Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(5), P. 1902 - 1918

Published: Jan. 23, 2023

Abstract Cognitive deficits are a core feature of schizophrenia, account for much the impaired functioning associated with disorder and not responsive to existing treatments. In this review, we first describe clinical presentation natural history these deficits. We then consider aetiological factors, highlighting how range similar genetic environmental factors both cognitive function schizophrenia. review pathophysiological mechanisms thought underlie symptoms, including role dopamine, cholinergic signalling balance between GABAergic interneurons glutamatergic pyramidal cells. Finally, management impairments candidate novel

Language: Английский

---

Radiopharmaceuticals for PET and SPECT Imaging: A Literature Review over the Last Decade

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 5023 - 5023

Published: April 30, 2022

Positron emission tomography (PET) uses radioactive tracers and enables the functional imaging of several metabolic processes, blood flow measurements, regional chemical composition, and/or absorption. Depending on targeted processes within living organism, different are used for various medical conditions, such as cancer, particular brain pathologies, cardiac events, bone lesions, where most commonly radiolabeled with 18F (e.g., [

Language: Английский

---

Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 92(6), P. 501 - 513

Published: June 22, 2022

Language: Английский

---

The synaptic hypothesis of schizophrenia version III: a master mechanism

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(5), P. 1843 - 1856

Published: April 11, 2023

Abstract The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there a step-change in the evidence available, and some tenets earlier versions are not supported by recent findings. Here, we review normal development from structural functional imaging post-mortem studies that this is abnormal people at risk with schizophrenia. We then consider mechanism could underlie changes update hypothesis. Genome-wide association have identified number variants converging on pathways regulating elimination, formation plasticity, including complement factors microglial-mediated pruning. Induced pluripotent stem cell demonstrated patient-derived neurons show pre- post-synaptic deficits, signalling alterations, elevated, complement-dependent elimination structures compared to control-derived lines. Preclinical data environmental linked schizophrenia, such as stress immune activation, can lead synapse loss. Longitudinal MRI patients, prodrome, divergent trajectories grey matter volume cortical thickness controls, PET shows vivo for lower density patients Based evidence, propose version III This multi-hit model, whereby genetic and/or render synapses vulnerable excessive glia-mediated triggered during later neurodevelopment. loss disrupts pyramidal neuron function cortex contribute negative cognitive symptoms disinhibits projections mesostriatal regions dopamine overactivity psychosis. It accounts typical onset adolescence/early adulthood, its major factors, symptoms, identifies potential synaptic, microglial targets treatment.

Language: Английский

---

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 48(1), P. 151 - 167

Published: Sept. 2, 2022

Abstract Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or activity are relevant understanding if there is lower disorder. We conducted literature searches identify meta-analyses other studies patients with chronic first-episode schizophrenia, people at high genetic clinical risk psychosis. identified 18 including over 50,000 subjects total, covering: MRI gyrification index, grey matter volume, cortical thickness, neurite orientation dispersion imaging, PET imaging regional glucose metabolism magnetic resonance spectroscopy N-acetylaspartate. also review preclinical relationship between ex vivo protein 2A (SV2A). These show schizophrenia associated volumes accelerated loss time, abnormal patterns, SV2A levels markers comparison controls (effect sizes from ~ −0.11 −1.0). Key regions affected include frontal, anterior cingulate temporal cortices hippocampi. several limitations interpretation findings terms alterations. Nevertheless, taken post-mortem they suggest some regions. However, gaps evidence, particular whether generalise cohorts.

Language: Английский

---

Imaging of Synaptic Density in Neurodegenerative Disorders

Journal of Nuclear Medicine, Journal Year: 2022, Volume and Issue: 63(Supplement 1), P. 60S - 67S

Published: June 1, 2022

PET technology has produced many radiopharmaceuticals that target specific brain proteins and other measures of function. Recently, a new approach emerged to image synaptic density by targeting the vesicle protein 2A (SV2A), an integral glycoprotein in membrane vesicles widely distributed throughout brain. Multiple SV2A ligands have been developed translated human use. The most successful these date is ¹¹C-UCB-J, because its high uptake, moderate metabolism, effective quantification with 1-tissue-compartment model. Further, since antiepileptic drug levetiracetam, blocking studies characterized binding potential reference regions. Regional levels were shown correlate those synaptophysin, another commonly used marker density, providing basis for imaging broad utility across neuropathologic diseases. In this review, we highlight development tracers evaluation methods, including compartment modeling simple tissue ratios. Mouse rat models neurodegenerative diseases studied small-animal PET, validation comparison direct measures. Next, review results multiple disorders. Studies on Parkinson disease Alzheimer progressed rapidly at centers, generally consistent patterns or loss. disease, loss differ from amyloid, tau, ¹⁸F-FDG, although intertracer interregional correlations found. Smaller reported disorders, Lewy body dementia, frontotemporal Huntington progressive supranuclear palsy, corticobasal degeneration. conclusion, developed, qualified radioligands are available. humans indicate might be disease-associated regions recent availability ¹⁸F tracers, ¹⁸F-SynVesT-1 ¹⁸F-SynVesT-2, will substantially broaden application PET. Future needed larger patient cohorts establish clinical value diagnosis progression monitoring diseases, as well efficacy assessment disease-modifying therapies.

Language: Английский

---

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 10, 2022

Abstract Numerous brain disorders demonstrate structural abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these connectomic vulnerabilities remain unknown, has yet be studied in a single multi-disorder framework. Using MRI morphometry the ENIGMA consortium, we construct maps cortical abnormalities for thirteen neurodevelopmental, neurological, psychiatric N = 21,000 participants 26,000 controls, collected using harmonised processing protocol. We systematically compare multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, myelination (molecular vulnerability), as well global measures number connections, centrality, connection diversity (connectomic vulnerability). find relationship between vulnerability white-matter architecture that drives disorder profiles. Local attributes, particularly receptor profiles, constitute best predictors both disorder-specific morphology cross-disorder similarity. Finally, consistently subtended by small subset network epicentres bilateral sensory-motor, inferior temporal lobe, precuneus, superior parietal cortex. Collectively, our results highlight how local attributes connectivity jointly shape abnormalities.

Language: Английский

---

Targeting synapse function and loss for treatment of neurodegenerative diseases

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 23(1), P. 23 - 42

Published: Nov. 27, 2023

Language: Английский

---

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: April 28, 2022

In recent years, the field of neuroimaging dramatically moved forward by means expeditious development specific radioligands novel targets. Among these targets, synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein vesicles, present in all terminals, irrespective neurotransmitter content. It involved key functions neurons, focused on regulation release. The ubiquitous expression gray matter regions brain basis its candidacy as marker density. Following molecules derived from structure anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized allow study SV2A distribution with positron emission tomography (PET). These permit evaluation vivo changes held be potential measure density physiological and pathological conditions. use biomarker raises important questions. Despite numerous studies over last decades, biological function expressional properties remain poorly understood. Some were claimed, but not fully elucidated. While ubiquitous, stronger associations between Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses observed some structures. A further issue unclear interaction tracers, reflects need clarify what really detected tools. Here, we summarize current knowledge discuss uncertain aspects biology physiology. As likely more strongly related certain type neurotransmission particular circumstances, extensive would greatly facilitate analysis interpretation results allowing only an increase or decrease level, also involved.

Language: Английский

---

Neurodegenerative model of schizophrenia: Growing evidence to support a revisit

Schizophrenia Research, Journal Year: 2022, Volume and Issue: 243, P. 154 - 162

Published: March 25, 2022

Language: Английский

---