Protollin, a nasal adjuvant, was evaluated in a randomized double-blind phase 1 study of 16 early Alzheimer’s disease (AD) patients to determine safety and to assess its immunomodulatory effects. In a double-blind dose escalation study, subjects received nasal Protollin at doses of 0.1 mg, 0.5 mg, 1.0 mg, and 1.5 mg or placebo twice over a two-week period. Treatment was well-tolerated with minimal side effects. Transcriptomic and single-cell analyses demonstrated that prior to treatment, AD blood monocytes had downregulation of phagocytosis-related genes and an increased pro-inflammatory signature. These AD monocyte abnormalities were reversed by nasal Protollin beginning at a dose of 1.0 mg. Protollin induced a robust phagocytic gene signature, including upregulation of CD36, ITGAL, LYST, and FCGR1A. A similar phagocytic signature was observed in brain-infiltrating amyloid-clearing monocytes in an APP Tg mouse model treated with nasal Protollin. Protollin treatment decreased the expression of costimulatory molecules on monocytes and decreased CD8 + T cell activation and cytotoxicity. Our results provide the basis for a phase 2 study of nasal Protollin in subjects with AD in which nasal Protollin at a dose of 1.0 mg will be administered weekly over 6 months to modulate peripheral immunity and clear amyloid from the brain. ClinicalTrials.gov registration no NCT07187141.

Background and Objectives Progression independent of relapses (PIRA) is a major therapeutic challenge in multiple sclerosis (MS). Nasal anti-CD3 treats animal models of progressive MS by inducing regulatory T cells (Tregs) that suppress CNS inflammation and lessen clinical disease. Methods Ten patients with nonactive secondary progressive MS (naSPMS) that continued to progress on B-cell therapy were treated with nasal anti-CD3 (foralumab) for a minimum of 6 months in an open-label study. Safety monitoring included otolaryngology evaluation and neurologic assessments including Expanded Disability Status Scale (EDSS), MS Functional Composite, Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test, and Low Contract Visual Acuity. MRI and microglial translocator protein (TSPO)-PET imaging with [F-18]PBR06 were conducted. Serum and CSF proteomic biomarkers and single-cell RNA sequencing of blood were performed to evaluate foralumab-induced immunomodulation. The end points of our study were safety, clinical effects, microglial signal, and immune measures. Results Our clinical observations were that all patients stabilized on EDSS scores and 3 of 4 patients treated continuously for 12 months had improvement on EDSS. Six of 10 patients had improvement in fatigue on the MFIS scale. There were no treatment-related serious adverse events or severe AEs, and no new T2 lesions were observed on MRI. There was a reduction in TSPO-PET signal over 6 months (p < 0.05). Changes in peripheral blood gene expression occurred as early as 3 months and affected antigen presentation, interferon responses, and regulatory pathways in multiple cell types including FoxP3+ Tregs, CD4(+) Tcm cells, CD8(+) Tem cells, CD14(+) and CD16(+) monocytes, and B cells. TGF beta expression was increased across multiple cell subsets. Discussion These findings identify a novel, nontoxic immune based therapy for the treatment for PIRA that acts by the induction of a regulatory immune responses and dampens microglial inflammation. Double-blind placebo-controlled trials are warranted to explore nasal foralumab for the treatment of naSPMS.

Abstract Introduction Chronic neuroinflammation in multiple sclerosis (MS) can persist independently of relapse activity, revealing mechanisms of progression not addressed by current therapies. Dysregulated T-cell activity plays a central role in this process and is the main target of nasal Foralumab immunotherapy. Here, we aimed to identify CNS-related biomarkers in the CSF of MS patients linked to disease progression and to define the molecular effects of Foralumab in secondary progressive (SP) MS. Methods We integrated single-cell and proteomic data from PBMC (n = 4) and CSF (n = 23) of MS patients on anti-CD20 therapy or untreated. Data-independent acquisition (DAI) proteomics was performed in CSF of relapsing-remitting (RR) and SP patients. Results CSF proteomic profiling revealed distinct molecular signatures between RR and SP patients. RR samples showed higher levels of immune activation markers (PTPRC, RGS10) and proteins associated with neuronal plasticity and axonal injury (NPTX2, NETO1). In contrast, SP samples were enriched for fibroblast-related proteins involved in tissue injury, fibrosis, and extracellular matrix (ECM) remodeling (FAP, COL8A1), along with elevated cytotoxicity markers (CTSW) and components of the complement cascade. Foralumab treatment significantly reduced the expression of proteins linked to cytotoxic activity (LAMP1), interferon signaling (IFNAR1), tissue injury/fibrosis (COBA1), and NF-κB—dependent inflammation (SIGLEC14, LY86). Notably, increased TGFB1 expression was observed in both CSF and PBMCs, suggesting a regulatory and immunomodulatory effect of the therapy. Conclusion We identified accessible biomarkers distinguishing RR and SP patients and proteins linked to disease progression and found that nasal Foralumab ameliorates MS by increasing TGFB1 and suppressing T cell cytotoxicity and inflammation. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)

A 62-year-old woman with Sjögren syndrome, rheumatoid arthritis, and autoimmune hepatitis presented with subacute confusion and generalized seizures. MRI revealed bilateral mesial temporal T2/FLAIR hyperintensity. Serology revealed anti-SSA and anti-SSB antibodies elevated at 5 times above the upper limit of normal. FDG-PET demonstrated marked relative mesial temporal hypermetabolism with widespread hypometabolism in the rest of the brain; z-score mapping confirmed focal mesial temporal hyperactivity. They received immunotherapy and antiseizure therapy. After 1 year, cognition improved, though memory deficits persisted. Follow-up FDG-PET showed a transition from mesial temporal hypermetabolism to relative hypometabolism, with recovery of cortical metabolism, highlighting FDG-PET's role in diagnosing and monitoring autoimmune limbic encephalitis in Sjögren syndrome.

BACKGROUND:Cognitive impairment is common in persons with multiple sclerosis (pwMS) and is associated with reduced health-related quality of life. Self-report measures are sometimes used to identify cognitive deficits, but the association between subjective and objective cognitive function is unclear. METHODS:We analyzed data from 345 pwMS who were administered two objective measures of cognitive functioning: Symbol Digit Modalities Test (SDMT), a measure of processing speed, and California Verbal Learning Test-II (CVLT-II), a measure of verbal learning. Participants also completed the computer adaptive testing version of Quality of Life in Neurological Disorders (Neuro-QoL). Subjective cognitive function was assessed using the Neuro-QoL Cognitive Function domain, which measures perceived difficulties with memory, attention, and decision-making. Neuro-QoL Anxiety, Depression, and Fatigue domains were also included in the analysis. RESULTS:In univariate analyses, subjective cognitive function was associated with SDMT, CVLT-II, Neuro-QoL Anxiety, Neuro-QoL Depression, and Neuro-QoL Fatigue (p < 0.05 for each comparison). Using a multivariable regression model that included SDMT, CVLT-II, Neuro-QoL Anxiety, Neuro-QoL Depression, and Neuro-QoL Fatigue, self-reported cognitive function was not associated with SDMT or CVLT-II. Instead, fatigue had the strongest association with subjective cognitive function in the presence of the other variables. Anxiety and depression were also independent predictors of self-reported cognitive function. CONCLUSIONS:In pwMS, self-reported cognitive function was more closely associated with anxiety, depression, and fatigue than objective measures of cognitive functioning. These findings suggest that screening for anxiety, depression, and fatigue is important in the clinical interpretation of self-reported cognitive deficits.

Background:Progression independent of relapses (PIRA) is a major therapeutic challenge in multiple sclerosis (MS). Nasal anti-CD3 treats animal models of progressive MS by inducing regulatory T cells (Tregs) that suppress central nervous system (CNS) inflammation and lessen clinical disease. Methods:Ten patients with non-active secondary progressive MS (naSPMS) that continued to progress on B cell therapy were treated with nasal anti-CD3 (foralumab) for a minimum of six months in an open label study. Safety monitoring included otolaryngology evaluation and neurologic assessments including Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC-4), Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test (CVLT-II) and Low Contract Visual Acuity (LCVA). MRI and microglial translocator protein (TSPO)-PET imaging with [F-18]PBR06 were conducted. Serum and cerebrospinal fluid (CSF) proteomic biomarkers and single cell RNA sequencing of blood was performed to evaluate foralumab-induced immunomodulation. The endpoints of our study were safety, clinical effects, microglial signal and immune measures. Results:All patients stabilized on EDSS scores and three of four patients treated continuously for 12 months had improvement on EDSS. Six of 10 patients had improvement in fatigue on the MFIS scale. There were no treatment-related serious adverse events (SAEs) or severe AEs and no new T2 lesions were observed on MRI. There was a reduction in TSPO-PET signal over six months (p<0.05). Changes in peripheral blood gene expression occurred as early as three months and affected antigen presentation, interferon responses and regulatory pathways in multiple cell types including FoxP3+ Tregs, CD4+ Tcm cells, CD8+ Tem cells, CD14+ and CD16+ monocytes and B cells. TGFβ expression was increased across cell multiple subsets. Interpretation:These findings identify a novel, non-toxic immune based therapy for the treatment for PIRA that acts by the induction of a regulatory immune responses and dampens microglial inflammation. Double blind placebo-controlled trials are warranted to explore nasal foralumab for the treatment of naSPMS.

BACKGROUND AND PURPOSE:Cladribine, an FDA-approved disease-modifying immunotherapy for multiple sclerosis (MS), penetrates the CSF and mitigates T cells and B cells, and thus may impact the development of cortical gray matter lesions (CLs) and leptomeningeal enhancement (LME). 7T MRI is a highly sensitive tool for monitoring these outcomes in relapsing-remitting (RR) MS. METHODS:MS subjects (n = 19, age [mean ± standard deviation]: 48.8 ± 10.0 years, 63.1% RRMS, 36.9% secondary progressive MS, Expanded Disability Status Scale [EDSS] score 4.1 ± 2.0) underwent 7T MRI with 0.7-mm3 voxels within a mean 1.9 months of oral cladribine initiation and ∼1 year later in this real-world study. CLs and LME were quantified by an expert. Wilcoxon signed rank tests and paired t-tests compared baseline to follow-up data. RESULTS:A total of 88.2% of subjects had CLs at baseline (mean 14.1 CLs/patient, range 1-77). No subjects accrued new CLs, and CL volume remained stable (0.33 ± 0.48 mL baseline vs. 0.31 ± 0.46 mL follow-up, p = 0.22). LME was found in 88.9% of subjects at baseline. LME foci number was stable in seven (41.2%), increased in five (29.4%), and decreased in five (29.4%) subjects at follow-up, but overall LME burden was stable (3.1 ± 1.8 vs. 3.2 ± 1.6 foci per subject, p = 1.0). No EDSS or timed 25-foot walk change was noted (both p > 0.35). No subjects had clinical relapses or new T2 or gadolinium-enhancing white matter lesions during the study. CONCLUSION:These observational data suggest that cladribine therapy stabilizes cortical demyelination in MS over the first year of treatment. Overall, LME burden remained stable over 1 year; however, within-subject resolution and accrual were noted.

A 78-year-old man with moderate Alzheimer disease (AD) dementia was treated with nasal-foralumab, a fully human anti-CD3 monoclonal antibody, as part of a Food and Drug Administration expanded-access-program, based on previously demonstrated efficacy of anti-CD3 antibody in animal models. 18 F-PBR06-PET, utilizing a second-generation 18-kDa-translocator-protein ligand targeting microglia, showed diffuse reduction of radiotracer uptake throughout the brain, following 3 months of nasal-foralumab compared with baseline. In particular, precuneus, posterior cingulate and anterior cingulate gyri, regions that had high levels of amyloid deposition on a baseline 18 F-Florbetapir-PET scan, showed reduction in microglial activation after nasal-foralumab treatment for 3 months.

These days, there is increasing curiosity regarding the topic of spiking neural networks (SNNs). Compared to artificial neural networks (ANNs), which are the subsequent equivalents, they bear a greater resemblance to the real neural networks found in the brain. SNNs are based on events such as neuromorphic factors; hardware based on SNNs may be less energy-intensive than ANNs. Since the energy usage would be far lower than that of typical deep learning models housed in the cloud today, this could result in a significant reduction in maintenance costs for neural network models. Such gear is still not readily accessible, however. This chapter presents a Systematic Review of Spiking Neural Networks and Their Applications. This study examines the benefits and drawbacks of various neural model types, coding techniques, methods for learning, and Neuromorphic platforms for computing. Based on these analyses, some anticipated developments are suggested, including balancing biological imitation and computing costs for neuron theories, the process of compounding coding techniques, unsupervised algorithms for learning in SNN, and digital-analog computation systems.

Energy harvesting has emerged as a crucial field of science and engineering at the crossroads. Energy harvesting involves capturing energy from the surroundings and transforming it into usable electricity. This paper investigates the design and simulation of an efficient solar energy harvesting system based on single electron transistor (SET) charge quantification. The unique capability of SET to accurately quantify the charge generated by solar cell is used in this investigation. The MATLAB environment is used for refinement of algorithm used for precise charge estimation with in SET system. The impact of different environment parameters that includes temperature fluctuations, influence of noise and change in intensity of light is also obtained using MATLAB simulation. The robustness and accuracy of the system in charge quantification is evaluated using impact of these physical parameters. The results exhibited a robust sensitivity of the system, maintaining an average accuracy of 97.5 % across varying environmental parameters.

To assess the effect of nasal foralumab, a fully-human anti-CD3 monoclonal-antibody on microglial activation in non-active secondary progressive multiple sclerosis (na-SPMS) with PIRA (progression independent of relapses).