Automatic Speech Classifier for Mild Cognitive Impairment and Early Dementia

The World Health Organization estimates that 50 million people are currently living with dementia worldwide and this figure will almost triple by 2050. Current pharmacological treatments are only symptomatic, and drugs or other therapies are ineffective in slowing down or curing the neurodegenerative process at the basis of dementia. Therefore, early detection of cognitive decline is of the utmost importance to respond significantly and deliver preventive interventions. Recently, the researchers showed that speech alterations might be one of the earliest signs of cognitive defect, observable well in advance before other cognitive deficits become manifest. In this article, we propose a full automated method able to classify the audio file of the subjects according to the progress level of the pathology. In particular, we trained a specific type of artificial neural network, called autoencoder, using the visual representation of the audio signal of the subjects, that is, the spectrogram. Moreover, we used a data augmentation approach to overcome the problem of the large amount of annotated data usually required during the training phase, which represents one of the most major obstacles in deep learning. We evaluated the proposed method using a dataset of 288 audio files from 96 subjects: 48 healthy controls and 48 cognitively impaired participants. The proposed method obtained good classification results compared to the state-of-the-art neuropsychological screening tests and, with an accuracy of 90.57%, outperformed the methods based on manual transcription and annotation of speech.

Microbial pathogens induce neurodegeneration in Alzheimer’s disease mice: protection by microglial regulation

Background Neurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer’s disease (AD) and that microglia play a central role in this process. Methods We examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD. Results We examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural (“dirty”) environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists. Conclusions Exposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs’ neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.

Age-Related Trajectories of Brain Structure–Function Coupling in Female Roller Derby Athletes

Contact and collision sports are believed to accelerate brain aging. Postmortem studies of the human brain have implicated tau deposition in and around the perivascular space as a biomarker of an as yet poorly understood neurodegenerative process. Relatively little is known about the effects that collision sport participation has on the age-related trajectories of macroscale brain structure and function, particularly in female athletes. Diffusion MRI and resting-state functional MRI were obtained from female collision sport athletes (n = 19 roller derby (RD) players; 23–45 years old) and female control participants (n = 14; 20–49 years old) to quantify structural coupling (SC) and decoupling (SD). The novel and interesting finding is that RD athletes, but not controls, exhibited increasing SC with age in two association networks: the frontoparietal network, important for cognitive control, and default-mode network, a task-negative network (permuted p = 0.0006). Age-related increases in SC were also observed in sensorimotor networks (RD, controls) and age-related increases in SD were observed in association networks (controls) (permuted p ≤ 0.0001). These distinct patterns suggest that competing in RD results in compressed neuronal timescales in critical networks as a function of age and encourages the broader study of female athlete brains across the lifespan.

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.

MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer’s Disease

Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.

Physiological and Pathophysiological Role of Cysteine Metabolism in Human Metabolic Syndrome

: Cysteine is one of the major intermediate products of cellular amino-acid metabolism. It is a semi-essential amino acid for protein synthesis. Besides, it is also employed in the regulation of major endogenous anti-oxidant molecules i.e., reduced glutathione (GSH). Further, it is a precursor of multiple sulfur-containing molecules like hydrogen sulfide, lanthionine, taurine, coenzyme A and biotin. It is also one of the key molecules for post-translational modifications of various cellular proteins. In physiological conditions, it is employed in the sulfhydration process and plays a key role in the physiology modification of the inflammatory process in various organs, including the neurological system. The catabolism of cysteine is regulated by cysteine dioxygenase enzyme activity. The dysregulated conditions of cysteine and cysteine-associated hydrogen sulfide metabolism are widely employed in the acceleration of the neurodegenerative process. Moreover, the upregulation of cysteine and hydrogen sulfide synthesis occurs via the reverse trans-sulfuration process. This process helps to manage the worsening of a pathological condition of a cellular system. Moreover, it is also employed in the accumulation of homocysteine contents. Further, both cysteine and homocysteine molecules are widely accepted as biomarkers for various types of diseases. Therefore, the targets involved in the regulation of cysteine have been considered as valid targets to treat various disorders like cardiac disease, ischemic stroke, diabetes, cancer, and renal dysfunction.

The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

The role of infectious agents in the development of neurodegenerative diseases

Actually, there is no consensus about the causes of the development in most neurodegenerative diseases. Recent international publications describe various hypotheses of the genesis of such diseases. Infectious is considered as one of them, assuming an infectious agent can trigger a cascade of pathological processes that eventually lead to the manifestation of various neurodegenerative diseases. The direct relationship between infectious invasion and the development of neurodegenerative diseases is not fully proved yet, but these publications confirm the hypothesis that a variety of pathogens (viruses, bacteria, intracellular parasites etc.) can induce the process of neuronal inflammation with subsequent neurodegeneration. As a result of the scientific research, various ways of penetration of infectious agents into the central nervous system have been studied and proven. In the case of neuroinfections already studied, inflammatory and alterative changes in nervous tissue occur with the direct participation of neuroglia and cells of the immune system, which may be part of the universal trigger mechanism of the neurodegenerative process. At the same time, in the case of a number of diseases, the primary role of specific infectious agents is possible. It has been shown that neurological complications of a novel coronavirus infection can also occur as a result of both direct cytopathic action of the pathogen or activation of neuroinflammation processes. Of course, this hypothesis of neurodegenerative pathology requires a comprehensive analysis and subsequent confirmation, however, the investigation of molecular and cellular mechanisms of neuroinflammation and neurodegeneration already opens up broad prospects for finding possible pathogenetic therapy of these diseases (bibliography: 42 refs)

Contributions of sex, depression, and cognition on brain connectivity dynamics in Parkinson’s disease

Alterations in time-varying functional connectivity (FC) have been found in Parkinson’s disease (PD) patients. To date, very little is known about the influence of sex on brain FC in PD patients and how this could be related to disease severity. The first objective was to evaluate the influence of sex on dynamic FC characteristics in PD patients and healthy controls (HC), while the second aim was to investigate the temporal patterns of dynamic connectivity related to PD motor and non-motor symptoms. Ninety-nine PD patients and sixty-two HC underwent a neuropsychological and clinical assessment. Rs-fMRI and T1-weighted MRI were also acquired. Dynamic FC analyses were performed in the GIFT toolbox. Dynamic FC analyses identified two States: State I, characterized by within-network positive coupling; and State II that showed between-network connectivity, mostly involving somatomotor and visual networks. Sex differences were found in dynamic indexes in HC but these differences were not observed in PD. Hierarchical clustering analysis identified three phenotypically distinct PD subgroups: (1) Subgroup A was characterized by mild motor symptoms; (2) Subgroup B was characterized by depressive and motor symptoms; (3) Subgroup C was characterized by cognitive and motor symptoms. Results revealed that changes in the temporal properties of connectivity were related to the motor/non-motor outcomes of PD severity. Findings suggest that while in HC sex differences may play a certain role in dynamic connectivity patterns, in PD patients, these effects may be overcome by the neurodegenerative process. Changes in the temporal properties of connectivity in PD were mainly related to the clinical markers of PD severity.

Probing Gut-Brain Links in Alzheimer's Disease with Rifaximin

Gut-microbiome-inflammation interactions have been linked to neurodegeneration in Alzheimers disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut-specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open-label trial, we treated 10 subjects with mild to moderate probable AD dementia (MMSE = 17 + 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament-light levels (p <0.004) and a significant increase in fecal phylum Firmicutes microbiota. Serum pTau181 and GFAP levels were reduced (effect sizes of -0.41 and -0.48 respectively) but did not reach significance. There was also a non-significant downward trend in serum cytokine IL-6 and IL-13 levels. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau 181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo-controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.