Age-dependent effects of microglial inhibition in vivo on Alzheimer’s disease neuropathology using bioactive-conjugated iron oxide nanoparticles

Background: Tau dysfunction is believed to be the primary cause of neurodegenerative disorders referred to as tauopathies, including Alzheimer’s disease, Pick’s disease, frontotemporal dementia and Parkinsonism. The role of microglial cells in the pathogenesis of tauopathies is still unclear. The activation of microglial cells has been correlated with neuroprotective effects through the release of neurotrophic factors and through clearance of cell debris and phagocytosis of cells with intracellular inclusions. In contrast, microglial activation has also been linked with chronic neuroinflammation contributing to the development of neurodegenerative diseases such as tauopathies. Microglial activation has been recently reported to precede tangle formation and the attenuation of tau pathology occurs after immunosuppression of transgenic mice. Methods: Here we report the specific inhibition of microglial cells in rTg4510 tau-mutant mice by using fibrin γ377-395 peptide conjugated to iron oxide (γ-Fe2O3) nanoparticles of 21 ± 3.5 nm diameter. Results: Stabilization of the peptide by its covalent conjugation to the γ-Fe2O3 nanoparticles significantly decreased the number of the microglial cells compared to the same concentration of the free peptide. The specific microglial inhibition induces different effects on tau pathology in an age dependent manner. The reduction of activation of microglial cells at an early age increases the number of neurons with hyperphosphorylated tau in transgenic mice. In contrast, reduction of activation of microglial cells reduced the severity of the tau pathology in older mice. The number of neurons with hyperphosphorylated tau and the number of neurons with tangles are reduced than those in animals not receiving the fibrin γ377-395 peptide-nanoparticle conjugate. Conclusions: These results demonstrate a differential effect of microglial activity on tau pathology using the fibrin γ377-395 peptide-nanoparticle conjugate, depending on age and/or stage of the neuropathological accumulation and aggregation

Visual Field Endpoints Based on Subgroups of Points May Be Useful in Glaucoma Clinical Trials: A Study With the Humphrey Field Analyzer and Compass Perimeter

PRECIS: Visual field endpoints based on average deviation of specific subsets of points rather than all points may offer a more homogenous dataset without necessarily worsening test-retest variability and so may be useful in clinical trials. PURPOSE: To characterize outcome measures encompassing particular subsets of visual field points and compare them as obtained with Humphrey (HVF) and Compass perimeters. METHODS: 30 patients with imaging-based glaucomatous neuropathy performed a pair of 24-2 tests with each of 2 perimeters. Non-weighted mean deviation (MD) was calculated for the whole field and separate vertical hemifields, and again after censoring of points with low sensitivity (MDc) and subsequently including only "abnormal" points with total deviation probability of <5% (MDc5%) or <2% (MDc2%). Test-retest variability was assessed using Bland-Altman 95% limits of agreement (95%LoA). RESULTS: For the whole field, using HVF, MD was -7.5±6.9▒dB, MDc -3.6±2.8▒dB, MDc5% -6.4±1.7▒dB and MDc2% -7.3±1.5▒dB. With Compass MD was -7.5±6.6, MDc -2.9±1.7▒dB, MDc5% -6.3±1.5, and MDC2% -7.9±1.6. The respective 95% LoA were 5.5, 5.3, 4.6 and 5.6 with HVF, and 4.8, 3.7, 7.1 and 7.1 with Compass. The respective number of eligible points were 52, 42±12, 20±11 and 15±9 with HVF, and 52, 41.2±12.6, 10±7 and 7±5 with Compass. With both machines, standard deviation (SD) and 95%LoA increased in hemifields compared to the total field, but this increase was mitigated after censoring. CONCLUSIONS: Restricting analysis to particular subsets of points of interest in the visual field after censoring points with low sensitivity, as compared with using the familiar total field mean deviation, can provide outcome measures with a broader range of mean deviation, a markedly reduced SD and therefore more homogenous dataset, without necessarily worsening test-retest variability

Rheological properties of magnetic biogels

We report an experimental and theoretical study of the rheological properties of magnetic biogels consisting of fibrin polymer networks with embedded magnetite nanoparticles, swollen by aqueous solutions. We studied two types of magnetic biogels, differenced by the presence or absence of an applied magnetic field during the initial steps of cross-linking. The experiments demonstrated very strong dependence of the elastic modulus of the magnetic biogels on the concentration of the magnetic particles. We finally developed some theoretical models that explain the observed strong concentration effects.This study was supported by projects FIS2013-41821-R (Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, MINECO, Spain, co-funded by ERDF, European Union) and FIS2017-85954-R (Ministerio de Economía, Industria y Competitividad, MINECO, andAgencia Estatal de Investigación, AEI, Spain, co-funded by Fondo Europeo de Desarrollo Regional, FEDER, European Union). A.Z. is grateful to the program of the Ministry of Education and Science of the Russian Federation, projects 02.A03.21.0006, 3.1438.2017/4.6, and 3.5214.2017/6.7, as well as to the Russian Fund of Basic Researches, project 18-08-00178

Cognitive Performance of Patients With Multiple Sclerosis and Optic Neuritis at Presentation

Cognitive dysfunction is common among patients with multiple sclerosis (MS), but the effect of coexisting optic neuritis (ON) at the first presentation of multiple sclerosis on the course of cognitive decline is unknown. The purpose of this study was to assess whether ON at presentation has any effect on the progression of cognitive decline in MS

Ultrasound cyclo plasty for treatment of surgery-naïve open-angle glaucoma patients: A prospective, multicenter, 2-year follow-up trial

Background: The purpose of this prospective study was to evaluate the efficacy and safety of the Ultrasound Cyclo Plasty (UCP) procedure using high-intensity focused ultrasound in sur-gery-naïve open-angle glaucoma patients. Methods: prospective, non-randomized, single-arm, multicenter clinical trial. Sixty-six eyes with primary open-angle glaucoma, intraocular pressure (IOP) ≥21 mmHg and with no history of filtering surgery were enrolled. Patients were treated by UCP with a therapy probe comprising six piezoelectric transducers, consecutively activated for 8 s each. Complete ophthalmic examination was performed before the procedure, 1 day after the pro-cedure, and 1, 3, 6, 12, 18 and 24 months after the procedure. Primary outcomes were complete success (defined as IOP lowering from baseline ≥20% without additional glaucoma medications) and vision-threatening complications. Secondary outcomes were the presence of complications and the reduction of the number of medications used. Results: IOP was significantly reduced after one procedure (p &lt; 0.05), from a mean pre-operative value of 24.3 ± 2.9 mmHg (n = 2.3 hypotensive medications) to a mean value of 15.9 ± 3.6 mmHg (n = 2.2 hypotensive medications) at 2 years (mean IOP lowering of 33%). Surgical success was achieved in 74% of eyes. Notwithstanding side effects such as transient anterior chamber inflammation, refractive error changes, transient hypotony and macular edema, no major intra or post-operative complications such as phthisis, induced cataract, neovascularization or significant vision loss were observed. Conclusions: Ultrasound Cyclo Plasty is a valuable, effective and well-tolerated procedure to lower IOP in patients with open-angle glaucoma without previous filtering surgery

Visual field endpoints based on subgroups of points may be useful in glaucoma clinical trials: A study with the humphrey field analyzer and compass perimeter

Precis: Visual field (VF) endpoints based on average deviation of specific subsets of points rather than all points may offer a more homogeneous data set without necessarily worsening test-retest variability and so may be useful in clinical trials. Purpose: The purpose of this study was to characterize the outcome measures encompassing particular subsets of VF points and compare them as obtained with Humphrey [Humphrey visual field analyser (HVF)] and Compass perimeters. Methods: Thirty patients with imaging-based glaucomatous neuropathy performed a pair of 24-2 tests with each of 2 perimeters. Nonweighted mean deviation (MD) was calculated for the whole field and separate vertical hemifields, and again after censoring of points with low sensitivity (MDc) and subsequently including only “abnormal” points with a total deviation probability of < 5% (MDc5%) or <2% (MDc2%). Test-retest variability was assessed using Bland-Altman 95% limits of agreement (95%LoA). Results: For the whole field, using HVF, MD was −7.5 ± 6.9 dB, MDc −3.6 ± 2.8 dB, MDc5% −6.4 ± 1.7 dB, and MDc2% −7.3 ± 1.5 dB. With Compass the MD was −7.5 ± 6.6, MDc −2.9 ± 1.7 dB, MDc5% −6.3 ± 1.5, and MDC2% −7.9 ± 1.6. The respective 95%LoA were 5.5, 5.3, 4.6, and 5.6 with HVF, and 4.8, 3.7, 7.1, and 7.1 with Compass. The respective number of eligible points were 52, 42 ± 12, 20 ± 11, and 15 ± 9 with HVF, and 52, 41.2 ± 12.6, 10 ± 7, and 7 ± 5 with Compass. With both machines, SD and 95%LoA increased in hemifields compared with the total field, but this increase was mitigated after censoring. Conclusion: Restricting analysis to particular subsets of points of interest in the VF after censoring points with low sensitivity, as compared with using the familiar total field MD, can provide outcome measures with a broader range of MD, a markedly reduced SD and therefore more homogeneous data set, without necessarily worsening test-retest variability

Association between Rates of Retinal Nerve Fiber Layer Thinning and Previous Disc Hemorrhage in Glaucoma.

PurposeTo investigate the relationship between previous disc hemorrhage (DH) and subsequent rates of retinal nerve fiber layer (RNFL) thinning.DesignLongitudinal, observational cohort study.ParticipantsTwenty-eight patients with glaucoma and patients with suspected glaucoma who had a history of DH in 1 eye (unilateral DH), but not in the fellow eye, enrolled in the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study were included.MethodsAll subjects underwent annual optic disc photography and semiannual spectral-domain OCT RNFL thickness measurements. Multivariable linear mixed-effects models were used to investigate the relationship between the presence of previous DH and RNFL thinning rates while adjusting for potential confounding factors, such as race, age, mean intraocular pressure (IOP), baseline disease severity, and central corneal thickness (CCT). The relationship between the timing of DH and the rates of RNFL thinning also was investigated in eyes with a history of DH.Main outcome measuresRates of global and local RNFL thinning.ResultsPrevious DH was significantly associated with faster RNFL thinning rates globally (-0.39 μm/year faster, P&nbsp;= 0.010), in DH quadrants (-0.77 μm/year faster, P&nbsp;= 0.012), and non-DH quadrants (-0.49 μm/year faster, P&nbsp;= 0.038) after adjustment for race, mean IOP, baseline age, baseline standard automated perimetry mean deviation, and CCT. Higher IOP was also significantly associated with faster thinning rates globally (-0.07 μm/year faster per 1 mmHg higher, P&nbsp;= 0.047) and in DH quadrants (-0.10 μm/year faster per 1 mmHg higher, P&nbsp;= 0.044). In eyes with a history of DH, the time elapsed from the latest DH episode to the first OCT examination was not significantly associated with the rate of RNFL thinning.ConclusionsA history of DH is an independent risk factor for faster rates of RNFL thinning in non-DH quadrants and in DH quadrants; this risk is present even in eyes that exhibited DH several years earlier

Association between Rates of Retinal Nerve Fiber Layer Thinning and Previous Disc Hemorrhage in Glaucoma.

PurposeTo investigate the relationship between previous disc hemorrhage (DH) and subsequent rates of retinal nerve fiber layer (RNFL) thinning.DesignLongitudinal, observational cohort study.ParticipantsTwenty-eight patients with glaucoma and patients with suspected glaucoma who had a history of DH in 1 eye (unilateral DH), but not in the fellow eye, enrolled in the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study were included.MethodsAll subjects underwent annual optic disc photography and semiannual spectral-domain OCT RNFL thickness measurements. Multivariable linear mixed-effects models were used to investigate the relationship between the presence of previous DH and RNFL thinning rates while adjusting for potential confounding factors, such as race, age, mean intraocular pressure (IOP), baseline disease severity, and central corneal thickness (CCT). The relationship between the timing of DH and the rates of RNFL thinning also was investigated in eyes with a history of DH.Main outcome measuresRates of global and local RNFL thinning.ResultsPrevious DH was significantly associated with faster RNFL thinning rates globally (-0.39 μm/year faster, P&nbsp;= 0.010), in DH quadrants (-0.77 μm/year faster, P&nbsp;= 0.012), and non-DH quadrants (-0.49 μm/year faster, P&nbsp;= 0.038) after adjustment for race, mean IOP, baseline age, baseline standard automated perimetry mean deviation, and CCT. Higher IOP was also significantly associated with faster thinning rates globally (-0.07 μm/year faster per 1 mmHg higher, P&nbsp;= 0.047) and in DH quadrants (-0.10 μm/year faster per 1 mmHg higher, P&nbsp;= 0.044). In eyes with a history of DH, the time elapsed from the latest DH episode to the first OCT examination was not significantly associated with the rate of RNFL thinning.ConclusionsA history of DH is an independent risk factor for faster rates of RNFL thinning in non-DH quadrants and in DH quadrants; this risk is present even in eyes that exhibited DH several years earlier