An Overview of the Ferroptosis Hallmarks in Friedreich's Ataxia.

BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. SCOPE OF REVIEW: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. MAJOR CONCLUSIONS: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.

Pathogenesis of cerebral toxocariasis and neurodegenerative diseases.

Toxocara canis belongs to one of zoonotic parasites that commonly infects canines worldwide, and its eggs in host faeces may contaminate the food, water, soil and their fur as well as the larvae entrapped in the granuloma can infect paratenic hosts including mice and humans. Survivability of T. canis embryonated eggs under moist, cool conditions may be as long as 2-4 years or more. In paratenic hosts such as mice and humans, T. canis L3 larvae neither moult, grow, nor replicate and will wander through a number of internal organs in humans so as to cause Th2-dominant pathology in various internal organs as leading to neurotoxocariasis (NT), ocular toxocariasis (OT), or visceral larva migrans (VLM). Although the systemic immune response to T. canis has been widely reported, the immune response in the brain has received little attention. Differential cytokine expression and other brain injury-associated biomarkers or neurodegeneration-associated factors have been observed in infected versus uninfected outbred and inbred mice. Preliminary data have also suggested a possible link between significant memory impairment and cytokine production associated with T. canis infection in the hippocampus which has been long recognised as being responsible for learning and memory functions. Notably, it remains an enigma concerning cerebral invasion by T. canis larvae rarely induces a recognisable neurological syndrome or its involvement in neuropathological disorders in humans. Exploration of the relationship between host and parasite in the brain may elucidate the cryptic symptoms of human cerebral toxocariasis, with patients presenting with mental retardation, epilepsy, neurodegeneration and other central nervous system (CNS) disorders.

The outcome and burden of Chinese patients with neurodegenerative diseases: A 10-year clinical feature study.

BACKGROUND: As the Chinese population continues to age, the incidence of neurodegenerative diseases (NDDs) has increased dramatically, which results in heavy medical and economic burden for families and society. OBJECTIVE: The objective of this study was to evaluate NDDs in a southern Chinese hospital over a 10-year period and examine trends in demographics, outcome, length of stay (LOS) and cost. METHODS: Retrospective medical records of patients from January 2010 to December 2019 were collected, including 7231 patients with NDDs (as case group) and 9663 patients without any NDDs (as control group). The information of social demographic data, admission source, reasons for admission, outcomes, LOS, and cost were extracted and analysed. RESULT: The average hospitalisation age of the patients with NDDs is over 65 years (peak age 70-89 years). Compared with the control group, the case group had a longer LOS and a higher cost and the numbers of patients with NDDs increased yearly from 2010 to 2019. The LOS shortened while the cost increased. Clinical features affected LOS and cost. Patients suffering from infection, abnormal blood pressure and the imbalance of water-electrolyte homoeostasis as main reasons for admission were decreased; however, heart disease, cerebrovascular accident and mental diseases were significantly increased, the overall change trend of fracture/trauma remained stable. The rate of discharge to home care and mortality declined; discharge to other medical or community facilities increased over 10 years. CONCLUSION: The majority of NDDs patients tended to be older. During the last 10 years from 2010 to 2019, the numbers of NDDs patients increased yearly, the trend of LOS became shortening and the cost gradually increasing. The main reasons of admission and outcomes of hospital showed different trends.

Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

Toxocara canis and T. cati are highly prevalent nematode infections of the intestines of dogs and cats. In paratenic hosts, larvae do not mature in the intestine but instead migrate through the somatic tissues and organs of the body. The presence of these migrating larvae can contribute to pathology. Toxocara larvae can invade the brains of humans, and while case descriptions of cerebral toxocariasis are historically rare, improved diagnosis and greater awareness have contributed to increased detection. Despite this, cerebral or neurological toxocariasis (NT) remains a poorly understood phenomenon. Furthermore, our understanding of cognitive deficits due to toxocariasis in human populations remains particularly deficient. Recent data describe an enhanced expression of biomarkers associated with brain injury, such as GFAP, AßPP, transforming growth factor ß1 (TGF-ß1), NF-L, S100B, tTG, and p-tau, in mice receiving even low doses of Toxocara ova. Finally, this review outlines a hypothesis to explore the relationship between the presence of T. canis larvae in the brain and the progression of Alzheimer's disease (AD) due to enhanced AD-associated neurodegenerative biomarker expression.

Possible link between Toxoplasma gondii and the anosmia associated with neurodegenerative diseases.

Toxoplasma gondii is an intracellular protozoan infecting 30% to 50% of global human population. Recently, it was suggested that chronic latent neuroinflammation caused by the parasite may be responsible for the development of several neurodegenerative diseases manifesting with the loss of smell. Studies in animals inoculated with the parasite revealed cysts in various regions of the brain, including olfactory bulb. Development of behavioral changes was paralleled by the preferential persistence of cysts in defined anatomic structures of the brain, depending on the host, strain of the parasite, its virulence, and route of inoculation. Olfactory dysfunction reported in Alzheimer's disease, multiple sclerosis, and schizophrenia was frequently associated with the significantly increased serum anti-T gondii immunoglobulin G antibody levels. Damage of the olfactory system may be also at least in part responsible for the development of depression because T gondii infection worsened mood in such patients, and the olfactory bulbectomized rat serves as a model of depression.

The impact of placental malaria on neurodevelopment of exposed infants: a role for the complement system?

The in utero environment can have a profound impact on early brain development and subsequent childhood school performance and behavior. Over 125 million pregnant women are at risk of malaria each year, yet the impact of in utero malaria exposure on the neurological and cognitive development of their exposed infants is unknown. Based on recent evidence supporting a role for the complement system in regulating neurodevelopment, and mediating neuroinflammation and neurodegenerative diseases, we hypothesize that excessive complement activation induced by placental malaria may disrupt normal neurodevelopment resulting in neurocognitive impairment of infants exposed to malaria in utero. Complement components may mediate these effects through the initiation of neuroinflammation, dysregulation of neurovascular angiogenesis, and the disruption of normal synaptic pruning.

Effects of Acute Chagas'Disease on Mice Central Nervous System

This study has been done to evaluate the central nervous system (CNS) of mice infected with Trypanosoma cruzi and its relationships with the irreversible decrease of motor activity of the rear limbs during acute Chagas´disease. The course of the present study shows the in vivo behaviour of three parasites strains which were isolated from different sources and geographical areas, with the purpose of explaining the parasitemia, mortality rate, clinical, pathological and histopathological changes in the CNS of infected mice. The mice were injected intraperitoneally with 5.103 bloodstreams of different T. cruzi strains. The mice infected with PR and ASM strains from Venezuela, showed low parasitemia and high mortality, while the Y strain produced higher parasitemia levels. At the 30th day post-infection both left parietal brain cortex (LPC) and spinal cord (SC) were sectioned, stained with hematoxilin and eosin (H-E) and examined by means of confocal ligth microscopy. At this time, the pathology of the CNS exhibited focal infiltrates of monocytes, lymphocytes, plasmocytes, polymorphonuclear cells and loss of neuronas and motoneurons. The sections of LPC of infected mice with ASM strain, showed loss neuronal, parasites and abundant T. cruzi antigen deposits in the proximity of the swollen neurons. The sections of SC stained with Enolase-Avidin-Biotin-Peroxidase showed a reduction in the average number of neurons of the cervical region (CR) of the infected mice with PR, ASM and Y strains. Sections stained with Propidium Ioduro (IP) showed a reduction of the number of motoneurons in all regions of the SC, with a significant difference between groups infected with different T. cruzi strains and control uninfected mice (P < 0.05). This study established a correlation between the parasitism in the proximity to inflammatory cells, together the appearance of T. cruzi antigen and neuronal destruction in the brain. Therefore it can be concluded that the changes in CNS may be attributed to early parasitism in nervous tissue, which occur in a few days, involving clinico-pathological manifestations, which produced alterations of the mobility with paralysis of the rear limbs and death in 100% of mice with acute infection produced by PR and ASM-T. cruzi strains from Venezuela.

Intraventricular infusion of antagonists of IL-1 and TNF alpha attenuates neurodegeneration induced by the infection of Trypanosoma brucei.

Infection of Trypanosoma brucei causes specific patterns of neurodegeneration in association with chronic expression of proinflammatory cytokines in the brain. To investigate whether the induction of proinflammatory cytokines contributed to the observe pathology in this disease, we infected rats with T. brucei and treated them with intracerebral infusion of the cytokine antagonists interleukin-1 receptor antagonist (IL-1ra) and/or soluble type-I receptor of the tumor necrosis factor (sTNFr1). Infusion of IL-1ra, not sTNFr1, restored the reduction of body weight gain induced by the infection. Infusion of IL-1ra+sTNFr1 reduced the expression of IL-1beta and the cytokine response gene IkappaBalpha, but not TNFalpha. Infusion of sTNFr1 reduced trypanosome-induced neurodegeneration. Further reduction of neurodegeneration was seen after IL-1ra+sTNFr1 infusion. Infusion of IL-1ra alone, however, did not significantly affect the patterns of neurodegeneration. These results suggest that TNFalpha is a major mediator for trypanosome-induced neurodegeneration although its neurotoxic effects can be augmented by IL-1.