-
Brain Multiphysics Jun 2024Knowledge of the mechanical properties of brain tissue is essential to understanding the mechanisms underlying traumatic brain injury (TBI) and to creating accurate...
UNLABELLED
Knowledge of the mechanical properties of brain tissue is essential to understanding the mechanisms underlying traumatic brain injury (TBI) and to creating accurate computational models of TBI and neurosurgical simulation. Brain white matter, which is composed of aligned, myelinated, axonal fibers, is structurally anisotropic. White matter also exhibits mechanical anisotropy, as measured by magnetic resonance elastography (MRE), but measurements of anisotropy obtained by mechanical testing of white matter have been inconsistent. The minipig has a gyrencephalic brain with similar white matter and gray matter proportions to humans and therefore provides a relevant model for human brain mechanics. In this study, we compare estimates of anisotropic mechanical properties of the minipig brain obtained by identical, non-invasive methods in the live ( and dead animals . To do so, we combine wave displacement fields from MRE and fiber directions derived from diffusion tensor imaging (DTI) with a finite element-based, transversely-isotropic nonlinear inversion (TI-NLI) algorithm. Maps of anisotropic mechanical properties in the minipig brain were generated for each animal alive and at specific times post-mortem. These maps show that white matter is stiffer, more dissipative, and more anisotropic than gray matter when the minipig is alive, but that these differences largely disappear post-mortem, with the exception of tensile anisotropy. Overall, brain tissue becomes stiffer, less dissipative, and less mechanically anisotropic post-mortem. These findings emphasize the importance of testing brain tissue properties .
STATEMENT OF SIGNIFICANCE
In this study, MRE and DTI in the minipig were combined to estimate, for the first time, anisotropic mechanical properties in the living brain and in the same brain after death. Significant differences were observed in the anisotropic behavior of brain tissue post-mortem. These results demonstrate the importance of measuring brain tissue properties as well as and provide new quantitative data for the development of computational models of brain biomechanics.
PubMed: 38933498
DOI: 10.1016/j.brain.2024.100091 -
Micromachines Jun 2024Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the gene....
BACKGROUND
Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the gene. Using this model, the study describes early clinical disease markers for canine glaucoma.
METHODS
Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, -mutant (median age 45.6 months, range 28.8-52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/- SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/- SEM 0.53 mmHg).
RESULTS
Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/- SEM 38.4 μm to 9.3 +/- SEM 22.1 μm; < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: -0.78; < 0.003). There were no significant differences in the thickness of any retinal layers evaluated.
CONCLUSIONS
SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin.
PubMed: 38930749
DOI: 10.3390/mi15060780 -
Journal of Clinical Medicine Jun 2024: Myelin oligodendrocyte glycoprotein (MOG) is exclusively expressed in the central nervous system (CNS) and is found on the outer surface of oligodendrocytes.... (Review)
Review
: Myelin oligodendrocyte glycoprotein (MOG) is exclusively expressed in the central nervous system (CNS) and is found on the outer surface of oligodendrocytes. Antibodies to MOG are associated with CNS demyelination, whereas peripheral nervous system (PNS) demyelination is seldom reported to be related to MOG-IgG. : The database of patients seen in our neurological academic center was searched for MOG-IgG seropositivity and concomitant demyelinating polyneuropathy. For the purpose of the review, in March 2024, we searched for case reports and case series in the following databases: PubMed, Scopus, Cochrane, and ScienceDirect. Inclusion criteria were MOG-IgG seropositivity and demyelinating polyneuropathy. Exclusion criteria were type of publication other than case reports and case series, unconfirmed diagnosis of demyelinating polyneuropathy, and other diseases causing demyelination in either the CNS or PNS. Critical appraisal of the selected case reports and case series was realized by JBI. : Four new cases were identified with MOG-IgG and confirmed demyelinating polyneuropathy. This review identified 22 cases that have been published since 2018. Clinical, imaging, neurophysiological, and immunological characteristics, as well as treatment options and outcomes are presented and compared to those of other cases with combined central and peripheral demyelination (CCPD). : The pathogenetic mechanism is unclear; thus, different hypotheses are discussed. New case reporting and large cohort studies will help further the exploration of the underlying mechanism and guide more effective therapeutic interventions.
PubMed: 38930142
DOI: 10.3390/jcm13123604 -
Journal of Personalized Medicine Jun 2024Primary demyelinating disorders of the central nervous system (CNS) include multiple sclerosis and the orphan conditions neuromyelitis optica spectrum disorder (NMOSD)...
Development Perspectives for Curative Technologies in Primary Demyelinating Disorders of the Central Nervous System with Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) at the Forefront.
Primary demyelinating disorders of the central nervous system (CNS) include multiple sclerosis and the orphan conditions neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD). Curative technologies under development aim to selectively block autoimmune reactions against specific autoantigens while preserving the responsiveness of the immune system to other antigens. Our analysis focused on target patient selection for such developments, carefully considering the relevant clinical, regulatory, and market-related aspects. We found that the selection of patients with orphan conditions as target populations offers several advantages. Treatments for orphan conditions are associated with limited production capacity, qualify for regulatory incentives, and may require significantly shorter and lower-scale clinical programs. Furthermore, they may meet a higher acceptable cost-effectiveness threshold in order to compensate for the low numbers of patients to be treated. Finally, curative technologies targeting orphan indications could enter less competitive markets with lower risk of generic price erosion and would benefit from additional market protection measures available only for orphan products. These advantages position orphan conditions and subgroups as the most attractive target indications among primary demyelinating disorders of the CNS. The authors believe that after successful proof-of-principle demonstrations in orphan conditions, broader autoimmune patient populations may also benefit from the success of these pioneering developments.
PubMed: 38929820
DOI: 10.3390/jpm14060599 -
Brain Sciences Jun 2024Vestibular schwannoma (VS), also known as acoustic neuroma, is a benign, well-encapsulated, and slow-growing tumor that originates from Schwann cells, which form the...
BACKGROUND
Vestibular schwannoma (VS), also known as acoustic neuroma, is a benign, well-encapsulated, and slow-growing tumor that originates from Schwann cells, which form the myelin sheath around the vestibulocochlear nerve (VIII cranial nerve). The surgical treatment of this condition presents a challenging task for surgeons, as the tumor's location and size make it difficult to remove without causing damage to the surrounding structures. In recent years, fluorescein sodium (FS) has been proposed as a tool to enhance surgical outcomes in VS surgery. This essay will provide an analytical comparison of the use of FS in VS surgery, evaluating its benefits and limitations and comparing surgical outcomes with and without FS-assisted surgery.
METHODS
In a retrospective study conducted at San Filippo Neri Hospital, we examined VS cases that were operated on between January 2017 and December 2023. The patients were divided into two groups: group A, which consisted of patients who underwent surgery without the use of FS until January 2020 (102 cases), and group B, which included patients who underwent surgery with FS after January 2020 (55 cases). All operations were performed using the retrosigmoid approach, and tumor size was classified according to the Koos, et al. classification system. The extent of surgical removal was evaluated using both the intraoperative surgeon's opinion and postoperative MRI imaging. Preoperatively and postoperatively, facial nerve function and hearing were assessed. In group B, FS was used to assist the surgical procedures, which were performed using a surgical microscope equipped with an integrated fluorescein filter. Postoperative clinical and MRI controls were performed at six months and annually, with no patients lost to follow-up.
RESULTS
This study investigated the impact of intraoperative fluorescein exposure on tumor resection and clinical outcomes in patients with VS. The study found a statistically significant difference in the tumor resection rates between patients who received fluorescein intraoperatively ( = 0.037). Further analyses using the Koos classification system revealed a significant effect of fluorescein exposure, particularly in the Koos 3 subgroup ( = 0.001). Notably, no significant differences were observed in hearing loss or facial nerve function between the two groups. A Spearman correlation analysis revealed a positive correlation between tumor size and Koos, age, and size, but no significant correlation was found between facial nerve function tests.
CONCLUSIONS
FS-assisted surgery for VS may potentially enhance tumor resection, allowing for more comprehensive tumor removal.
PubMed: 38928571
DOI: 10.3390/brainsci14060571 -
International Journal of Molecular... Jun 2024Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which...
Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG) and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4 T cells and Lag-3 and Tim-3 on CD8 T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.
Topics: Encephalomyelitis, Autoimmune, Experimental; Animals; Mice; Interleukin-6; Female; CD4-Positive T-Lymphocytes; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Multiple Sclerosis; Aging; Interleukin-10; Spinal Cord; Programmed Cell Death 1 Receptor; Signal Transduction
PubMed: 38928437
DOI: 10.3390/ijms25126732 -
International Journal of Molecular... Jun 2024Clinical treatment options to combat Encephalopathy of Prematurity (EoP) are still lacking. We, and others, have proposed (intranasal) mesenchymal stem cells (MSCs) as a...
Clinical treatment options to combat Encephalopathy of Prematurity (EoP) are still lacking. We, and others, have proposed (intranasal) mesenchymal stem cells (MSCs) as a potent therapeutic strategy to boost white matter repair in the injured preterm brain. Using a double-hit mouse model of diffuse white matter injury, we previously showed that the efficacy of MSC treatment was time dependent, with a significant decrease in functional and histological improvements after the postponement of cell administration. In this follow-up study, we aimed to investigate the mechanisms underlying this loss of therapeutic efficacy. Additionally, we optimized the regenerative potential of MSCs by means of genetic engineering with the transient hypersecretion of beneficial factors, in order to prolong the treatment window. Though the cerebral expression of known chemoattractants was stable over time, the migration of MSCs to the injured brain was partially impaired. Moreover, using a primary oligodendrocyte (OL) culture, we showed that the rescue of injured OLs was reduced after delayed MSC coculture. Cocultures of modified MSCs, hypersecreting IGF1, LIF, IL11, or IL10, with primary microglia and OLs, revealed a superior treatment efficacy over naïve MSCs. Additionally, we showed that the delayed intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, improved myelination and the functional outcome in EoP mice. In conclusion, the impaired migration and regenerative capacity of intranasally applied MSCs likely underlie the observed loss of efficacy after delayed treatment. The intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, is a promising optimization strategy to prolong the window for effective MSC treatment in preterm infants with EoP.
Topics: Animals; Mesenchymal Stem Cells; Mice; Mesenchymal Stem Cell Transplantation; Secretome; Disease Models, Animal; Oligodendroglia; Humans; Coculture Techniques; Microglia; Mice, Inbred C57BL
PubMed: 38928201
DOI: 10.3390/ijms25126494 -
International Journal of Molecular... Jun 2024Alzheimer's disease (AD), the leading cause of dementia worldwide, remains a challenge due to its complex origin and degenerative character. The need for accurate...
Alzheimer's disease (AD), the leading cause of dementia worldwide, remains a challenge due to its complex origin and degenerative character. The need for accurate biomarkers and treatment targets hinders early identification and intervention. To fill this gap, we used a novel longitudinal proteome methodology to examine the temporal development of molecular alterations in the cortex of an intracerebroventricular streptozotocin (ICV-STZ)-induced AD mouse model for disease initiation and progression at one, three-, and six-weeks post-treatment. Week 1 revealed metabolic protein downregulation, such as Aldoa and Pgk1. Week 3 showed increased Synapsin-1, and week 6 showed cytoskeletal protein alterations like Vimentin. The biological pathways, upstream regulators, and functional effects of proteome alterations were dissected using advanced bioinformatics methods, including Ingenuity Pathway Analysis (IPA) and machine learning algorithms. We identified Mitochondrial Dysfunction, Synaptic Vesicle Pathway, and Neuroinflammation Signaling as disease-causing pathways. Huntington's Disease Signaling and Synaptogenesis Signaling were stimulated while Glutamate Receptor and Calcium Signaling were repressed. IPA also found molecular connections between PPARGC1B and AGT, which are involved in myelination and possible neoplastic processes, and MTOR and AR, which imply mechanistic involvements beyond neurodegeneration. These results help us comprehend AD's molecular foundation and demonstrate the promise of focused proteomic techniques to uncover new biomarkers and therapeutic targets for AD, enabling personalized medicine.
Topics: Animals; Alzheimer Disease; Disease Models, Animal; Proteomics; Mice; Proteome; Male; Signal Transduction; Biomarkers; Disease Progression
PubMed: 38928172
DOI: 10.3390/ijms25126469 -
International Journal of Molecular... Jun 2024The use of acellular nerve allografts (ANAs) to reconstruct long nerve gaps (>3 cm) is associated with limited axon regeneration. To understand why ANA length might...
Limited Nerve Regeneration across Acellular Nerve Allografts (ANAs) Coincides with Changes in Blood Vessel Morphology and the Development of a Pro-Inflammatory Microenvironment.
The use of acellular nerve allografts (ANAs) to reconstruct long nerve gaps (>3 cm) is associated with limited axon regeneration. To understand why ANA length might limit regeneration, we focused on identifying differences in the regenerative and vascular microenvironment that develop within ANAs based on their length. A rat sciatic nerve gap model was repaired with either short (2 cm) or long (4 cm) ANAs, and histomorphometry was used to measure myelinated axon regeneration and blood vessel morphology at various timepoints (2-, 4- and 8-weeks). Both groups demonstrated robust axonal regeneration within the proximal graft region, which continued across the mid-distal graft of short ANAs as time progressed. By 8 weeks, long ANAs had limited regeneration across the ANA and into the distal nerve (98 vs. 7583 axons in short ANAs). Interestingly, blood vessels within the mid-distal graft of long ANAs underwent morphological changes characteristic of an inflammatory pathology by 8 weeks post surgery. Gene expression analysis revealed an increased expression of pro-inflammatory cytokines within the mid-distal graft region of long vs. short ANAs, which coincided with pathological changes in blood vessels. Our data show evidence of limited axonal regeneration and the development of a pro-inflammatory environment within long ANAs.
Topics: Animals; Nerve Regeneration; Rats; Sciatic Nerve; Allografts; Axons; Male; Blood Vessels; Inflammation; Cellular Microenvironment; Transplantation, Homologous; Cytokines; Rats, Sprague-Dawley
PubMed: 38928119
DOI: 10.3390/ijms25126413 -
Genes Jun 2024Extracellular vesicles (EVs) are "micro-shuttles" that play a role as mediators of intercellular communication. Cells release EVs into the extracellular environment in... (Review)
Review
Extracellular vesicles (EVs) are "micro-shuttles" that play a role as mediators of intercellular communication. Cells release EVs into the extracellular environment in both physiological and pathological conditions and are involved in intercellular communication, due to their ability to transfer proteins, lipids, and nucleic acids, and in the modulation of the immune system and neuroinflammation. Because EVs can penetrate the blood-brain barrier and move from the central nervous system to the peripheral circulation, and vice versa, recent studies have shown a substantial role for EVs in several neurological diseases, including multiple sclerosis (MS). MS is a demyelinating disease where the main event is caused by T and B cells triggering an autoimmune reaction against myelin constituents. Recent research has elucidate the potential involvement of extracellular vesicles (EVs) in the pathophysiology of MS, although, to date, their potential role both as agents and therapeutic targets in MS is not fully defined. We present in this review a summary and comprehensive examination of EVs' involvement in the pathophysiology of multiple sclerosis, exploring their potential applications as biomarkers and indicators of therapy response.
Topics: Humans; Multiple Sclerosis; Extracellular Vesicles; Biomarkers; Animals; Blood-Brain Barrier
PubMed: 38927708
DOI: 10.3390/genes15060772