Corticosteroid treatment for acute hydrocephalus in neurosarcoidosis: a case report.

BACKGROUND: Neurosarcoidosis occurs symptomatically in 5-10% of patients with sarcoidosis, and hydrocephalus is a rare complication of neurosarcoidosis, with either acute or subacute onset and presenting symptoms related to increased intracranial pressure. It represents a potentially fatal manifestation with a mortality rate of 22% (increased to 75% in case of coexistence of seizures) that requires a prompt initiation of treatment. High-dose intravenous corticosteroid treatment and neurosurgical treatment must be considered in all cases of neurosarcoidosis hydrocephalus. CASE PRESENTATION: Here we present a case of hydrocephalus in neurosarcoidosis, complicated by generalized seizures, in a 29-year-old Caucasian male patient treated with medical treatment only, with optimal response. CONCLUSION: Since neurosurgery treatment can lead to severe complications, this case report underlines the possibility to undergo only medical treatment in selected cases. Further studies are needed to stratify patients and better identify those eligible for only medical approach.

Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell-target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD-related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN-KO). In the former, we evaluated the ability of ß-amyloid oligomers (AßOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN-KO mice. Next, we generated a tamoxifen-inducible astrocyte-specific CaNB1 knock-out in 3xTg-AD mice (indACNKO-AD). CaNB1 was deleted, by tamoxifen injection, in 11.7-month-old 3xTg-AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; ß-amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AßOs in 2-month-old wild type mice impaired recognition memory and fostered a pro-inflammatory microglia phenotype, whereas in ACN-KO mice, AßOs were inactive. In indACNKO-AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte-specific CaNB1 deletion is beneficial for both the abolishment of AßO-mediated detrimental effects and treatment of ongoing AD-related pathology, hence representing an intriguing target for AD therapy.

Current use of fluid biomarkers as outcome measures in Multiple Sclerosis (MS): a review of ongoing pharmacological clinical trials.

The present study aims to describe the state of the art of fluid biomarkers use in ongoing multiple sclerosis (MS) clinical trials.A review of 608 ongoing protocols in the clinicaltrials.gov and EudraCT databases was performed. The trials enrolled patients with a diagnosis of relapsing remitting MS, secondary progressive MS, and/or primary progressive MS according to Revised McDonald criteria or relapsing MS according to Lublin et al. (2014). The presence of fluid biomarkers among the primary and/or secondary study outcomes was assessed.Overall, 5% of ongoing interventional studies on MS adopted fluid biomarkers. They were mostly used as secondary outcomes in phase 3-4 clinical trials to support the potential disease-modifying properties of the intervention. Most studies evaluated neurofilament light chains (NfLs). A small number considered other novel fluid biomarkers of neuroinflammation and neurodegeneration such as glial fibrillary acid protein (GFAP).Considering the numerous ongoing clinical trials in MS, still a small number adopted fluid biomarkers as outcome measures, thus testifying the distance from clinical practice. In most protocols, fluid biomarkers were used to evaluate the effectiveness of approved second-line therapies, but also, new drugs (particularly Bruton kinase inhibitors). NfLs were also adopted to monitor disease progression after natalizumab suspension in stable patients, cladribine efficacy after anti-CD20 discontinuation, and the efficacy of autologous hematopoietic stem cell transplant (AHSCT) compared to medical treatment. Nevertheless, further validation studies are needed for all considered fluid biomarkers to access clinical practice, and cost-effectiveness in the "real word" remains to be clarified.

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aß) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE-Aß interaction inhibitors produced positive results in transgenic AD mouse models.

Repositioning doxycycline for treating synucleinopathies: Evidence from a pre-clinical mouse model.

BACKGROUND AND PURPOSE: Parkinson's disease remains orphan of valuable therapies capable to interfere with the disease pathogenesis despite the large number of symptomatic approaches adopted in clinical practice to manage this disease. Treatments simultaneously affecting α-synuclein (α-syn) oligomerization and neuroinflammation may counteract Parkinson's disease and related disorders. Recent data demonstrate that Doxycycline, a tetracycline antibiotic, can inhibit α-syn aggregation as well as neuroinflammation. We herein investigate, for the first time, the potential therapeutic properties of Doxy in a human α-syn A53T transgenic Parkinson's disease mouse model evaluating behavioural, biochemical and histopathological parameters. EXPERIMENTAL APPROACH: Human α-syn A53T transgenic mice were treated with Doxycycline (10 mg/kg daily ip) for 30 days. The effect of treatment on motor, cognitive and daily live activity performances were examined. Neuropathological and neurophysiological parameters were assessed through immunocytochemical, electrophysiological and biochemical analysis of cerebral tissue. KEY RESULTS: Doxy treatment abolished cognitive and daily life activity deficiencies in A53T mice. The effect on cognitive functions was associated with neuroprotection, inhibition of α-syn oligomerization and gliosis both in the cortex and hippocampus. Doxy treatment restored hippocampal long-term potentiation in association with the inhibition of pro-inflammatory cytokines expression. Moreover, Doxy ameliorated motor impairment and reduced striatal glial activation in A53T mice. CONCLUSIONS AND IMPLICATIONS: Our findings promote Doxy as a valuable multi-target therapeutic approach counteracting both symptoms and neuropathology in the complex scenario of α-synucleinopathies.

K index utility as diagnostic and prognostic biomarker in the assessment of patients with suspected Multiple Sclerosis.

The aim of the present study is to evaluate the composite role of k index in the initial assessment of Multiple Sclerosis (MS) patients and to select useful cut-offs exportable in clinical practice. We analysed CSF/serum samples of 140 patients and followed-up the CIS/MS subgroup for 7 years. Our results suggest κ index as a quantitative diagnostic and prognostic biomarker in MS, significantly associated to baseline lesion load and to successive clinical course. We propose k index ≥106 as a prognostic cut-off to select patients at major risk of relapse, potentially influencing initial therapeutic decisions.

Oligomeropathies, inflammation and prion protein binding.

The central role of oligomers, small soluble aggregates of misfolded proteins, in the pathogenesis of neurodegenerative disorders is recognized in numerous experimental conditions and is compatible with clinical evidence. To underline this concept, some years ago we coined the term oligomeropathies to define the common mechanism of action of protein misfolding diseases like Alzheimer, Parkinson or prion diseases. Using simple experimental conditions, with direct application of synthetic ß amyloid or α-synuclein oligomers intraventricularly at micromolar concentrations, we could detect differences and similarities in the biological consequences. The two oligomer species affected cognitive behavior, neuronal dysfunction and cerebral inflammatory reactions with distinct mechanisms. In these experimental conditions the proposed mediatory role of cellular prion protein in oligomer activities was not confirmed. Together with oligomers, inflammation at different levels can be important early in neurodegenerative disorders; both ß amyloid and α-synuclein oligomers induce inflammation and its control strongly affects neuronal dysfunction. This review summarizes our studies with ß-amyloid or α-synuclein oligomers, also considering the potential curative role of doxycycline, a well-known antibiotic with anti-amyloidogenic and anti-inflammatory activities. These actions are analyzed in terms of the therapeutic prospects.

The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer's disease.

The development of new therapeutic avenues that target the early stages of Alzheimer's disease (AD) is urgently necessary. A disintegrin and metalloproteinase domain 10 (ADAM10) is a sheddase that is involved in dendritic spine shaping and limits the generation of amyloid-ß. ADAM10 endocytosis increases in the hippocampus of AD patients, resulting in the decreased postsynaptic localization of the enzyme. To restore this altered pathway, we developed a cell-permeable peptide (PEP3) with a strong safety profile that is able to interfere with ADAM10 endocytosis, upregulating the postsynaptic localization and activity of ADAM10. After extensive validation, experiments in a relevant animal model clarified the optimal timing of the treatment window. PEP3 administration was effective for the rescue of cognitive defects in APP/PS1 mice only if administered at an early disease stage. Increased ADAM10 activity promoted synaptic plasticity, as revealed by changes in the molecular compositions of synapses and the spine morphology. Even though further studies are required to evaluate efficacy and safety issues of long-term administration of PEP3, these results provide preclinical evidence to support the therapeutic potential of PEP3 in AD.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

A critical appraisal of tau-targeting therapies for primary and secondary tauopathies.

INTRODUCTION: Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. METHODS: We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. RESULTS: The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti-tau monoclonal antibodies have not shown clinical efficacy. DISCUSSION: The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non-specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and post-translational tau modifications.

COVID-19-associated immune-mediated encephalitis mimicking acute-onset Creutzfeldt-Jakob disease.

We report a subtype of immune-mediated encephalitis associated with COVID-19, which closely mimics acute-onset sporadic Creutzfeldt-Jakob disease. A 64-year-old man presented with confusion, aphasia, myoclonus, and a silent interstitial pneumonia. He tested positive for SARS-CoV-2. Cognition and myoclonus rapidly deteriorated, EEG evolved to generalized periodic discharges and brain MRI showed multiple cortical DWI hyperintensities. CSF analysis was normal, except for a positive 14-3-3 protein. RT-QuIC analysis was negative. High levels of pro-inflammatory cytokines were present in the CSF and serum. Treatment with steroids and intravenous immunoglobulins produced EEG and clinical improvement, with a good neurological outcome at a 6-month follow-up.

Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures.

Calcineurin (CaN), acting downstream of intracellular calcium signals, orchestrates cellular remodeling in many cellular types. In astrocytes, major homeostatic players in the central nervous system (CNS), CaN is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we report that in mice with conditional deletion of CaN in GFAP-expressing astrocytes (astroglial calcineurin KO, ACN-KO), at 1 month of age, transcription was largely unchanged, while the proteome was deranged in the hippocampus and cerebellum. Gene ontology analysis revealed overrepresentation of annotations related to myelin sheath, mitochondria, ribosome and cytoskeleton. Over-represented pathways were related to protein synthesis, oxidative phosphorylation, mTOR and neurological disorders, including Alzheimer's disease (AD) and seizure disorder. Comparison with published proteomic datasets showed significant overlap with the proteome of a familial AD mouse model and of human subjects with drug-resistant seizures. ACN-KO mice showed no alterations of motor activity, equilibrium, anxiety or depressive state. However, in Barnes maze ACN-KO mice learned the task but adopted serial search strategy. Strikingly, beginning from about 5 months of age ACN-KO mice developed spontaneous tonic-clonic seizures with an inflammatory signature of epileptic brains. Altogether, our data suggest that the deletion of astroglial CaN produces features of neurological disorders and predisposes mice to seizures. We suggest that calcineurin in astrocytes may serve as a novel Ca2+-sensitive switch which regulates protein expression and homeostasis in the central nervous system.

Hippuric acid: Could became a barometer for frailty and geriatric syndromes?

Aging is a natural biological event that has some downsides such as increased frailty, decline in cognitive and physical functions leading to chronical diseases, and lower quality of life. There is therefore a pressing need of reliable biomarkers to identify populations at risk of developing age-associated syndromes in order to improve their quality of life, promote healthy ageing and a more appropriate clinical management, when needed. Here we discuss the importance of hippuric acid, an endogenous co-metabolite, as a possible hallmark of human aging and age-related diseases, summarizing the scientific literature over the last years. Hippuric acid, the glycine conjugate of benzoic acid, derives from the catabolism by means of intestinal microflora of dietary polyphenols found in plant-based foods (e.g. fruits, vegetables, tea and coffee). In healthy conditions hippuric acid levels in blood and/or urine rise significantly during aging while its excretion drops in conditions related with aging, including cognitive impairments, rheumatic diseases, sarcopenia and hypomobility. This literature highlights the utility of hippuric acid in urine and plasma as a plausible hallmark of frailty, related to low fruit and vegetable intake and changes in gut microflora.

Plasmatic Hippuric Acid as a Hallmark of Frailty in an Italian Cohort: The Mediation Effect of Fruit-Vegetable Intake.

Frailty syndrome is an age-related condition involving a loss of resilience, susceptibility to adverse health outcomes, and poor quality of life. This study was conducted in the framework of InveCe.Ab, an ongoing longitudinal population-based study. Plasma from 130 older individuals (older adults aged 76-78 years) was analyzed and validated (on 303 participants) using mass spectrometry-based metabolomics approaches. Equivalence tests showed that metabolites from the central cellular metabolic pathways were equivalent in frail and fit participants. Hippuric acid was the only cometabolite that distinguished fit from frail older adults. Logistic regression analysis indicated that high hippuric acid levels are significantly associated with a reduction of the risk of frailty after 4 years. Mediation analysis using a Frailty Index, hippuric acid, and fruit-vegetable intake supported the role of fruit-vegetable consumption in the hippuric acid relationship with the Frailty Index. These data point to low plasma hippuric acid as a plausible hallmark of frailty status, associated with lower fruit-vegetable intakes.

Accelerating Alzheimer's disease drug discovery and development: what's the way forward?

Introduction: As the global burden of Alzheimer's disease (AD) grows, an effective disease-modifying therapy remains a distant prospect following the repeated failure of multiple therapeutics targeting ß-amyloid and (it seems) tau over many years of costly effort. The repeated failure of single-target therapies to meaningfully modify disease progression raises major questions about the validity of many aspects of drug development in this area, especially target selection.Area covered: The authors explore the critical questions raised by a review of the collective experience to date, relating to why findings with non-clinical models and clinical biomarkers so frequently fail to translate to positive outcomes in clinical trials, which alternatives should be considered, and how we can design and conduct clinical trials that can successfully identify and quantify meaningful benefits in the future.Expert opinion: It is our opinion that we must recognize and accept the need to consider less specific, more multimodal approaches to addressing neurodegeneration in AD if we are to make progress - and we must avoid repeating the well intentioned, but ultimately erroneous, assumptions of the past.

Corrigendum: X-ray Phase Contrast Tomography Serves Preclinical Investigation of Neurodegenerative Diseases.

[This corrects the article DOI: 10.3389/fnins.2020.584161.].

Who is really blind in the time of coronavirus: the patient or the doctor? A rare case of Balint's syndrome.

BACKGROUND: Selective bilateral lesions of the parietal-occipital lobes can lead to an uncommon and incompletely understood clinical entity, Balint' syndrome, which consists of simultanagnosia, oculomotor apraxia, optic ataxia and difficulty in perceiving distances between objects. CASE PRESENTATION: We herein report a rare presentation of Balint's syndrome in a 65-year-old woman suffering from stroke and SARS-CoV2 infection. CONCLUSION: During SARS-CoV2 pandemic, Italian physicians were forced to work with less instrumental diagnostic resources, relying on their clinical knowledge mostly. The aim of this case report is to highlight the importance of performing a precise neurological evaluation, particularly during these challenging times: it might avoid incorrect diagnosis and favour the discovery of rare clinical diseases.

Inflammation and Parkinson's disease pathogenesis: Mechanisms and therapeutic insight.

After Alzheimer's disease, Parkinson's disease is the most frequent neurodegenerative disorder. Although numerous treatments have been developed to control the disease symptomatology, with some successes, an efficacious therapy affecting the causes of PD is still a goal to pursue. The genetic evidence and the identification of α-synuclein as the main component of intracellular Lewy bodies, the neuropathological hallmark of PD and related disorders, have changed the approach to these disorders. More recently, the detrimental role of α-synuclein has been further extended to explain the wide spread of cerebral pathology through its oligomers. To emphasize the central pathogenic role of these soluble aggregates, we have defined synucleinopathies and other neurodegenerative disorders associated with protein misfolding as oligomeropathies. Another common element in the pathogenesis of oligomeropathies is the role played by inflammation, both at the peripheral and cerebral levels. In the brain parenchyma, inflammatory reaction has been considered an obvious consequence of neuronal degeneration, but recent observations indicate a direct contribution of glial alteration in the early phase of the disease. Furthermore, systemic inflammation also influences the development of neuronal dysfunction caused by specific elements, ß amyloid, α-synuclein, tau or prion. However, each disorder has its own specific pathological process and within the same pathological condition, it is possible to find inter-individual differences. This heterogeneity might explain the difficulties developing efficacious therapeutic approaches, even though the possibility of intervention is supported by robust biological evidence. We have recently demonstrated that peripheral inflammation can amplify the neuronal dysfunction induced by α-synuclein oligomers and the neuropathological consequences observed in a Parkinson's disease model. In both cases, activation of microglia was incremented by the "double hit" process, compared to the single treatment. In contrast, astrocyte activation was attenuated and these cells appeared damaged when chronic inflammation was combined with α-synuclein exposure. This evidence might indicate a more specific anti-inflammatory strategy rather than the generic anti-inflammatory treatment.