Synaptic degeneration in Alzheimer disease

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 19(1), P. 19 - 38

Published: Dec. 13, 2022

Language: Английский

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Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [¹¹C]UCB‐J

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 18(12), P. 2527 - 2536

Published: Feb. 17, 2022

Abstract Introduction For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With recent advent synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun evaluate consequences alterations vivo. Methods We examined relationship between density measured [ 11 C]UCB‐J PET and neuropsychological test performance 45 participants with early AD. Results Global showed a significant positive association global cognition five individual domains Synaptic was stronger predictor than gray matter volume. Conclusion These results confirm neuropathologic studies demonstrating performance, suggest that correlation extends stages

Language: Английский

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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

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Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation

Annual Review of Immunology, Journal Year: 2023, Volume and Issue: 41(1), P. 431 - 452

Published: Feb. 8, 2023

The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation innate and adaptive immunity. With the convergence a revolution complement-directed clinical therapeutics, discovery specific complement-associated targetable pathways central nervous system, development integrated multi-omic technologies that have all emerged over last 15 years, precision therapeutic targeting Alzheimer disease other neurodegenerative diseases processes appears to be within reach. As sensor tissue distress, protects brain from microbial challenge as well accumulation dead and/or damaged molecules cells. Additional more recently discovered diverse functions make it paramount importance design neurotherapeutics such beneficial neurodevelopment, adult neural plasticity, neuroprotective are retained.

Language: Английский

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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

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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

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In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2023, Volume and Issue: 43(6), P. 977 - 988

Published: Jan. 30, 2023

Synapse loss has been considered as a major pathological change in Alzheimer’s disease (AD). It remains unclear about whether and how synapse relates to functional structural connectivity dysfunction AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using 18 F-SynVesT-1 PET evaluate alterations 33 participants with AD, 31 mild cognitive impairment (MCI), 30 controls. examined the correlation between density function. Functional MRI was performed analyze lower regions. tracked white matter tracts impaired regions Diffusion MRI. In AD group, bilateral cortex hippocampus found when compared The changes right insular caudal middle frontal gyrus (MFG) were correlated decline. Among them, MFG positively associated - superior (SFG) connectivity. had probability of tract (POT) SFG than controls, which significantly global cognition. These findings provide evidence supporting contributes related underlying

Language: Английский

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Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(3), P. 619 - 628

Published: July 28, 2023

Abstract Recent studies have demonstrated that neuroplasticity, such as synaptic plasticity and neurogenesis, exists throughout the normal lifespan but declines with age is significantly impaired in individuals Alzheimer’s disease. Hence, promoting neuroplasticity may represent an effective strategy which disease can be alleviated. Due to their significant ability self-renew, differentiate, migrate, neural stem cells play essential role reversing neuronal damage, reducing pathology of disease, including amyloid-β, tau protein, neuroinflammation, secreting neurotrophic factors growth are related plasticity. These events promote neurogenesis repair microenvironment mammalian brain. Consequently, considered a potential regenerative therapy improve other neurodegenerative diseases. In this review, we discuss how regulate optimize effects enhance for treating clinic.

Language: Английский

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Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7258 - 7258

Published: April 14, 2023

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, neurodegeneration. Diverse alterations have been associated with progression, including genetic mutations, neuroinflammation, blood-brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, metal ion imbalance.Additionally, recent studies shown an association between altered heme metabolism AD. Unfortunately, decades of research drug development not produced any effective treatments for Therefore, understanding the cellular molecular mechanisms underlying pathology identifying potential therapeutic targets are crucial development. This review discusses most common promising discovery. Furthermore, it highlights role in summarizes mathematical models AD, stochastic model effect Aβ on We also summarize treatment strategies these can offer clinical trials.

Language: Английский

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A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 25, 2024

Abstract Background Effective, disease-modifying therapeutics for the treatment of Alzheimer’s disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aβ) is central to AD pathophysiology, and Aβ oligomers are among most toxic forms Aβ. CT1812 novel brain penetrant sigma-2 receptor ligand interferes with binding neurons. Preclinical studies have demonstrated its ability displace from neurons, restore synapses in cell cultures, improve cognitive measures mouse models AD. was found be generally safe well tolerated placebo-controlled phase 1 clinical trial healthy volunteers 1a/2 trials patients mild moderate dementia due The unique objective this study incorporate synaptic positron emission tomography (PET) imaging as an outcome measure patients. Methods present 1/2 randomized, double-blind, placebo-controlled, parallel-group conducted 23 participants primarily evaluate safety secondarily pharmacodynamic effects. Participants received either placebo or 100 mg 300 per day oral 24 weeks. Pharmacodynamic effects were assessed using exploratory efficacy endpoints vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) volumetric MRI, measures, cerebrospinal fluid (CSF) biomarkers pathology degeneration. Results No differences relative observed change baseline at weeks SV2A FDG PET signal, rating scales, CSF biomarkers. Composite region MRI revealed trend towards tissue preservation treated dose CT1812, nominally significant both doses compared pericentral, prefrontal, hippocampal cortices. tolerated. Conclusions findings 24-week changes on support further development. Trial registration described manuscript registered clinicaltrials.gov (NCT03493282).

Language: Английский

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