Journal: Translational neurodegeneration
Autism spectrum disorder (ASD) is defined by standardized criteria of qualitative impairments in social interaction, qualitative impairments in communication, and restricted and stereotyped patterns of behavior, interests, and activities. A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills, which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth. To date, the etiology of ASD remains under debate, however, many studies suggest toxicity, especially from mercury (Hg), in individuals diagnosed with an ASD. The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal (49.55% Hg by weight) in childhood vaccines by conducting a two-phased (hypothesis generating/hypothesis testing) study with documented exposure to varying levels of Thimerosal from vaccinations.
Presenilins (PSs) are the catalytic core of gamma-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of gamma-secretase and focus on the catalytic components – presenilins and their biological functions and contributions to the AD pathogenesis. The functions of presenilins are divided into gamma-secretase dependent and gamma-secretase independent ones. The gamma-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the gamma-secretase independent functions of presenilins include stabilizing beta-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.
There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B (MAOB) inhibitors. They have been studied for their potential disease-modifying effects in Parkinson’s disease (PD) for over 20 years in various clinical trials. This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD. Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug. Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles, some of which may be insurmountable.
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders of aging, characterized by the degeneration of dopamine neurons (DA neurons) in the substantial nigra, leading to the advent of both motor symptoms and non-motor symptoms. Current treatments include electrical stimulation of the affected brain areas and dopamine replacement therapy. Even though both categories are effective in treating PD patients, the disease progression cannot be stopped. The research advance into cell therapies provides exciting potential for the treatment of PD. Current cell sources include neural stem cells (NSCs) from fetal brain tissues, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) and directly induced dopamine neurons (iDA neurons). Here, we evaluate the research progress in different cell sources with a focus on using iPSCs as a valuable source and propose key challenges for developing cells suitable for large-scale clinical applications in the treatment of PD.
A significant number of children diagnosed with autism spectrum disorder suffer a loss of previously-acquired skills, suggesting neurodegeneration or a type of progressive encephalopathy with an etiological basis occurring after birth. The purpose of this study is to investigate the effectof the age at which children got their first Measles-Mumps-Rubella (MMR) vaccine on autism incidence. This is a reanalysis of the data set, obtained from the U.S. Centers for Disease Control and Protection (CDC), used for the Destefano et al. 2004 publication on the timing of the first MMR vaccine and autism diagnoses.
Alzheimer’s Disease (AD) is a global health issue given the increasing prevalence rate and the limitations of drug effects. As a consequent, non-pharmacological interventions are of importance. Music therapy (MT) is a non-pharmacological way with a long history of use and a fine usability for dementia patients. In this review, we will summarize different techniques, diverse clinical trials, and the mechanisms of MT as it is helpful to the cognition in AD, providing reference for future research. Many articles have demonstrated that MT can reduce cognitive decline especially in autobiographical and episodic memories, psychomotor speed, executive function domains, and global cognition. MT is a promising intervention for strategy of dementia especially of AD and it must be started as early as possible. However, more evidences with prospective, randomized, blinded, uniform and rigorous methodological investigations are needed. And we should consider to combine MT with other cognitive stimulations such as dance, physical exercise, video game, art and so on.
Wilson disease is an autosomal recessive disorder of copper metabolism. Diagnosis depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Genetic analysis for mutations within ATP7B is a convincing diagnostic tool. The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake. Medical therapy is effective but WD is not yet curable. Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure, although evaluation of its long-term effect are still in need.
Nearly 30% of adults 40 years and older in the United States are on a statin. Their widespread use heightens the importance of careful consideration of their varied effects on the body. Although randomized controlled trials have not confirmed cognitive impairing effects with statins, continuing evidence suggests statins have the ability to cause reversible cognitive impairment in some patients. Paradoxically, statins have also been shown to decrease the risk of dementia, Alzheimer’s disease, and improve cognitive impairment in some cases. However, randomized controlled trials have similarly failed to find the beneficial effect. Supporting evidence for both claims is compelling whereas known limitations of the clinical trials may explain the lack of findings. This narrative review aims to explain why there is still controversy and how both effects can, and may, be possible. The mechanisms that have been hypothesized for each effect are seemingly independent from one another and may explain the contradicting results. Being mindful of the complex effects of statins, health care providers need to be able to identify patients who are at risk for or already experiencing cognitive impairment from statin use while also identifying those who could potentially decrease their risk of dementia with statins.
Evidence from epidemiological studies suggest a relationship between cigarette smoking and low risk of Parkinson disease (PD). As a major component of tobacco smoke, nicotine has been proposed to be a substance for preventing against PD risk, with a key role in regulating striatal activity and behaviors mediated through the dopaminergic system. Animal studies also showed that nicotine could modulate dopamine transmission and reduce levodopa-induced dyskinesias. However, previous clinical trials yield controversial results regarding nicotine treatment. In this review, we updated epidemiological, preclinical and clinical data, and studies on nicotine from diet. We also reviewed interactions between genetic factors and cigarette smoking. As a small amount of nicotine can saturate a substantial portion of nicotine receptors in the brain, nicotine from other sources, such as diet, could be a promising therapeutic substance for protection against PD.
Huntington’s Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (> 36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT). Unfortunately, this modality requires repeated dosing, commonly exhibit off target effects (OTEs), and exert renal and hepatic toxicity. In contrast, a single AAV-mediated short-hairpin RNA (shRNA) dose can last years with low toxicity. In addition, we highlight research indicating that shRNA elicits fewer OTEs than siRNA when tested head-to-head. Despite this promise, shRNA therapy has been held back by difficulties controlling expression (oversaturating cells with toxic levels of RNA construct). In this review, we compare RNAi modalities for HD and propose novel methods of optimizing shRNA expression and on-target fidelity.