Retinal correlates of psychiatric disorders

Diagnosis and monitoring of psychiatric disorders rely heavily on subjective self-reports of clinical symptoms, which are complicated by the varying consistency of accounts reported by patients with an impaired mental state. Hence, more objective and quantifiable measures have been sought to provide clinicians with more robust methods to evaluate symptomology and track progression of disease in response to treatments. Owing to the shared origins of the retina and the brain, it has been suggested that changes in the retina may correlate with structural and functional changes in the brain. Vast improvements in retinal imaging, namely optical coherence tomography (OCT) and electrodiagnostic technology, have made it possible to investigate the eye at a microscopic level, allowing for the investigation of potential biomarkers in vivo. This review provides a summary of retinal biomarkers associated with schizophrenia, bipolar disorder and major depression, demonstrating how retinal biomarkers may be used to complement existing methods and provide structural markers of pathophysiological mechanisms that underpin brain dysfunction in psychiatric disorders.

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Unraveling the neurotoxicity of titanium dioxide nanoparticles: focusing on molecular mechanisms

Beilstein Journal of Nanotechnology ◽

10.3762/bjnano.7.57 ◽

2016 ◽

Vol 7 ◽

pp. 645-654 ◽

Cited By ~ 17

Author(s):

Bin Song ◽

Yanli Zhang ◽

Jia Liu ◽

Xiaoli Feng ◽

Ting Zhou ◽

...

Keyword(s):

Dna Methylation ◽

Titanium Dioxide ◽

Molecular Mechanisms ◽

Titanium Dioxide Nanoparticles ◽

Brain Dysfunction ◽

In Vivo Studies ◽

Cell Components ◽

New Perspective ◽

The Brain

Titanium dioxide nanoparticles (TiO2 NPs) possess unique characteristics and are widely used in many fields. Numerous in vivo studies, exposing experimental animals to these NPs through systematic administration, have suggested that TiO2 NPs can accumulate in the brain and induce brain dysfunction. Nevertheless, the exact mechanisms underlying the neurotoxicity of TiO2 NPs remain unclear. However, we have concluded from previous studies that these mechanisms mainly consist of oxidative stress (OS), apoptosis, inflammatory response, genotoxicity, and direct impairment of cell components. Meanwhile, other factors such as disturbed distributions of trace elements, disrupted signaling pathways, dysregulated neurotransmitters and synaptic plasticity have also been shown to contribute to neurotoxicity of TiO2 NPs. Recently, studies on autophagy and DNA methylation have shed some light on possible mechanisms of nanotoxicity. Therefore, we offer a new perspective that autophagy and DNA methylation could contribute to neurotoxicity of TiO2 NPs. Undoubtedly, more studies are needed to test this idea in the future. In short, to fully understand the health threats posed by TiO2 NPs and to improve the bio-safety of TiO2 NPs-based products, the neurotoxicity of TiO2 NPs must be investigated comprehensively through studying every possible molecular mechanism.

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A Three-Component-System Hypothesis of Psychosis

The British Journal of Psychiatry ◽

10.1192/s0007125000295962 ◽

1989 ◽

Vol 155 (S5) ◽

pp. 37-39 ◽

Cited By ~ 42

Author(s):

Hinderk M. Emrich

Keyword(s):

Human Brain ◽

Causative Factor ◽

Microscopic Level ◽

Point Of View ◽

Component System ◽

Pathogenetic Factor ◽

Pet Scans ◽

The Brain ◽

Different Levels

Hypotheses as to the pathogenesis of schizophrenia can be discussed at different levels of a possible manifestation of the causative factor: the macroscopic-morphological, the microscopic-morphological, and the molecular. Some abnormalities have been observed on all of them: e.g. increased ventricular-brain ratios in CT, hypofrontality in SPECT and in glucographic PET-scans, and other macromorphological abnormalities (for reviews cf. Bogerts 1984; Mundt, 1986; Bogerts et al, 1987), gliosis on a microscopic level (Stevens, 1982), and an increased dopamine-binding in in vivo receptor studies (PET as well as in post-mortem studies; Cazzullo, 1988). However, the diversity and variability of these findings point to the view that rather than there being a single distinct pathogenetic factor responsible for the pathogenesis of schizophrenic psychoses, a constitutional disposition exists, which can be described as a functional dysequilibrium within the human brain. From this point of view, schizophrenia would not appear as an inherited disorder of metabolism, but as a weakness of a neurobiological ‘system’, i.e. as an interactional disorder of a complex of networks, in which the interaction between different substructures is labile in such a way that under special conditions (e.g. ‘stress’), a decompensation (functional breakdown) results. In this sense, ‘vulnerability’ to schizophrenia may be interpreted as a consequence of a constitutional deficiency of the brain which results in an inability to stabilise, under specially challenging conditions, the interaction between different substructures of the human brain. Before this ‘functional dysequilibrium-hypothesis’ (which is a special form of a constitutional structural deficiency-hypothesis) is discussed, and before the question is raised as to which are the relevant dysequilibrated components, some indication will be given as to why such an hypothesis appears plausible.

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Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

eLife ◽

10.7554/elife.38744 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 20

Author(s):

Isabelle Arnoux ◽

Michael Willam ◽

Nadine Griesche ◽

Jennifer Krummeich ◽

Hirofumi Watari ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Symptoms ◽

Activity Patterns ◽

Disease Onset ◽

Network Activity ◽

Critical Window ◽

Functional Changes ◽

Window Of Vulnerability

Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca2+ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms.

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Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy

International Journal of Molecular Sciences ◽

10.3390/ijms20010220 ◽

2019 ◽

Vol 20 (1) ◽

pp. 220 ◽

Cited By ~ 8

Author(s):

Sandesh Reddy ◽

Iyan Younus ◽

Vidya Sridhar ◽

Doodipala Reddy

Keyword(s):

Animal Models ◽

Refractory Epilepsy ◽

Single Photon ◽

Neuronal Damage ◽

Photon Emission ◽

Brain Magnetic Resonance Imaging ◽

Functional Changes ◽

Neuroimaging Biomarkers ◽

The Brain

This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.

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PET and the multitracer concept in the study of neurodegenerative diseases

Dementia & Neuropsychologia ◽

10.1590/1980-57642015dn94000343 ◽

2015 ◽

Vol 9 (4) ◽

pp. 343-349 ◽

Cited By ~ 1

Author(s):

Henry Engler ◽

Andres Damian ◽

Cecilia Bentancourt

Keyword(s):

Positron Emission Tomography ◽

Molecular Imaging ◽

Neurodegenerative Diseases ◽

Brain Tissue ◽

Neurodegenerative Disorders ◽

Clinical Symptoms ◽

Emission Tomography ◽

Positron Emission ◽

The Brain

ABSTRACT The complexity of the pathological reactions of the brain to an aggression caused by an internal or external noxa represents a challenge for molecular imaging. Positron emission tomography (PET) can indicate in vivo,anatomopathological changes involved in the development of different clinical symptoms in patients with neurodegenerative disorders. PET and the multitracer concept can provide information from different systems in the brain tissue building an image of the whole disease. We present here the combination of 18F-flourodeoxyglucose (FDG) and N-[11C-methyl]-L-deuterodeprenyl (DED), FDG and N-[11C-methyl] 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), PIB and L-[11C]-3'4-Dihydrophenylalanine (DOPA) and finally PIB and [15O]H2O.

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JNK signaling provides a novel therapeutic target for Rett syndrome

BMC Biology ◽

10.1186/s12915-021-01190-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Clara Alice Musi ◽

Anna Maria Castaldo ◽

Anna Elisa Valsecchi ◽

Sara Cimini ◽

Noemi Morello ◽

...

Keyword(s):

Rett Syndrome ◽

Clinical Symptoms ◽

Neurodevelopmental Disorder ◽

Loss Of Function ◽

Jnk Signaling ◽

Functional Changes ◽

Jnk Activation ◽

Stress Pathway

Abstract Background Rett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach. Results We discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons. Conclusions As a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT.

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Diphtheria toxin induced but not CSF1R inhibitor mediated microglia ablation model leads to the loss of CSF/ventricular spaces in vivo that is independent of cytokine upregulation

Journal of Neuroinflammation ◽

10.1186/s12974-021-02367-w ◽

2022 ◽

Vol 19 (1) ◽

Author(s):

Alicia Bedolla ◽

Aleksandr Taranov ◽

Fucheng Luo ◽

Jiapeng Wang ◽

Flavia Turcato ◽

...

Keyword(s):

Diphtheria Toxin ◽

Pathological Condition ◽

Underlying Mechanism ◽

Cytokine Profile ◽

Edema Formation ◽

Functional Changes ◽

Genetic Ablation ◽

The Brain ◽

Ablation Model

Abstract Background Two recently developed novel rodent models have been reported to ablate microglia, either by genetically targeting microglia (via Cx3cr1-creER: iDTR + Dtx) or through pharmacologically targeting the CSF1R receptor with its inhibitor (PLX5622). Both models have been widely used in recent years to define essential functions of microglia and have led to high impact studies that have moved the field forward. Methods Using either Cx3cr1-iDTR mice in combination with Dtx or via the PLX5622 diet to pharmacologically ablate microglia, we compared the two models via MRI and histology to study the general anatomy of the brain and the CSF/ventricular systems. Additionally, we analyzed the cytokine profile in both microglia ablation models. Results We discovered that the genetic ablation (Cx3cr1-iDTR + Dtx), but not the pharmacological microglia ablation (PLX5622), displays a surprisingly rapid pathological condition in the brain represented by loss of CSF/ventricles without brain parenchymal swelling. This phenotype was observed both in MRI and histological analysis. To our surprise, we discovered that the iDTR allele alone leads to the loss of CSF/ventricles phenotype following diphtheria toxin (Dtx) treatment independent of cre expression. To examine the underlying mechanism for the loss of CSF in the Cx3cr1-iDTR ablation and iDTR models, we additionally investigated the cytokine profile in the Cx3cr1-iDTR + Dtx, iDTR + Dtx and the PLX models. We found increases of multiple cytokines in the Cx3cr1-iDTR + Dtx but not in the pharmacological ablation model nor the iDTR + Dtx mouse brains at the time of CSF loss (3 days after the first Dtx injection). This result suggests that the upregulation of cytokines is not the cause of the loss of CSF, which is supported by our data indicating that brain parenchyma swelling, or edema are not observed in the Cx3cr1-iDTR + Dtx microglia ablation model. Additionally, pharmacological inhibition of the KC/CXCR2 pathway (the most upregulated cytokine in the Cx3cr1-iDTR + Dtx model) did not resolve the CSF/ventricular loss phenotype in the genetic microglia ablation model. Instead, both the Cx3cr1-iDTR + Dtx ablation and iDTR + Dtx models showed increased activated IBA1 + cells in the choroid plexus (CP), suggesting that CP-related pathology might be the contributing factor for the observed CSF/ventricular shrinkage phenotype. Conclusions Our data, for the first time, reveal a robust and global CSF/ventricular space shrinkage pathology in the Cx3cr1-iDTR genetic ablation model caused by iDTR allele, but not in the PLX5622 ablation model, and suggest that this pathology is not due to brain edema formation but to CP related pathology. Given the wide utilization of the iDTR allele and the Cx3cr1-iDTR model, it is crucial to fully characterize this pathology to understand the underlying causal mechanisms. Specifically, caution is needed when utilizing this model to interpret subtle neurologic functional changes that are thought to be mediated by microglia but could, instead, be due to CSF/ventricular loss in the genetic ablation model.

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Epidemiologia zaburzeń neuropoznawczych u pacjentów w wieku podeszłym

Medycyna Rodzinna ◽

10.25121/mr.2018.21.3.252 ◽

2018 ◽

Vol 21 (3) ◽

Author(s):

Wioletta Mędrzycka-Dąbrowska ◽

Katarzyna Kwiecień-Jaguś ◽

Renata Piotrkowska ◽

Piotr Jarzynkowski

Keyword(s):

The Elderly ◽

Brain Dysfunction ◽

Aging Brain ◽

Psychomotor Slowing ◽

Functional Changes ◽

Slowing Down ◽

Memory Functioning ◽

Compensation Mechanisms ◽

Key Issues ◽

The Brain

The phenomenon of progressive impairment of cognitive functions is characteristic for the aging process. More than half of people over 50 complain about weakening of their previous intellectual performance, reduced mood, impaired memory, psychomotor slowing down, decreased ability to concentrate and divide attention, extend reaction time and reduce motor performance. The basis of mental changes in the elderly are changes in the brain. The changes arising in the aging brain are the result of pathological processes: metabolic and altered cerebral circulation. These changes, and mainly their extent, consequently cause brain dysfunction and are manifested mainly in the deterioration of mental functions. The brain is first and foremost the material basis of a mental life. With age, slow, cumulative and irreversible morphological and functional changes occur in the human brain. This process is slow, which is why it is accompanied by a number of compensation mechanisms. This phenomenon occurs regardless of gender. The aim of this article is to present the key issues related to memory functioning in the elderly, with particular emphasis on neurocognitive impairment after surgery.

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Aberrant Calcium Signals in Reactive Astrocytes: A Key Process in Neurological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms20040996 ◽

2019 ◽

Vol 20 (4) ◽

pp. 996 ◽

Cited By ~ 17

Author(s):

Eiji Shigetomi ◽

Kozo Saito ◽

Fumikazu Sano ◽

Schuichi Koizumi

Keyword(s):

Neurological Disorders ◽

Molecular Mechanisms ◽

Brain Disease ◽

Reactive Astrocytes ◽

Brain Functions ◽

Progression Of Disease ◽

Brain Insults ◽

The Brain

Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca2+ signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca2+ signals. We discuss the molecular mechanisms underlying aberrant Ca2+ signals in reactive astrocytes and the functional significance of aberrant Ca2+ signals in neurological disorders.

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Potential Moderators of Physical Activity on Brain Health

Journal of Aging Research ◽

10.1155/2012/948981 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 19

Author(s):

Regina L. Leckie ◽

Andrea M. Weinstein ◽

Jennifer C. Hodzic ◽

Kirk I. Erickson

Keyword(s):

Physical Activity ◽

Brain Dysfunction ◽

Future Research ◽

Omega 3 ◽

Brain Health ◽

Functional Changes ◽

Age Related ◽

Genetic Risks ◽

The Individual ◽

The Brain

Age-related cognitive decline is linked to numerous molecular, structural, and functional changes in the brain. However, physical activity is a promising method of reducing unfavorable age-related changes. Physical activity exerts its effects on the brain through many molecular pathways, some of which are regulated by genetic variants in humans. In this paper, we highlight genes including apolipoprotein E (APOE), brain derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT) along with dietary omega-3 fatty acid, docosahexaenoic acid (DHA), as potential moderators of the effect of physical activity on brain health. There are a growing number of studies indicating that physical activity might mitigate the genetic risks for disease and brain dysfunction and that the combination of greater amounts of DHA intake with physical activity might promote better brain function than either treatment alone. Understanding whether genes or other lifestyles moderate the effects of physical activity on neurocognitive health is necessary for delineating the pathways by which brain health can be enhanced and for grasping the individual variation in the effectiveness of physical activity interventions on the brain and cognition. There is a need for future research to continue to assess the factors that moderate the effects of physical activity on neurocognitive function.

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