Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aβ) load in patients with Alzheimer’s disease. We applied focused ultrasound with each of six monthly aducanumab infusions to ...temporarily open the blood–brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aβ was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment. (Funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.)
In three patients with Alzheimer’s disease, focused ultrasound was applied with aducanumab therapy. Reduction in amyloid was greater in treated regions than in matched contralateral regions over 6 months.
Background:
Post-stroke depression (PSD) affects up to 50% of stroke survivors, reducing quality of life, and increasing adverse outcomes. Conventional therapies to treat PSD may not be effective for ...some patients. Repetitive transcranial magnetic stimulation (rTMS) is well-established as an effective treatment for Major Depressive Disorder (MDD) and some small trials have shown that rTMS may be effective for chronic PSD; however, no trials have evaluated an accelerated rTMS protocol in a subacute stroke population. We hypothesized that an accelerated rTMS protocol will be a safe and viable option to treat PSD symptoms.
Methods:
Patients (
N
= 6) with radiographic evidence of ischemic stroke within the last 2 weeks to 6 months with Hamilton Depression Rating Scale (HAMD-17) scores >7 were recruited for an open label study using an accelerated rTMS protocol as follows: High-frequency (20-Hz) rTMS at 110% resting motor threshold (RMT) was applied to the left dorsolateral prefrontal cortex (DLPFC) during five sessions per day over four consecutive days for a total of 20 sessions. Safety assessment and adverse events were documented based on the patients' responses following each day of stimulation. Before and after the 4-days neurostimulation protocol, outcome measures were obtained for the HAMD, modified Rankin Scale (mRS), functional independence measures (FIM), and National Institutes of Health Stroke Scales (NIHSS). These same measures were obtained at 3-months follow up.
Results:
HAMD significantly decreased (Wilcoxon
p
= 0.03) from M = 15.5 (2.81)−4.17 (0.98) following rTMS, a difference which persisted at the 3-months follow-up (
p
= 0.03). No statistically significant difference in FIM, mRS, or NIHSS were observed. No significant adverse events related to the treatment were observed and patients tolerated the stimulation protocol well overall.
Conclusions:
This pilot study indicates that an accelerated rTMS protocol is a safe and viable option, and may be an effective alternative or adjunctive therapy for patients suffering from PSD. Future randomized, controlled studies are needed to confirm these preliminary findings.
Clinical Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT04093843
.
The blood-brain barrier (BBB) limits therapeutic delivery in Alzheimer's disease (AD) and other neurological disorders. Animal models have demonstrated safe BBB opening and reduction in β-amyloid ...plaque with focused ultrasound (FUS). We recently demonstrated the feasibility, safety, and reversibility of FUS-induced BBB opening in the hippocampus and entorhinal cortex in six participants with early AD. We now report the effect of BBB opening with FUS treatment on β-amyloid plaque. Six participants underwent
F-Florbetaben PET scan at baseline and 1 week after the completion of the third FUS treatment (60 days interval). PET analysis comparing the hippocampus and entorhinal cortex in the treated and untreated hemispheres revealed a decrease in the ratio of
F-Florbetaben ligand binding. The standard uptake value ratios (SUVr) reduction ranged from 2.7% to 10% with an average of 5.05% (±2.76) suggesting a decrease in β-amyloid plaque.
Purpose of Review
People with migraine disease face many challenges, and these challenges can be magnified when someone is part of an “underserved” population. We set out to examine various ...categories of “underserved” populations, consider the unique challenges faced by these groups, and discuss mechanisms to mitigate these challenges as much as possible.
Recent Findings
Very little research has been performed to specifically evaluate underserved populations related to people with migraine disease. Recent research has shown the overall limitations of limited numbers of physicians with specialty training in headache disorders, and the socioeconomic implications of migraine disease have long been reported.
Summary
Even the definition of “underserved” is not completely clear. We undertook to define this concept in the setting of migraine disease, breaking into different categories, including financial, geographic, and cultural/racial. Each underserved population has both shared and unique challenges, and in reality, given the paucity of medical expertise throughout the United States, one could make the argument that nearly all people with migraine disease are at risk for being underserved. In the future, epidemiologic as well as therapeutic research should incorporate analyses of these and any other underserved population to improve the application of study results across broad and varied populations whose commonality, in many cases, ends with sharing the same disease.
Background
Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been ...identified.
Methods
We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS.
Results
Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed.
Conclusion
Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The spectrum of chronic urticaria Najib, Umer; Sheikh, Javed
Allergy and asthma proceedings,
01/2009, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Chronic urticaria is a common heterogeneous condition that can be quite debilitating. There are a number of potential causes of urticaria, and the severity and clinical pattern can vary considerably ...from patient to patient. Eighty to 90% of patients with chronic urticaria have no specific external cause for their disease, which is therefore labeled "chronic idiopathic urticaria." We now know, however, that up to 30-50% of idiopathic cases may be autoimmune or related to mast cell and basophil abnormalities. There is evidence of an autoantibody to the high-affinity receptor for IgE (FcepsilonRI), specifically binding to the alpha-chain (FcepsilonRIalpha), which may be pathogenic. At this point in time, the gold standard for detecting clinically relevant autoantibodies to FcepislonRI is the functional in-vitro donor basophil histamine release assay. The exact prevalence and role of these autoantibodies is still under investigation. Histamine antagonists are the mainstays of therapy. For patients whose symptoms are not controlled by antihistamines alone, there are a number of adjunct therapy options, but there is still a need to develop better agents for this disease.
Transcranial magnetic stimulation (TMS) is a useful tool to induce and measure plasticity in the human brain. However, the cortical effects are generally indirectly evaluated with motor‐evoked ...potentials (MEPs) reflective of modulation of cortico‐spinal excitability. In this study, we aim to provide direct measures of cortical plasticity by combining TMS with electroencephalography (EEG). Continuous theta‐burst stimulation (cTBS) was applied over the primary motor cortex (M1) of young healthy adults, and we measured modulation of (i) MEPs, (ii) TMS‐induced EEG evoked potentials (TEPs), (iii) TMS‐induced EEG synchronization and (iv) eyes‐closed resting EEG. Our results show the expected cTBS‐induced decrease in MEP size, which we found to be paralleled by a modulation of a combination of TEPs. Furthermore, we found that cTBS increased the power in the theta band of eyes‐closed resting EEG, whereas it decreased single‐pulse TMS‐induced power in the theta and alpha bands. In addition, cTBS decreased the power in the beta band of eyes‐closed resting EEG, whereas it increased single‐pulse TMS‐induced power in the beta band. We suggest that cTBS acts by modulating the phase alignment between already active oscillators; it synchronizes low‐frequency (theta and/or alpha) oscillators and desynchronizes high‐frequency (beta) oscillators. These results provide novel insight into the cortical effects of cTBS and could be useful for exploring cTBS‐induced plasticity outside of the motor cortex.
Continuous theta‐burst stimulation applied to the motor cortex is a noninvasive brain stimulation protocol suppressing activity in the stimulated area. We show that cTBS (i) modulates a combination of TMS‐evoked EEG potentials, providing a measure of excitability; (ii) decreases TMS‐induced and increased resting oscillations in theta band, and has the opposite effects in beta band, consistent with hypothetical (de)synchronization mechanisms of active oscillators. Thus, cTBS exerts a complex, system‐level impact on the brain.
Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. ...Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD).
At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI.
Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant.
FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics.
ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.
Multiple lines of evidence from genetic linkage studies to animal models implicate aberrant cortical plasticity and metaplasticity in the pathophysiology of autism spectrum disorder (ASD) and fragile ...X syndrome (FXS). However, direct experimental evidence of these alterations in humans with these disorders is scarce. Transcranial magnetic stimulation (TMS) is a noninvasive tool for probing mechanisms of plasticity and metaplasticity in vivo, in humans. The aim of the current study was to examine mechanisms of plasticity and metaplasticity in humans with ASD and FXS. We employed a repetitive TMS protocol developed specifically to probe cortical plasticity, namely continuous theta burst stimulation (cTBS).
We applied a 40-second train of cTBS to primary motor cortex (M1) to healthy control participants and individuals with ASD or FXS, and we measured the cTBS-induced modulation in motor-evoked potentials (MEPs) in a contralateral intrinsic hand muscle. Each participant completed two sessions of the same protocol on two consecutive days. The degree of modulation in MEPs after cTBS on the first day was evaluated as a putative index of cortical plasticity. Examination of the changes in the effects of cTBS on the second day, as conditioned by the effects on the first day, provided an index of metaplasticity, or the propensity of a given cortical region to undergo plastic change based on its recent history.
After a 40-second cTBS train, individuals with ASD show a significantly longer duration of suppression in MEP amplitude as compared with healthy controls, whereas individuals with FXS show a significantly shorter duration. After a second train of cTBS, 24 hours later, the ASD group was indistinguishable from the control group, and while in the FXS group MEPs were paradoxically facilitated by cTBS.
These findings offer insights into the pathophysiology of ASD and FXS, specifically providing direct experimental evidence that humans with these disorders show distinct alterations in plasticity and metaplasticity, consistent with the findings in animal models. If confirmed in larger test-retest studies, repeated TMS measures of plasticity and metaplasticity may provide a valuable physiologic phenotype for ASD and FXS.
This case report investigates the potential use of metabolism as a sensitive biomarker in monitoring the effectiveness of anti-amyloid therapy in a patient with mild cognitive impairment due to early ...Alzheimer's disease. The study centers around a 74-year-old male patient treated with aducanumab, a monoclonal antibody developed for anti-amyloid therapy. Alongside an expected decline in cerebral amyloid monitored using PET amyloid tracers, we observed significant improvements in the patient's brain metabolic activity, measured via 18-fluorodeoxyglucose positron emission tomography (FDG PET). Despite limitations posed by the single-patient case study, the findings invite further research and consider the utilization of FDG PET as a surrogate for clinically meaningful changes in the treatment of early Alzheimer's disease. These findings suggest the potential for more personalized and effective therapeutic interventions.
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