Explore the vast range of titles available.

The architects Cross & Cross shaped the streetscape and skyline of New York City in the 1920s and 1930s with Upper East Side townhouses and apartment buildings, the RCA Victor Building, and Tiffany's flagship store on 57th Street. Working through a period of American history that saw dramatic change, from luxurious apartment buildings during the economic boom of the 1920s, to federal commissions during the Depression, the brothers John and Eliot Cross were masters of their craft. Well-connected society men who also showed remarkable foresight in business, Cross & Cross supported their practice with a partnered real estate firm and played a vital role in residential developments like Sutton Place along the East River. Cross & Cross oversaw the development of handsome clubs and houses throughout New York City, including the Links Club and the Upper East Side houses of Lewis Spencer Morris and George Whitney. They designed country houses in exclusive residential pockets outside New York: the Southampton estate of Winterthur founder Henry Francis du Pont; houses on the North Shore of Long Island, and in Greenwich, Connecticut; the childhood home of Sister Parish in Far Hills, New Jersey; and the Shelburne, Vermont home of J. Watson and Electra Webb.-- Source other than Library of Congress.

In two identical trials involving a total of 1882 patients with multiple sclerosis, the human anti-CD20 monoclonal antibody ofatumumab was associated with a lower annualized relapse rate than the pyrimidine-synthesis inhibitor teriflunomide, as well as fewer lesions on MRI.

Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2 −/− ) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2 −/− microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2 −/− microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.

The original anti-CD20 therapy, rituximab, is used off-label in some countries, and results from a clinical trial (RIFUND-MS) by Anders Svenningsson and colleagues1 published in The Lancet Neurology help to fill a gap in our knowledge about how useful this monoclonal antibody might be for patients with relapsing-remitting multiple sclerosis. Because immunoglobulins are made by B cells and by plasma cells that differentiate from B cells, these cells became an early focus of multiple sclerosis immunological research. Relapses (the primary endpoint) occurred in three (3%) of the 98 patients eligible for primary outcome analysis in the rituximab group and 16 (16%) of 97 in the dimethyl fumarate group.1 In a post-hoc analysis, numbers of new and enlarged T2 lesions and contrast-enhancing lesions were significantly lower for rituximab than for dimethyl fumarate (mean 0·3 [SD 0·7] vs 1·5 [4·0] T2 lesions; mean 0·04 [0·20] vs 0·26 [0·70] contrast-enhancing lesions).1 However, limitations of the study include that patients and treating clinicians were not masked to treatment and that data on ethnic background of participants were not collected, so the applicability to populations elsewhere is unknown.

The effect of extra-fiber structural and pathological components confounding diffusion tensor imaging (DTI) computation was quantitatively investigated using data generated by both Monte-Carlo simulations and tissue phantoms. Increased extent of vasogenic edema, by addition of various amount of gel to fixed normal mouse trigeminal nerves or by increasing non-restricted isotropic diffusion tensor components in Monte-Carlo simulations, significantly decreased fractional anisotropy (FA) and increased radial diffusivity, while less significantly increased axial diffusivity derived by DTI. Increased cellularity, mimicked by graded increase of the restricted isotropic diffusion tensor component in Monte-Carlo simulations, significantly decreased FA and axial diffusivity with limited impact on radial diffusivity derived by DTI. The MC simulation and tissue phantom data were also analyzed by the recently developed diffusion basis spectrum imaging (DBSI) to simultaneously distinguish and quantify the axon/myelin integrity and extra-fiber diffusion components. Results showed that increased cellularity or vasogenic edema did not affect the DBSI-derived fiber FA, axial or radial diffusivity. Importantly, the extent of extra-fiber cellularity and edema estimated by DBSI correlated with experimentally added gel and Monte-Carlo simulations. We also examined the feasibility of applying 25-direction diffusion encoding scheme for DBSI analysis on coherent white matter tracts. Results from both phantom experiments and simulations suggested that the 25-direction diffusion scheme provided comparable DBSI estimation of both fiber diffusion parameters and extra-fiber cellularity/edema extent as those by 99-direction scheme. An in vivo 25-direction DBSI analysis was performed on experimental autoimmune encephalomyelitis (EAE, an animal model of human multiple sclerosis) optic nerve as an example to examine the validity of derived DBSI parameters with post-imaging immunohistochemistry verification. Results support that in vivo DBSI using 25-direction diffusion scheme correctly reflect the underlying axonal injury, demyelination, and inflammation of optic nerves in EAE mice. •99- and 25-direction diffusion encoding schemes performed equally well in coherent white matter.•DBSI accurately assessed fiber directional diffusivity under conditions where DTI failed.•25-Direction DBSI of mouse optic nerve matched IHC detected pathologies.

Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55 years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55 years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55–59, 60–65, 66–69, etc. Optimally, such studies should be 3 years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.

Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Design: Secondary analysis of existing data from the FAERS database. Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1. Results: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132–0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109–0.248), liraglutide (ROR: 0.161; 95% CI: 0.091–0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146–0.377), and metformin (ROR: 0.387; 95% CI: 0.340–0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384–0.806). Conclusion: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

Volume loss in some limbic region structures has been observed in multiple sclerosis (MS) patients. However, in vivo evaluation of existing tissue cellular microstructure integrity has received less attention. The goal of studies reported here was to quantitatively assess loss of limbic system volumes and tissue integrity, and to evaluate associations of these measures with cognitive and physical dysfunction in MS patients. Thirty-one healthy controls (HC) and 80 MS patients, including 32 relapsing remitting (RRMS), 32 secondary progressive (SPMS) and 16 primary progressive (PPMS), participated in this study. Tissue cellular integrity was evaluated by means of recently introduced tissue-specific parameter R2t* that was calculated from multi-gradient-echo MRI signals using a recently developed method that separates R2t* from BOLD (blood oxygen level dependent) contributions to GRE signal decay rate constant (R2*), and accounting for physiological fluctuations and artifacts from background gradients. Volumes in limbic system regions, normalized to skull size (NV), were measured from standard MPRAGE images. MS patients had lower R2t* and smaller normalized volumes in the hippocampus, amygdala, and several other limbic system regions, compared to HC. Alterations in R2t* of several limbic system regions correlated with clinical and neurocognitive test scores in MS patients. In contrast, smaller normalized volumes in MS were only correlated with neurocognitive test scores in the hippocampus and amygdala. This study reports the novel finding that R2t*, a measure that estimates tissue integrity, is more sensitive to tissue damage in limbic system structures than is atrophy. R2t* measurements can serve as a biomarker that is distinct from and complementary to volume measurements.

Single-cell transcriptomics applied to cerebrospinal fluid (CSF) for elucidating the pathophysiology of neurologic diseases has produced only a preliminary characterization of CSF immune cells. CSF derives from and borders central nervous system (CNS) tissue, allowing for comprehensive accounting of cell types along with their relative abundance and immunologic profiles relevant to CNS diseases. Using integration techniques applied to publicly available datasets in combination with our own studies, we generated a compendium with 139 subjects encompassing 135 CSF and 58 blood samples. Healthy subjects and individuals across a wide range of diseases, such as multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, COVID-19, and autoimmune encephalitis, were included. We found differences in lymphocyte and myeloid subset frequencies across different diseases as well as in their distribution between blood and CSF. We identified what we believe to be a new subset of AREG+ dendritic cells exclusive to the CSF that was more abundant in subjects with MS compared with healthy controls. Finally, transcriptional cell states in CSF microglia-like cells and lymphoid subsets were elucidated. Altogether, we have created a reference compendium for single-cell transcriptional profiling encompassing CSF immune cells useful to the scientific community for future studies on neurologic diseases.

Establishing baseline MRI biomarkers for normal brain aging is significant and valuable for separating normal changes in the brain structure and function from different neurological diseases. In this paper for the first time we have simultaneously measured a variety of tissue specific contributions defining R2* relaxation of the gradient recalled echo (GRE) MRI signal in human brains of healthy adults (ages 22 to 74years) and related these measurements to tissue structural and functional properties. This was accomplished by separating tissue (R2t⁎) and extravascular BOLD contributions to the total tissue specific GRE MRI signal decay (R2⁎) using an advanced version of previously developed Gradient Echo Plural Contrast Imaging (GEPCI) approach and the acquisition and post-processing methods that allowed the minimization of artifacts related to macroscopic magnetic field inhomogeneities, and physiological fluctuations. Our data (20 healthy subjects) show that in most cortical regions R2t⁎ increases with age while tissue hemodynamic parameters, i.e. relative oxygen extraction fraction (OEFrel), deoxygenated cerebral blood volume (dCBV) and tissue concentration of deoxyhemoglobin (Cdeoxy) remain practically constant. We also found the important correlations characterizing the relationships between brain structural and hemodynamic properties in different brain regions. Specifically, thicker cortical regions have lower R2t⁎ and these regions have lower OEF. The comparison between GEPCI-derived tissue specific structural and functional metrics and literature information suggests that (a) regions in a brain characterized by higher R2t⁎ contain higher concentration of neurons with less developed cellular processes (dendrites, spines, etc.), (b) regions in a brain characterized by lower R2t⁎ represent regions with lower concentration of neurons but more developed cellular processes, and (c) the age-related increases in the cortical R2t⁎ mostly reflect the age-related increases in the cellular packing density. The baseline GEPCI-based biomarkers obtain herein could serve to help distinguish age-related changes in brain cellular and hemodynamic properties from changes which occur due to the neurodegenerative diseases. [Display omitted] •Transverse relaxation of MRI signal is separated in tissue (R2t⁎) and BOLD contributions.•We hypothesize that R2t⁎ can serve as a biomarker of the cortical cellular packing density.•Cortical regions with lower R2t⁎ are thicker and have lower oxygen extraction fraction (OEF).•R2t⁎ grows with age in most cortical regions while OEF remains constant.•Age-related increase in cortical R2t⁎ reflects increases in the cellular packing density.