Areas Of Central Nervous System Research Articles

Differential efficacy of SV-BR-1-GM in inducing intracranial metastasis regression.

e13119 Background: Breast cancer metastasis to the central nervous system (CNS) and intracranial area often leads to severe morbidity and mortality. While systemic treatments manage systemic tumors, their impact on CNS/intracranial metastases is limited. Cell based therapies like SV-BR-1-GM may overcome this limitation. SV-BR-1-GM is a GM-CSF secreting, antigen-presenting immortalized breast cancer cell line. We report its efficacy on CNS tumor regression. Methods: Post-hoc analysis of a subset of all advanced MBC patients with CNS/intracranial metastases from previous phase 1, 2, and an ongoing randomized phase 2, trials (n=7 subjects) of SV-BR-1-GM. Bria-IMT monotherapy (intradermal SV-BR-1-GM + cyclophosphamide 300 mg/m2, +interferon-alpha) was administered q3wks to 2 subjects; an immune checkpoint inhibitor (ICI) was administered with each cycle in the combination setting (n=5). Results: There were 7 patients with intracranial metastases at baseline of whom 5 had intracranial tumor responses. Of the 5 responders, median pt age = 66 (range 58-70), median prior lines = 5.5 (3-13), and median time from initial diagnosis = 7.5 years (3-10). 4/5 pts had ≥1 HLA class match with SV-BR-1-GM. 3 were HR + and 1 HER2 +. Pt A002 (ER+/PR+, HER2-) received 6/6 planned cycles, achieving an 83% reduction in breast lesions; after 3 months off therapy, imaging revealed multiple brain metastases and recurrence of right breast lesions. Following 3 additional cycles there was marked regression in both brain and breast lesions. Pt 02-003 (ER-/PR-, HER2 1+ (IHC)) received 5 cycles of SV-BR-1-GM and observed a 60% reduction (5mm -> 2mm) in a left parietal periventricular lesion, and complete resolution (CR) of a left parietal lobe. Pt 06-005 (ER+/PR-, HER2 1+) demonstrated a 56% (9mm -> 4mm) reduction in the thickness of a dural lesion overlying the left anterior temporal lobe after 6 cycles of SV-BR-1-GM + ICI. After 2 additional cycles of SV-BR-1-GM + ICI and 1 cycle of SV-BR-1-GM (ICI skipped on final cycle due to grade 2 AE), patient achieved CR of a left orbital mass observed at baseline (24mm -> 0m). Pt06-007’s (ER-/PR-, HER2 1+) CNS lesions showed a median reduction of 49% compared to baseline after 3 cycles. Pt 11-018 (ER+/PR-, HER2 +) showed standard progression (SD) at initial restaging; 14% increase in sum of diameters of intracranial metastasis. Subsequent imaging, after 3 cycles, showed significant orbital tumor reduction along with reported improvement in eye pain. Conclusions: This post-hoc analysis demonstrated promising efficacy of the Bria-IMT regimen either alone or in combination with ICIs in CNS/intracranial metastasis. The CNS/intracranial regression seen across all breast cancer subtypes among heavily pretreated patients highlights the potential of SV-BR-1-GM in managing CNS metastasis. Ongoing trials will further evaluate the efficacy of the Bria-IMT regimen in patients with CNS/intracranial metastasis. Clinical trial information: NCT03328026 .

Understanding upper-limb movements via neurocomputational models of the sensorimotor system and neurorobotics: where we stand

Roboticists and neuroscientists are interested in understanding and reproducing the neural and cognitive mechanisms behind the human ability to interact with unknown and changing environments as well as to learn and execute fine movements. In this paper, we review the system-level neurocomputational models of the human motor system, and we focus on biomimetic models simulating the functional activity of the cerebellum, the basal ganglia, the motor cortex, and the spinal cord, which are the main central nervous system areas involved in the learning, execution, and control of movements. We review the models that have been proposed from the early of 1970s, when the first cerebellar model was realized, up to nowadays, when the embodiment of these models into robots acting in the real world and into software agents acting in a virtual environment has become of paramount importance to close the perception-cognition-action cycle. This review shows that neurocomputational models have contributed to the comprehension and reproduction of neural mechanisms underlying reaching movements, but much remains to be done because a whole model of the central nervous system controlling musculoskeletal robots is still missing.

Stereotactic radiosurgery for the treatment of a distant recurrence of ependymoma on the optic nerve: illustrative case.

Ependymomas rarely disseminate to other central nervous system areas distant from the original site. Stereotactic radiosurgery (SRS) provides high control rates for recurring ependymomas. The treatment of optic nerve tumors carries high morbidity, but SRS is an acceptable option to manage these cases to reduce risks. The authors report the case of a 31-year-old male with a cervical spinal ependymoma who had a disseminated pattern of recurrence including the optic nerve after initial resection of the cervical lesion. The optic nerve tumor was treated with SRS, and the authors discuss the technical aspects of the treatment and its outcomes. At the last follow-up, the optic nerve tumor was controlled with SRS, and visual function was preserved. High-grade ependymomas such as the one in the presented case can have unpredictable patterns of recurrence. SRS provides excellent control of the distant recurring ependymoma with a low complication profile given the location of the tumor in this case.

Cognition and psychological wellbeing in hypopituitary patients.

Hypopituitarism (HP) frequently occurs in patients presenting with sellar masses and despite recent advances in therapeutic options, HP patients consistently suffer from impaired quality of life due to psychological distress and cognitive dysfunction. These neurocognitive complications tend to persist in spite of surgical or biochemical remission of the disease making it especially challenging to segregate the effect of HP per se from other comorbidities such as the effect of tumour, surgery, radiation therapy, or complications caused by excess hormone production. Regardless, there is ample evidence to suggest that receptors for various pituitary hormones are abundantly expressed in key areas of central nervous system that are associated with memory and behaviour function and HP is also associated with poor sleep which can further exacerbate neurocognitive dysfunction. There is also evidence that hormonal replacement in HP patients partially restores these neurocognitive functions and improves sleep disorders. However, there is a need for creating better awareness among healthcare providers interacting with HP patients to enhance an earlier recognition of these disorder and their impact on quality of life despite initial remission. Importantly, there is a need to not only develop better and more cost-effective replacement therapies that would closely mimic the physiological hormonal release patterns, but also develop coping strategies for HP patients suffering from these complications.

Interactions between Glycine and Glutamate through Activation of Their Transporters in Hippocampal Nerve Terminals.

Evidence supports the pathophysiological relevance of crosstalk between the neurotransmitters Glycine and Glutamate and their close interactions; some reports even support the possibility of Glycine-Glutamate cotransmission in central nervous system (CNS) areas, including the hippocampus. Functional studies with isolated nerve terminals (synaptosomes) permit us to study transporter-mediated interactions between neurotransmitters that lead to the regulation of transmitter release. Our main aims here were: (i) to investigate release-regulating, transporter-mediated interactions between Glycine and Glutamate in hippocampal nerve terminals and (ii) to determine the coexistence of transporters for Glycine and Glutamate in these terminals. Purified synaptosomes, analyzed at the ultrastructural level via electron microscopy, were used as the experimental model. Mouse hippocampal synaptosomes were prelabeled with [3H]D-Aspartate or [3H]Glycine; the release of radiolabeled tracers was monitored with the superfusion technique. The main findings were that (i) exogenous Glycine stimulated [3H]D-Aspartate release, partly by activation of GlyT1 and in part, unusually, through GlyT2 transporters and that (ii) D-Aspartate stimulated [3H]glycine release by a process that was sensitive to Glutamate transporter blockers. Based on the features of the experimental model used, it is suggested that functional transporters for Glutamate and Glycine coexist in a small subset of hippocampal nerve terminals, a condition that may also be compatible with cotransmission; glycinergic and glutamatergic transporters exhibit different functions and mediate interactions between the neurotransmitters. It is hoped that increased information on Glutamate-Glycine interactions in different areas, including the hippocampus, will contribute to a better knowledge of drugs acting at "glycinergic" targets, currently under study in relation with different CNS pathologies.

Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake

AimsBrown adipose tissue (BAT) can produce heat by metabolizing glucose and fatty acids. Activation of BAT is controlled by the central nervous system (CNS) through sympathetic innervation. Dysregulation of signalling molecules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS, triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake. Main methodsRats received DVC stereotactic surgery for local brain administration of viruses that express mutated Drp1 genes. BAT glucose uptake was measured with PET/CT scans. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT. Key findingsWe show that short-term HFD-feeding decreases BAT glucose uptake. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats partially restores BAT glucose uptake accompanied by lower blood glucose and insulin levels. Tyrosine Hydroxylase (TH) revealed that rats with inhibited mitochondrial fragmentation in NTS astrocytes had higher levels of catecholaminergic innervation in BAT compared to HFD-fed rats, and did not exhibit HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, TH immune-positive boutons and β3-adrenergic receptor levels. SignificanceOur data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.

Targeted Central Nervous System Irradiation with Proton Microbeam Induces Mitochondrial Changes in Caenorhabditis elegans.

Fifty percent of all patients with cancer worldwide require radiotherapy. In the case of brain tumors, despite the improvement in the precision of radiation delivery with proton therapy, studies have shown structural and functional changes in the brains of treated patients with protons. The molecular pathways involved in generating these effects are not completely understood. In this context, we analyzed the impact of proton exposure in the central nervous system area of Caenorhabditis elegans with a focus on mitochondrial function, which is potentially implicated in the occurrence of radiation-induced damage. To achieve this objective, the nematode C. elegans were micro-irradiated with 220 Gy of protons (4 MeV) in the nerve ring (head region) using the proton microbeam, MIRCOM. Our results show that protons induce mitochondrial dysfunction, characterized by an immediate dose-dependent loss of the mitochondrial membrane potential (ΔΨm) associated with oxidative stress 24 h after irradiation, which is itself characterized by the induction of the antioxidant proteins in the targeted region, observed using SOD-1::GFP and SOD-3::GFP strains. Moreover, we demonstrated a two-fold increase in the mtDNA copy number in the targeted region 24 h after irradiation. In addition, using the GFP::LGG-1 strain, an induction of autophagy in the irradiated region was observed 6 h following the irradiation, which is associated with the up-regulation of the gene expression of pink-1 (PTEN-induced kinase) and pdr-1 (C. elegans parkin homolog). Furthermore, our data showed that micro-irradiation of the nerve ring region did not impact the whole-body oxygen consumption 24 h following the irradiation. These results indicate a global mitochondrial dysfunction in the irradiated region following proton exposure. This provides a better understanding of the molecular pathways involved in radiation-induced side effects and may help in finding new therapies.

The glycine receptor alpha 3 subunit mRNA expression shows sex-dependent differences in the adult mouse brain

BackgroundThe glycinergic system plays an important inhibitory role in the mouse central nervous system, where glycine controls the excitability of spinal itch- and pain-mediating neurons. Impairments of the glycine receptors can cause motor and sensory deficits. Glycine exerts inhibition through interaction with ligand-gated ion channels composed of alpha and beta subunits. We have investigated the mRNA expression of the glycine receptor alpha 3 (Glra3) subunit in the nervous system as well as in several peripheral organs of female and male mice.ResultsSingle-cell RNA sequencing (scRNA-seq) data analysis on the Zeisel et al. (2018) dataset indicated widespread but low expression of Glra3 in vesicular glutamate transporter 2 (Vglut2, Slc17a6) positive and vesicular inhibitory amino acid transporter (Viaat, Slc32a1)positive neurons of the mouse central nervous system. Highest occurrence of Glra3 expression was identified in the cortex, amygdala, and striatal regions, as well as in the hypothalamus, brainstem and spinal cord. Bulk quantitative real-time-PCR (qRT-PCR) analysis demonstrated Glra3 expression in cortex, amygdala, striatum, hypothalamus, thalamus, pituitary gland, hippocampus, cerebellum, brainstem, and spinal cord. Additionally, male mice expressed higher levels of Glra3 in all investigated brain areas compared with female mice. Lastly, RNAscope spatially validated Glra3 expression in the areas indicated by the single-cell and bulk analyses. Moreover, RNAscope analysis confirmed co-localization of Glra3 with Slc17a6 or Slc32a1 in the central nervous system areas suggested from the single-cell data.ConclusionsGlra3 expression is low but widespread in the mouse central nervous system. Clear sex-dependent differences have been identified, indicating higher levels of Glra3 in several telencephalic and diencephalic areas, as well as in cerebellum and brainstem, in male mice compared with female mice.

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders.

Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the severalpathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered.

Migraine: from pathophysiology to treatment

Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. A growing increase in the understanding of migraine pathophysiology in recent years has facilitated translation of that knowledge into novel treatments, which are currently becoming available to patients in many parts of the world and are substantially changing the clinical approach to the disease. In the first part of this review, we will provide an up to date overview of migraine pathophysiology by analyzing the anatomy and function of the main regions involved in the disease, focusing on how these give rise to the plethora of symptoms characterizing the attacks and overall disease. The second part of the paper will discuss the novel therapeutic agents that have emerged for the treatment of migraine, including molecules targeting calcitonin gene-related peptide (gepants and monoclonal antibodies), serotonin 5-HT1F receptor agonists (ditans) and non-invasive neuromodulation, as well as providing a brief overview of new evidence for classic migraine treatments.

Expression of the cellular prion protein by mast cells in the human carotid body

ABSTRACT Prion diseases are fatal neurologic disorders that can be transmitted by blood transfusion. The route for neuroinvasion following exposure to infected blood is not known. Carotid bodies (CBs) are specialized chemosensitive structures that detect the concentration of blood gasses and provide feedback for the neural control of respiration. Sensory cells of the CB are highly perfused and densely innervated by nerves that are synaptically connected to the brainstem and thoracic spinal cord, known to be areas of early prion deposition following oral infection. Given their direct exposure to blood and neural connections to central nervous system (CNS) areas involved in prion neuroinvasion, we sought to determine if there were cells in the human CB that express the cellular prion protein (PrPC), a characteristic that would support CBs serving as a route for prion neuroinvasion. We collected CBs from cadaver donor bodies and determined that mast cells located in the carotid bodies express PrPC and that these cells are in close proximity to blood vessels, nerves, and nerve terminals that are synaptically connected to the brainstem and spinal cord.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Biofabrication of nanovesicles for brain diseases.

Biofabrication of nanovesicles for brain diseases.

ABCL-200 Primary and Secondary Extranodal Diffuse Large B-Cell Lymphoma: A Single-Center Survey from India

Approximately 30% of all non-Hodgkin lymphoma (NHL) cases arise from extranodal sites and almost half of them have diffuse large B-cell lymphoma (DLBCL) histology. Not only does the extranodal presentation require a site-specific diagnostic or therapeutic approach, but there is geographical variability in the overall frequency of extranodal presentation as well. To estimate the distribution of sites of extranodal DLBCL in patients treated at a tertiary care center in north India. This retrospective study was conducted at Dr. Bhim Rao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. Case files of patients (age >18 years) diagnosed with DLBCL at our institute between 2014 and 2018 were retrospectively studied and their sites of disease involvement were surveyed. A total of 550 patients were diagnosed with DLBCL during the study period, including 244 (44.3%) with nodal disease, 224 (40.7%) with extranodal involvement, and 82 (14.9%) with primary extranodal disease. A total of 306 (55.63%) patients have extranodal involvement, either primary or secondary. Among patients with primary extranodal DLBCL (n=82), the most common sites were gastrointestinal (n=36, 43.90%); the stomach was the most common region followed by the central nervous system (n=11, 13.4%), bone (n=8, 9.7%), head and neck area (n=7, 8.5%), breast (n=6, 7.3%), testis (n=4, 4.8%), and liver (n=4, 4.8%). The less commonly involved sites included the spleen (n=2, 2.4%), and one patient (1.2%) each had involvement in the prostate, pancreas, adrenal, and ovary. Bone was the most common site of secondary extranodal involvement observed in 32% of patients followed by gastrointestinal involvement in 30% of cases. Parallel to the incidence of DLBCL, the incidence of extranodal involvement, including primary and secondary extranodal presentation, is high in India. Bone is the most common site for secondary extranodal involvement, and the upper gastrointestinal system (stomach) is the most common site of primary extranodal lymphoma.

Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing

Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 – 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma -ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 µg/h dosing group, medians 65 – 122, than in the 20 µg/h group, medians 26 – 54. The subcutaneous injection (theoretical release rate 47.6 µg/h) produced higher concentrations than observed after 40 µg/h transdermal patch dosing. The median fetal/maternal concentration -ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8 – 13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs’ plasma and CNS tissues two days postdelivery. Norbuprenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.

Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors.

The dopaminergic system is one of the most important neurotransmitter systems in the central nervous system (CNS). It acts mainly by activation of the D1-like receptor family at the target cell. Additionally, fine-tuning of the signal is achieved via pre-synaptic modulation by the D2-like receptor family. Some dopamine drugs (both agonists and antagonists) bind in addition to DRs also to α2-ARs and 5-HT receptors. Unfortunately, these compounds are often considered subtype(s) specific. Thus, it is important to consider the presence of these receptor subtypes in specific CNS areas as the function virtually elicited by one receptor type could be an effect of other—or the co-effect of multiple receptors. However, there are enough molecules with adequate specificity. In this review, we want to give an overview of the most common off-targets for established dopamine receptor ligands. To give an overall picture, we included a discussion on subtype selectivity. Molecules used as antipsychotic drugs are reviewed too. Therefore, we will summarize reported affinities and give an outline of molecules sufficiently specific for one or more subtypes (i.e., for subfamily), the presence of DR, α2-ARs, and 5-HT receptors in CNS areas, which could help avoid ambiguous results.

Integrative Hedonic and Homeostatic Food Intake Regulation by the Central Nervous System: Insights from Neuroimaging.

Food intake regulation in humans is a complex process controlled by the dynamic interaction of homeostatic and hedonic systems. Homeostatic regulation is controlled by appetitive signals from the gut, adipose tissue, and the vagus nerve, while conscious and unconscious reward processes orchestrate hedonic regulation. On the one hand, sight, smell, taste, and texture perception deliver potent food-related feedback to the central nervous system (CNS) and influence brain areas related to food reward. On the other hand, macronutrient composition stimulates the release of appetite signals from the gut, which are translated in the CNS into unconscious reward processes. This multi-level regulation process of food intake shapes and regulates human ingestive behavior. Identifying the interface between hormones, neurotransmitters, and brain areas is critical to advance our understanding of conditions like obesity and develop better therapeutical interventions. Neuroimaging studies allow us to take a glance into the central nervous system (CNS) while these processes take place. This review focuses on the available neuroimaging evidence to describe this interaction between the homeostatic and hedonic components in human food intake regulation.

Multiple sclerosis impairment scale and brain MRI in secondary progressive multiple sclerosis.

To examine the Multiple Sclerosis Impairment Scale (MSIS) in secondary progressive MS (SPMS) in relation to the Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI) outcomes, and mobility. In this observational single-center study, 68 secondary progressive multiple sclerosis (SPMS) patients were examined by MSIS, EDSS, functional mobility tests of upper/lower extremities, and multimodal MRI. Participants had EDSS ≥3.5, a decline in daily activities over the last year unrelated to relapses, and/or 6-month confirmed disability progression. Mean disease duration was 23.1±8.3years and mean age 54.4±8.1years. MSIS, EDSS, and their corresponding motor, cerebellar, and sensory subscores correlated (p<.0001). Motor subscores of MSIS correlated stronger with Timed-25-Foot-Walk (T25FW) than pyramidal functional system score (FSS) (p=.03), but EDSS had a stronger correlation to T25FW than the total MSIS score (p=.01). MSIS cerebellar subscore correlated stronger with 9-Hole Peg Test (9-HPT) than cerebellar FSS (p=.04). The sensory MSIS subscore also showed correlation with 9-HPT in contrast to sensory FSS (p=.006). MSIS subscores had stronger correlations with MRI volumetry measures than FSS scores (lesion volume and putamen, thalamus, corpus callosum volumetry, p=.0001-0.0017). In patients with SPMS, MSIS correlated with functional motor tests. MSIS showed stronger correlations with atrophy of central nervous system areas, and may be more sensitive to scale cerebellar and sensory function than EDSS.

Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis

A few patients with Hashimoto’s thyroiditis or Graves’ disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto’s encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis.Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases.Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.