Passive Anti-Amyloid Beta Immunotherapies in Alzheimer's Disease: From Mechanisms to Therapeutic Impact.

Alzheimer's disease, the most common type of dementia worldwide, lacks effective disease-modifying therapies despite significant research efforts. Passive anti-amyloid immunotherapies represent a promising avenue for Alzheimer's disease treatment by targeting the amyloid-beta peptide, a key pathological hallmark of the disease. This approach utilizes monoclonal antibodies designed to specifically bind amyloid beta, facilitating its clearance from the brain. This review offers an original and critical analysis of anti-amyloid immunotherapies by exploring several aspects. Firstly, the mechanisms of action of these therapies are reviewed, focusing on their ability to promote Aß degradation and enhance its efflux from the central nervous system. Subsequently, the extensive history of clinical trials involving anti-amyloid antibodies is presented, from initial efforts using first-generation molecules leading to mixed results to recent clinically approved drugs. Along with undeniable progress, the authors also highlight the pitfalls of this approach to offer a balanced perspective on this topic. Finally, based on its potential and limitations, the future directions of this promising therapeutic strategy for Alzheimer's disease are emphasized.

Autoimmune and Non-Autoimmune Comorbidities in Myasthenic Patients of East-European Descent: A Case-Control Study.

Background: As the life expectancy of patients with myasthenia gravis (MG) is improving, so the number of comorbidities continues to rise, with a potentially significant impact on the overall morbidity and mortality. The main aim of the study was to assess comorbidities of MG in a group of patients of East-European descent. Methods: We retrospectively compared 185 adult myasthenic patients with 895 sex- and age-matched controls, admitted from January 2013 to December 2021. Results: Of these patients, 60% had late-onset MG (LOMG), with a clear predominance of women in both the LOMG and early-onset (EOMG) types; and 23.8% of the patients had a radiological description consistent with thymoma. All myasthenic patients had at least one comorbidity; 20 (10.8%) of the patients associated at least one autoimmune comorbidity. Obesity (p < 0.01), type 2 diabetes (p < 0.0001), cerebrovascular diseases (p < 0.0001), essential hypertension (p < 0.01), and cardiac arrythmias (p < 0.0001) were more frequent in patients than in the control group. The granulocyte-to-lymphocyte ratio was higher in the myasthenic patients compared to the controls (p < 0.01 for LOMG). Discussion: We, thus, suggest a common chronic low-grade inflammatory background as a possible connection between MG subtypes and some of these apparently unconnected comorbidities. Conclusions: The East-European origin of the patients offered a different social and cultural angle of a disease studied mainly on populations of West-European and Asian descent.

Migraine Comorbidities.

Novel knowledge about the interrelationships and reciprocal effects of migraine and epilepsy, migraine and mood disorders, or migraine and irritable bowel syndrome has emerged in recent decades. Over time, comorbid pathologies associated with migraine that share common physiopathological mechanisms were studied. Among these studied pathologies is epilepsy, a disorder with common ion channel dysfunctions as well as dysfunctions in glutamatergic transmission. A high degree of neuronal excitement and ion channel abnormalities are associated with epilepsy and migraine and antiepileptic drugs are useful in treating both disorders. The coexistence of epilepsy and migraine may occur independently in the same individual or the two may be causally connected. The relationship between cortical spreading depression (CSD) and epileptic foci has been suggested by basic and clinical neuroscience research. The most relevant psychiatric comorbidities associated with migraine are anxiety and mood disorders, which influence its clinical course, treatment response, and clinical outcome. The association between migraine and major depressive disorder can be explained by a robust molecular genetic background. In addition to its role as a potent vasodilator, CGRP is also involved in the transmission of nociception, a phenomenon inevitably linked with the stress and anxiety caused by frequent migraine attacks. Another aspect is the role of gut microbiome in migraine's pathology and the gut-brain axis involvement. Irritable bowel syndrome patients are more likely to suffer migraines, according to other studies. There is no precise explanation for how the gut microbiota contributes to neurological disorders in general and migraines in particular. This study aims to show that migraines and comorbid conditions, such as epilepsy, microbiota, or mood disorders, can be connected from the bench to the bedside. It is likely that these comorbid migraine conditions with common pathophysiological mechanisms will have a significant impact on best treatment choices and may provide clues for future treatment options.

Default mode function in patients with generalised epilepsy syndromes: from generalised to focal findings.

INTRODUCTION: Many recent studies have suggested that generalised epilepsy is associated with cortical epileptogenic focus, and therefore distinguishing between focal and generalised often becomes difficult. AIM OF STUDY: We aimed to detect differences between default mode function in patients with idiopathic generalised epilepsy who have discharges on EEG, and healthy persons. MATERIAL AND METHODS: This was a case-control study; we performed EEG analysis with LORETA in 17 patients with a type of generalised epilepsy and a control group represented by 17 healthy age-matched persons. We performed statistical non- -parametric tests for current density electrical distribution for our two groups ('t-statistic on Log transformed data') and we defined regions of interest (ROIs) from the default mode network. In the second part, we compared the average activation for each ROI for each timeframe in the epoch for the group with epilepsy, and for controls (we performed a Wilcoxon rank-sum test for two means). RESULTS: In the first part, we obtained that in the medial frontal gyrus (BA 9) delta oscillations significantly differed in patients with epilepsy who had electrical discharges on EEG in resting state conditions compared to healthy controls (medial frontal gyrus in this group had a greater number of synchronously oscillating neurons than did the controls). In the second part, we ran statistics on our localised activity from the default mode network (defined ROIs) and we obtained statistically significant differences in the left medial frontal gyrus (the values were higher for the group with epilepsy, p-value = 0.0066). CONCLUSIONS AND CLINICAL IMPLICATIONS: It may be possible to move from a 'generalised theory' about epilepsy to a 'focused theory' by understanding how various areas of interest are activated within default mode networks. Insights into the pathophysiology of generalised epilepsy may lead to new treatment options.

Autoimmune myasthenia gravis and COVID-19. A case report-based review.

A potential relationship between COVID-19 infection and new onset myasthenia gravis (MG) has been suggested by the coexistence of these two diseases in a number of reports. This study aimed to assess their relationship by reviewing case studies of COVID-19 followed by new onset MG published between 01 December 2019 and 30 June 2023 identified by a search of PubMed/Medline database. In addition, we reviewed evidence in favour and against a potential cause and effect association, and described possible mechanisms that would underpin such a relationship. We identified 14 publications that reported 18 cases. Analysis showed the following features: age 19-83 years; 10 men/8 women; median time interval between COVID-19 and MG (17, 5-56 days); autoimmune comorbidities (4); generalised MG (14); ocular MG (4); thymoma (3); antiacetylcholine receptor antibody (16); antimuscle-specific kinase antibodies (2). All patients improved following treatment. Proof of direct causality between the two conditions can only be established in time by confirming epidemiological increase in the incidence of MG or elucidating pathogenic mechanisms to substantiate a possible cause-effect association, or both.

The circadian rhythm of arterial blood pressure in Alzheimer's disease and vascular dementia.

Hypertension is considered a risk factor for stroke and dementia. Ambulatory blood pressure monitoring (ABPM) is a useful tool in the diagnosis and treatment of hypertension. This study aimed to evaluate blood pressure using ABPM, in 30 Alzheimer's disease (AD) patients and 30 vascular dementia (VaD) patients in comparison with 30 healthy controls. BP was recorded every 15 min from 6 AM to 10 PM, and every 30 min from 10 PM to 6 AM. Mean systolic (SBP) and diastolic (DBP) blood pressure during daytime, nighttime, diurnal index, pulse pressure, and heart rate were extracted from the ABPM recordings. VaD patients presented higher SBP values compared to AD patients and healthy controls. DBP values in the AD group were the lowest, while VaD patients presented the highest DBP values, including day and nighttime. Mean arterial pressure values were also the highest in the VaD group, while AD patients had similar values with the control group. The VaD patients presented the lowest systolic diurnal index compared to AD patients and controls. The mean pulse pressure and nighttime pulse pressure values were higher in both groups of dementia patients when compared with the control group. Increased SBP, pulse pressure, and alteration in the circadian pattern with the highest incidence of the non-dipper and reverse dipper patterns were found in patients with dementia when compared with the healthy elderly. Also, decreased values of DBP were found in AD patients, especially during the night period.

Cortical connectivity in stroke using signals from resting-state EEG: a review of current literature.

INTRODUCTION: Stroke is considered a substantial cause of disability worldwide and many researches are focused on rehabilitative interventions. Functional magnetic resonance imaging studies centered on brain networks after stroke describe affected functional connectivity between areas within the default mode, sensorimotor, visual, fronto-parietal and executive networks. Recent studies renewed the perspective of utilizing electroencephalography to describe markers of cortical activity in stroke and recovery neurophysiological processes. METHODS: We included in our research studies realized on patients that had an ischemic or hemorrhagic stroke that performed electroencephalography and had an analysis of connectivity indices. Resting-state electroencephalography has the advantage of including patients with any neurological deficit and it is easier to perform than the task-based variant. The changes in resting-state EEG networks after stroke are important to determine a relationship between frequency cortical activity and spatial conformation of a network. From conventional to quantitative EEG analysis in stroke, these techniques are improved with additional brain connectivity tools that lead to a better characterization between injured areas and other intra- and inter-hemispheric areas. RESULTS: There are studies that underline the disruptions in local networks in a frequency-dependent modality after stroke, while other results are focused on bilateral changes in resting-state cortical networks, independent of the side of the lesions. CONCLUSIONS: Many studies found alterations in various connectivity measures after stroke with the help of EEG, but the clinical significance of these findings is a field of increasing interest in research area.

Autoimmune myasthenia gravis after COVID-19 in a triple vaccinated patient.

Despite a well characterized mechanism, myasthenia gravis (MG) remains a dilemma in terms of etiology. Several case reports and series of cases suggest a potential cause-effect relation between SARS-CoV-2 infection or vaccination and MG. We present the case of an autoimmune MG occurring post Covid-19 in an elderly male, vaccinated with three doses of the BNT162b2/Pfizer-BioNTech vaccine. The 78-year-old male was admitted in the Neurology Clinic in early November 2021 with double vision, bilateral ptosis, dysphonia and dysphagia, 16 days after receiving a third dose of the BNT162b2/Pfizer-BioNTech SARS-CoV-2 vaccine and 12 days after testing positive for SARS-CoV-2 infection. The symptoms began to emerge at 9 days after COVID-19 diagnosis. Clinical neurological examination included ice-pack test and intramuscular neostigmine, both with positive results. Myasthenia gravis positive diagnosis was confirmed by slow repetitive nerve stimulation and abnormally increased serum levels of antibodies against acetylcholine receptors. Due to patient's refusal of further hospitalization, he was discharged with therapy recommendations. Under treatment with oral pyridostigmine, but no oral corticosteroid due to therapeutic noncompliance, the patient was readmitted two months later with aggravated symptoms. The myasthenic crisis was successfully treated with intravenous immunoglobulins, corticosteroid therapy and oral pyridostigmine. The novelty of the current case resides in the fact that, to the best of our knowledge, appears to be the first case of MG clinically manifested after COVID-19 infection in a fully vaccinated patient.

Cardiac autonomic modulation in drug-resistant epilepsy patients after vagus nerve stimulation therapy.

The positive effect of vagus nerve stimulation (VNS) in patients with drug-resistant epilepsy is considered to be mediated by the afferent pathways of the vagus nerve, but the efferent pathways may influence the cardiac autonomic activity. AIM OF THE STUDY: To assess the effects of VNS on cardiac autonomic modulation in epilepsy patients, over three months of neurostimulation. CLINICAL RATIONALE FOR THE STUDY: Linear and non-linear heart rate variability (HRV) analysis can provide information on the sympathovagal balance and reveal particularities of the central control of the autonomic cardiovascular function. MATERIALS AND METHODS: Using Biopac Acquisition System, we analysed HRV parameters in resting condition and during sympathetic and parasympathetic activation tests in five patients with drug-resistant epilepsy, who underwent VNS procedure. RESULTS: During the sympathetic and vagal activation tests, all five patients presented normal responses of cardiac autonomic activity, reflected in RMSSD, HFnu and LF/HF dynamics in both HRV evaluations. No bradycardia, cardiac arrhythmia or orthostatic hypotension was registered during the two evaluations. CONCLUSIONS: Our results indicate that VNS appears not to alter the cardiac autonomic function after three months of neurostimulation. HRV analysis is a useful tool for evaluating cardiac autonomic modulation in epilepsy patients during VNS therapy. CLINICAL IMPLICATIONS: Patients with decreased HRV should be periodically monitored. Cardiac changes in patients with epilepsy are important because of the additional risk of arrhythmias mediated through the autonomic dysfunction.

Heart Rate Variability Analysis: A Useful Tool to Assess Poststroke Cardiac Dysautonomia.

BACKGROUND: Neurogenic heart syndrome represents a phenomenon often encountered in clinical practice after ischemic stroke. Further poststroke cardiovascular complications are possibly related to cardiac autonomic dysregulation. Multiple Trigonometric Regressive Spectral (MTRS) analysis of the heart rate variability (HRV) allows a precise evaluation of cardiovascular modulation under different conditions. OBJECTIVES: This research aims to evaluate the impact of the middle cerebral artery (MCA) ischemic stroke on cardiac autonomic function, using the MTRS analysis of HRV, during sympathetic and parasympathetic activation tests. METHODS: The authors analyzed HRV parameters in 20 patients who had a right and 20 who had a left MCA ischemic stroke, under rest condition and during autonomic activation tests (deep breathing and standing tests). Data were compared with 20 age-matched and sex-matched healthy controls. RESULTS: Patients who had a right MCA ischemic stroke presented a decreased vagal modulation of the heart rate compared with healthy controls and patients who had a left MCA ischemic stroke, in resting state and during autonomic activation tests. Decreased root mean square of the successive differences, pNN50, high frequency, and high-frequency normalized units values (P<0.05) and increased low frequency/high frequency ratio (P<0.05) in resting state and during autonomic activation tests in patients who had a right MCA stroke indicate a sympathetic predominance in the control of the heart rate. The parasympathetic activation test did not change the sympathovagal balance in this group of patients. CONCLUSIONS: The autonomic nervous system represents an attractive target for the therapeutic approach. As MCA ischemic stroke, especially in the right hemisphere, seems to cause significant long-lasting autonomic dysregulation, implementing early pharmacological or nonpharmacological intervention for autonomic restoration may improve the outcome of patients who had an ischemic stroke.

Heart rate variability analysis and cardiac dysautonomia in ischemic stroke patients.

OBJECTIVES: Autonomic nervous system dysfunction after ischemic stroke predisposes to cardiovascular complications. We aimed to investigate cardiac autonomic activity in ischemic stroke patients using heart rate variability analysis, illustrating the sympathovagal balance at different sympathetic and parasympathetic activation tests. PATIENTS AND METHODS: We studied the dynamics of the linear and non-linear heart rate variability parameters in 31 left and 40 right middle cerebral artery ischemic stroke patients in rest condition and during autonomic activation tests (handgrip, standing, deep breathing and Valsalva maneuver). Data were compared with 30 age- and sex-matched healthy controls. RESULTS: We found different responses after autonomic activation tests in stroke patients depending on the cortical lateralization of the ischemic lesion. In resting state, left hemisphere stroke patients presented enhanced parasympathetic modulation of the heart rate (higher values for RMSSD, pNN50, HF and SD1, p < 0.05), comparing to right hemisphere stroke patients. This second group displayed a reduced cardiac parasympathetic control in resting state and during autonomic activation tests (handgrip and standing tests) compared to the left hemisphere stroke group and controls. Non-linear parameters SD1 and DFA α1 showed a decrease of variability and complexity of the heart rate in right hemisphere stroke patients, ameliorated during vagal activation tests. CONCLUSION: To prevent possible complications with vital risk, assessment of cardiovascular autonomic activity becomes a necessary stage in stroke patient management, facilitating immediate implementation of preventive and therapeutic strategies. Heart rate variability analysis in resting state and during autonomic activation tests allows identifying patients prone to sympathetic hyperactivity. New therapeutic perspectives for stroke management may emerge founded on the modulation of the autonomic nervous system.

Heart Rate Variability and Vagus Nerve Stimulation in Epilepsy Patients.

BACKGROUND: Vagus nerve stimulation (VNS) exerts a cortical modulating effect through its diffuse projections, especially involving cerebral structures related to autonomic regulation. The influence of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients is still debated. We aimed to evaluate the impact of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients, after three months of neurostimulation, using the heart rate variability (HRV) analysis. METHODOLOGY: Multiple Trigonometric Regressive Spectral analysis enables a precise assessment of the autonomic control on the heart rate. We evaluated time and frequency-domain HRV parameters in resting condition and during sympathetic and parasympathetic activation tests in five epilepsy patients who underwent VNS procedure. RESULTS: We found appropriate cardiac autonomic responses to sympathetic and parasympathetic activation tests, described by RMSSD, pNN50, HF and LF/HF dynamics after three months of VNS. ON period of the neurostimulation may generate a transient vagal activation reflected on heart rate and RMSSD values, as observed in one of our cases. CONCLUSION: VNS therapy in epilepsy patients seems not to disrupt the cardiac autonomic function. HRV represents a useful tool in evaluating autonomic activity. More extensive studies are needed to further explore cardiac autonomic response after neurostimulation.

Cortical modulation of cardiac autonomic activity in ischemic stroke patients.

The cardiovascular system is regulated by the autonomic nervous system, under cortical modulation. Stroke can induce cardiac autonomic imbalance, therefore, causing secondary cardiovascular complications. Heart rate variability (HRV) analysis is a simple method to appraise the autonomic nervous function. The purpose of this study was to investigate the cardiac autonomic activity in patients that suffered an ischemic stroke in middle cerebral artery (MCA) territory. Using Biopac Acquisition System, we monitored ECG in rest condition and during Ewing's tests. From these measurements, HRV parameters (using time and frequency domain analysis) were determined in 20 right MCA and 20 left MCA ischemic stroke patients, in the first 6 months after the acute event. Data were compared with 20 age- and sex-matched healthy controls. All the patients were right handed. In ischemic stroke patients, HRV parameters were significantly modified compared to controls (p < 0.05) and we found asymmetric responses to different stimulation autonomic tests between right and left hemisphere. Parameters illustrating the parasympathetic predominance in time domain (RMSSD) and frequency domain (HF) analysis were higher in left hemisphere stroke compared to right hemisphere stroke patients (p < 0.01) in resting state. From Ewing's battery test, patients with left hemisphere ischemic stroke showed predominance of parasympathetic activity to deep breathing (p < 0.01), while HRV parameters in right hemisphere ischemic stroke patients described a reduced cardiac parasympathetic innervation (p < 0.01). Cardiac autonomic imbalance occurs more often after right hemisphere ischemic stroke. HRV study may highlight cardiac dysfunctions that increase the risk of cardiovascular complications and portends a poor long-term outcome.