Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials

: We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants

Chiral QED in Terms of Chiral Boson with a Generalized Fadeevian Regularization

Chiral QED with a generalized Fadeevian regularization is considered. Imposing a chiral constraint a gauged version of Floranini-Jackiw lagrangian is constructed. The imposition of the chiral constarint has spoiled t he manifestly Lorentz covariance of the theory. The phase space structure for this theory has been det ermined. It is found that spectrum changes drastically but it is Lorentz invariant. Chiral fermion di sappears from the spectra and the photon anquire mass as well. Poincare algebra has been calculated to show physicial Lorentz invariance explicitely.Comment: 11 page

Are NSAIDs Useful to Treat Alzheimer's Disease or Mild Cognitive Impairment?

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect subjects carrying one or more ε4 allele of the apolipoprotein E (APOE ε4) against the onset of Alzheimer's disease (AD). The biological mechanism of this protection is not completely understood and may involve the anti-inflammatory properties of NSAIDs or their ability of interfering with the β-amyloid (Aβ) cascade. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and cyclooxygenase-2 (COX-2) selective inhibitors in mild-to-moderate AD patients produced negative results. A secondary prevention study with rofecoxib, a COX-2 selective inhibitor, in patients with mild cognitive impairment was also negative. A primary prevention study (ADAPT trial) of naproxen (a non-selective COX inhibitor) and celecoxib (a COX-2 selective inhibitor) in cognitively normal elderly subjects with a family history of AD was prematurely interrupted for safety reasons after a median period of treatment of 2 years. Although both drugs did not reduce the incidence of dementia after 2 years of treatment, a 4-year follow-up assessment surprisingly revealed that subjects previously exposed to naproxen were protected from the onset of AD by 67% compared to placebo. Thus, it could be hypothesized that the chronic use of NSAIDs may be beneficial only in the very early stages of the AD process in coincidence of initial Aβ deposition, microglia activation and consequent release of pro-inflammatory mediators. When the Aβ deposition process is already started, NSAIDs are no longer effective and may even be detrimental because of their inhibitory activity on chronically activated microglia that on long-term may mediate Aβ clearance. The research community should conduct long-term trials with NSAIDs in cognitively normal APOE ε4 carriers

A new anomalous contribution to the central charge of the N=2 monopole

We calculate the one-loop corrections to the mass and central charge of the BPS monopole in N=2 super-Yang-Mills theory in 3+1 dimensions using a supersymmetry-preserving version of dimensional regularization adapted to solitons. In the renormalization scheme where previous studies have indicated vanishing quantum corrections, we find nontrivial corrections that we identify as the 3+1 dimensional analogue of the anomaly in the conformal central charge of the N=1 supersymmetric kink in 1+1 dimensions. As in the latter case, the associated contribution to the ordinary central charge has exactly the required magnitude to preserve BPS saturation at the one-loop level. It also restores consistency of calculations involving sums over zero-point energies with the low-energy effective action of Seiberg and Witten.Comment: 1+10 pages. v3: version to appear in Physics Letters B (more precise title and abstract, additional explanations in the text concerning the nature of the anomaly involved

Alternative pharmacological treatment options for agitation in Alzheimer's disease

In patients with dementia and Alzheimer's disease (AD), treatment of neuropsychiatric symptoms (NPS) is a major concern in the management of these devastating diseases. Among NPS in AD, agitation and aggression are common with earlier institutionalization, increased morbidity and mortality, and greater caregiver burden. Pharmacological treatments for AD-related agitation, specifically off-label use of atypical antipsychotics, showed only modest improvements, with increased side-effect burden and risk of mortality. Non-pharmacological treatment approaches have become the preferred firstline option. However, when such treatments fail, pharmacological options are often used. Therefore, there is an urgent need to identify effective and safe pharmacological treatments for agitation/aggression in AD and dementia. Unfortunately, progresses have been slow, with a small number of methodologically heterogeneous randomized controlled trials (RCTs), with disappointing results. However, evidence coming from recently completed RCTs on novel or repositioned drugs (mibampator, dextromethorphan/ quinidine, cannabinoids, and citalopram) showed some promise in treating agitation in AD, but still with safety concerns. Further evidence will come from ongoing Phase II and III trials on promising novel drugs for treating these distressing symptoms in patients with AD and dementia

A SURVEY ON THE FRAUDULENT USE OF ANABOLIC SUBSTANCES IN BOVINES SLAUGHTERED IN MOLISE

An investigation has been performed on the fraudulent use of anabolic substances in the Region of Molise. One hundred fourty-four bovines (12-24 months old, 123 males and 21 females) have been included in the survey. Ante-mortem assessment on their behaviour and clinical analysis on some target organs were carried out. After slaughtering, samples of prostate, bulbo-urethral glands, Bartholin's glands, mammary gland, ovaries, thymus and thyroid were collected and processed for an anatomo-histopathological evaluation, as suggested in the guidelines of the Italian National Plan for Residues (PNR) 2009. Overall, the 15% of the subjects analysed have been classified as "suspect", whereas the 44% as "uncertain" and the remaining 59% as "negative". The lesion most frequently found was a serious atrophy of the thymic parenchyma with fat infiltration (15% of males and 14% of females), suggesting a prevalence of an illegal use of cortisonic drugs

Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials

Chiral Bosons Through Linear Constraints

We study in detail the quantization of a model which apparently describes chiral bosons. The model is based on the idea that the chiral condition could be implemented through a linear constraint. We show that the space of states is of indefinite metric. We cure this disease by introducing ghost fields in such a way that a BRST symmetry is generated. A quartet algebra is seen to emerge. The quartet mechanism, then, forces all physical states, but the vacuum, to have zero norm.Comment: 9 page

Integrable flows in c=1 string theory

In these notes we review the method to construct integrable deformations of the compactified c=1 bosonic string theory by primary fields (momentum or winding modes), developed recently in collaboration with S. Alexandrov and V. Kazakov. The method is based on the formulation of the string theory as a matrix model. The flows generated by either momentum or winding modes (but not both) are integrable and satisfy the Toda lattice hierarchy.Comment: sect.1 extended and typos correcte

Chiral bosons and improper constraints

We argue that a consistent quantization of the Floreanini-Jackiw model, as a constrained system, should start by recognizing the improper nature of the constraints. Then each boundary conditon defines a problem which must be treated sparately. The model is settled on a compact domain which allows for a discrete formulation of the dynamics; thus, avoiding the mixing of local with collective coordinates. For periodic boundary conditions the model turns out to be a gauge theory whose gauge invariant sector contains only chiral excitations. For antiperiodoc boundary conditions, the mode is a second-class theory where the excitations are also chiral. In both cases, the equal-time algebra of the quantum energy-momentum densities is a Virasoro algebra. The Poincar\'e symmetry holds for the finite as well as for the infinite domain.Comment: 13 pages, Revtex file, IF.UFRGS Preprin