Discussion This study is the first to explore the role of microstructural changes in the RST and proprioception in the assessment and prediction of DS following SCI. The findings aim to enhance theoretical understanding of SCS in spasticity management and to establish pre-treatment criteria for SCS interventions targeting motor function recovery in SCI. Trial registration number ChiCTR2400090724.

Abstract Background The unprecedented increase in the older population and ever-increasing incidence of dementia are leading to a “silver tsunami” in upcoming decades. To combat multimorbidity and maintain daily activities, elderly people face a high prevalence of polypharmacy. However, how these medications affect dementia-related pathology, such as Alzheimer’s β-amyloid (Aβ) fibrils formation, remains unknown. In the present study, we aimed to analyze the medication profiles of Alzheimer’s disease (AD; n = 124), mild cognitive impairment (MCI; n = 114), and non-demented (ND; n = 228) patients to identify highly prevalent drugs and to determine the effects of those drugs on Aβ fibrils formation. Methods Study subjects (≥ 65 years) were recruited from an academic geriatric practice that heavily focuses on memory disorders. The disease state was defined based on the score of multiple cognitive assessments. Individual medications for each subject were listed and categorized into 10 major drug classes. Statistical analysis was performed to determine the frequency of individual and collective drug classes, which are expressed as percentages of the respective cohorts. 10 µM monomeric β-amyloid (Aβ) 42 and fibrillar Aβ (fAβ) were incubated for 6–48 h in the presence of 25 µM drugs. fAβ was prepared with a 1:10 ratio of Aβ42 to Aβ40. The amount of Aβ fibrils was monitored using a thioflavin T (Th-T) assay. Neuronal cells (N2A and SHSY-5Y) were treated with 25 µM drugs, and cell death was measured using a lactose dehydrogenase (LDH) assay. Results We noticed a high prevalence (82–90%) of polypharmacy and diverse medication profiles including anti-inflammatory (65–77%), vitamin and mineral (64–72%), anti-cholesterol (33–41%), anti-hypersensitive (35–39%), proton pump inhibitor (23–34%), anti-thyroid (9–21%), anti-diabetic (5–13%), anti-constipation (9–11%), anti-coagulant (10–13%), and anti-insomnia (9–20%) drugs in the three cohorts. Our LDH assay with 18 highly prevalent drug components showed toxic effects of Norvasc, Tylenol, Colace, and Plavix on N2A cells, and of vitamin D and Novasc on SH-SY5Y cells. All these drugs except Colace significantly reduced the amount of Aβ fibril when incubated with Aβ42 for a short period (6 h). However, Lipitor, vitamin D, Levothyroxine, Prilosec, Flomax, and Norvasc prominently reduce the amount of fibrils when incubated with monomeric Aβ42 for a longer period (48 h). Furthermore, our disaggregation study with fAβ showed consistent results for cholecalciferol (vitamin D), omeprazole (Prilosec), clopidogrel hydrogensulfate (Flomax), levothyroxine, and amlodipine (Norvasc). The chemical structures of these four efficient molecules contain polyphenol components, a characteristic feature of the structures of polyphenolic inhibitors of Aβ fibrillation. Conclusion A higher polypharmacy incidence was observed in an elderly population of 228 ND, 114 MCI, and 124 AD patients. We found that several highly recommended drug components, including vitamin D3, Levothyroxine, Prilosec, Flomax, and Norvasc, efficiently reduce the amount of fibrils formed by monomeric Aβ42 and existing preformed Aβ fibrils in vitro. However, only Levothyroxine was able to prevent Aβ-mediated toxicity to SH-SY5Y cells. Our study suggested that these drugs likely function as polyphenolic inhibitors of Aβ.

Abstract Background Syringomyelia is a rare disease with diverse etiologies, and the syrinx is typically confined to certain segments of the spinal cord. Case of syringomyelia affecting the whole cord due to tethered cord is extremely rare, and the underlying pathophysiological mechanisms remain poorly understood. Case presentation We described an 18-year-old male patient who presented with progressive weakness in both lower extremities and bladder dysfunction over the past four years. Magnetic resonance imaging (MRI) of the entire spine revealed a tethered spinal cord with a large syrinx extending from C1 to L5. Common causes of syrinx such as Chiari malformation, intramedullary tumors and spinal cord injury were systematically ruled out, leading to a strong suspicion that the tethered cord was the primary etiology of the extensive syringomyelia. After undergoing un-tethering surgery, the patient experienced significant symptomatic improvement, and the subsequent follow-up MRI examinations demonstrated a remarkable reduction and eventual resolution of the large syrinx. Conclusions Although rare, tethered cord syndrome can serve as the sole etiology for extensive syringomyelia. For such patients, performing un-tethering surgery can lead to complete resolution of the syrinx and achieve a satisfactory clinical outcome.

Abstract Background Up to 25% of patients suffering from an acute stroke are diagnosed with delirium during the hospital stay, with older age increasing the risk. Generalized slowing in the electroencephalogram (EEG) supports the diagnosis of delirium. We examined the potential of single-channel EEG (DeltaScan®) as an easy-to-use device on intensive care units for detecting delirium. Our aim was to investigate characteristics of bihemispheric EEG recordings and single-channel EEG in patients suffering from strokes with and without delirium and to analyze the diagnostic accuracy of EEG-based diagnoses. Methods Within the first five days after stroke onset, patients received single-channel EEG DeltaScan® and a routine 21-channel EEG. The DeltaScan® analyzes right sided fronto-parietal EEG using a proprietary algorithm focusing on polymorphic delta activity (PDA). In routine EEG the power spectral density (PSD) in predefined frequency bands was analyzed based on 2-minute eyes-closed resting state segments. EEG-analyses were conducted in MNE (v1.3.1) in Python (3.10) and RStudio (v4.2.1). Results In 9 of 53 patients (52–90 years) delirium was diagnosed according to DSM-V criteria. Sensitivity of DeltaScan® was 44% (95% CI = 15.3–77.3%), while specificity was 71% (95% CI = 57–83%). We found patients with right hemispheric stroke having a higher probability to be false positive in DeltaScan® (p = 0.01). The 21-channel EEG based power analysis revealed significant differences in frontal delta and theta power between patients with and without delirium (p

Abstract Background 1,2-dichloroethane (DCE) induced toxic encephalopathy, a rare toxic disease of the central nervous system, is mainly reported in developing countries. Although clinicians have got some understanding about the clinical and neuroimaging features of 1,2-DCE-induced toxic encephalopathy, abnormality along the cortico-medullary junction on diffusion-weighted image (DWI) mimicking neuronal intranuclear inclusion disease (NIID) has not yet been described in this entity. Case presentation We reported a patient with 1,2-DCE-induced toxic encephalopathy who was admitted to our department due to a 7-day history of nausea, vomiting, and cognitive decline. Brain magnetic resonance imaging (MRI) showed symmetrical hyperintensities in bilateral subcortical white matte on T2-weghted and Fluid-attenuated inversion recovery (FLAIR) images. In addition, abnormal signal intensity could also be found in the cortico-medullary junction on DWI, mimicking NIID. After treated with glucocorticoid, dehydrating agents, neuroprotective agents, and hyperbaric oxygen, our patient received a partial recovery. Conclusion Our case highlights a special MRI finding—abnormalities along the cortico-medullary junction—that can be seen in 1,2-DCE-induced toxic encephalopathy. When confronted with patients with lesion located in the cortico-medullary junction and neuropsychiatric symptoms, our clinicians should not neglect the detailed inquiry of history of toxic exposure.

Abstract Background Autoimmune encephalitis (AE) is a disease caused by an abnormal reaction between the body’s autoimmunity and the central nervous system, in which the abnormal immune response targets antigenic components within or on the surface of neuronal cells. The main manifestations are mental and behavioural changes, cognitive impairment, impaired consciousness, seizures, movement disorders, etc. Most cell surface antibodies respond well to immunotherapy, intracellular antibodies, on the other hand, are usually associated with more tumours and are relatively difficult to treat with a poor prognosis. In recent years, autoimmune encephalitis that is positive for multiple anti-neuronal antibodies has been gradually recognized in the clinic, with complex and varied clinical manifestations, especially in combination with malignant tumours, which have worse treatment and prognosis. Current clinical studies on the coexistence of multiple anti-neuronal antibodies in patients with AE are mainly disseminated case reports. Patients with AE in which four anti-neuronal antibodies coexist are even rarer. Case presentation We report a patient who initially presented with an irritating dry cough and hyponatraemia and a chest CT suspicious for malignancy, followed by progressive deterioration of persistent status epilepticus, consciousness and cognitive deficits, and psycho-behavioural abnormalities. Serum and cerebrospinal fluid antibodies against neuronal surface or intracellular antigens were detected using a cell-based assay (CBA) method. Serum and cerebrospinal fluid were found to be positive for anti-GABABR, GAD65, SOX1 and Ma2 antibodies. And a definitive diagnosis of small cell lung cancer was made by immunohistochemistry. He eventually received gammaglobulin, steroid pulsed therapy and tumour chemotherapy. Conclusions The coexistence or overlap of multiple anti-neuronal surface antibodies with anti-neuronal intracellular antibodies is rare and increases the likelihood of underlying malignancy. Elucidating the impact of individualized immunotherapy and coexisting antibodies on the clinical presentation of patients has the potential to improve long-term prognosis.

Abstract Background This case report presents the case of a patient with P369S and R408Q variants in the MEFV gene who exhibited clinical features of Kikuchi disease and Mollaret meningitis. Furthermore, it discusses colchicine as a new potential treatment option for Kikuchi disease-associated meningitis. Case presentation A 41-year-old Japanese woman presented with fever and headache. She had nuchal rigidity and bilateral cervical lymphadenopathies. Her past medical history included multiple episodes of aseptic meningitis and cervical lymphadenopathy for more than twenty years. Lumbar puncture showed increased lymphocytes and IL-6 level and pathognomonic Mollaret cells. Excisional lymph node biopsy revealed histiocytic necrotizing lymphadenitis, confirming the diagnosis of Kikuchi disease. Subsequently, her recurrent Kikuchi disease and meningitis were successfully treated with colchicine. Furthermore, genetic analysis of the MEFV gene revealed heterozygous P369S/R408Q variants in exon 3. Conclusion Mollaret meningitis can be associated with Kikuchi disease, and recurrence of both conditions may be suppressed by colchicine when these two coexist.