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

---

Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11677 - 11677

Published: Oct. 28, 2021

The physiological balance between excitation and inhibition in the brain is significantly affected Alzheimer's disease (AD). Several neuroactive compounds their signaling pathways through various types of receptors are crucial homeostasis, among them glutamate γ-aminobutyric acid (GABA). Activation microglial regulates immunological response these cells, which AD could be neuroprotective or neurotoxic. novel research approaches revealed complexity function, including interplay with other cells during neuroinflammation brain. purpose this review to describe role several proteins multiple on microglia neurons, involvement a communication network that lead different metabolic loops cell death/survival. Our focused glutamatergic, GABAergic microglia-neuronal cross-talk neuroinflammation. Moreover, significance AD-related neurotoxic glutamate/GABA-mediated dialogue neurons was analyzed search targets neuroprotection, advanced pharmacological approaches.

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

---

In vivo evidence of lower synaptic vesicle density in schizophrenia

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(12), P. 7690 - 7698

Published: June 16, 2021

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

---

Reduced Synaptic Density in Patients with Lewy Body Dementia: An [¹¹C]UCB‐J PET Imaging Study

Movement Disorders, Journal Year: 2021, Volume and Issue: 36(9), P. 2057 - 2065

Published: April 25, 2021

ABSTRACT Background Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, vivo evidence lacking. Objective The objective of this study was assess density synapses non‐demented PD (nPD) subjects (N = 21), patients PD‐dementia or Dementia bodies (DLB) 13), age‐matched healthy controls 15). Method Using PET imaging novel synaptic‐vesicle‐glycoprotein 2A (SV2A) radioligand [11C]UCB‐J, SUVR‐1 values were obtained for 12 pre‐defined regions. Volumes‐of‐interest defined on MRI T1 scans. Voxel‐level between‐group comparisons [11C]UCB‐J performed. All underwent neuropsychological assessment. Correlations between [11C]UCB‐ J domain‐specific functioning examined. Results nPD only demonstrated significantly reduced substantia nigra (SN) compared HC. DLB/PDD SN all cortical VOIs except hippocampus amygdala. voxel‐based analysis supported VOI results. Significant correlation seen middle frontal gyrus performance tests executive function. Conclusion Widespread reduction documented a cohort using PET. Our confirms previously reported loss patients. binding selected correlated their levels function across relevant domains. These findings suggest that contributes impairment DLB/PDD. © 2021 International Parkinson Movement Disorder Society

Language: Английский

---

Imaging Synaptic Density: The Next Holy Grail of Neuroscience?

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

Published: March 25, 2022

The brain is the central and most complex organ in nervous system, comprising billions of neurons that constantly communicate through trillions connections called synapses. Despite being formed mainly during prenatal early postnatal development, synapses are continually refined eliminated throughout life via complicated hitherto incompletely understood mechanisms. Failure to correctly regulate numbers distribution has been associated with many neurological psychiatric disorders, including autism, epilepsy, Alzheimer’s disease, schizophrenia. Therefore, measurements synaptic density, as well detection dysfunction, essential for understanding normal abnormal development. To date, multiple density markers have proposed investigated experimental models disorders. majority gold standard methodologies (e.g., electron microscopy or immunohistochemistry) visualize measure changes pre- postsynaptic proteins ex vivo . However, invasive nature these classic precludes their use living organisms. recent development positron emission tomography (PET) tracers [such ( 18 F)UCB-H 11 C)UCB-J] bind a putative marker, vesicle 2A (SV2A) protein, heralding likely paradigm shift detecting alterations patients. limited specificity, novel, non-invasive magnetic resonance (MR)-based methods also show promise inferring information by linking glutamate neurotransmission. Although promising, all entail various advantages limitations must be addressed before becoming part routine clinical practice. In this review, we summarize discuss current quantifying an evaluation reliability utility. We conclude critical assessment challenges need overcome successfully employing biomarkers diagnostic and/or prognostic tools study neuropsychiatric

Language: Английский

---

Neurophysiological signatures of cortical micro-architecture

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 26, 2023

Abstract Systematic spatial variation in micro-architecture is observed across the cortex. These micro-architectural gradients are reflected neural activity, which can be captured by neurophysiological time-series. How spontaneous dynamics organized cortex and how they arise from heterogeneous cortical remains unknown. Here we extensively profile regional human brain estimating over 6800 time-series features resting state magnetoencephalography (MEG) signal. We then map profiles to a comprehensive multi-modal, multi-scale atlas of micro-architecture, including microstructure, metabolism, neurotransmitter receptors, cell types laminar differentiation. find that dominant axis reflects characteristics power spectrum density linear correlation structure signal, emphasizing importance conventional electromagnetic while identifying additional informative have traditionally received less attention. Moreover, co-localized with multiple features, gene expression gradients, intracortical myelin, receptors transporters, oxygen glucose metabolism. Collectively, this work opens new avenues for studying anatomical basis activity.

Language: Английский

---

Detecting Early Cognitive Decline in Alzheimer’s Disease with Brain Synaptic Structural and Functional Evaluation

Biomedicines, Journal Year: 2023, Volume and Issue: 11(2), P. 355 - 355

Published: Jan. 26, 2023

Early cognitive decline in patients with Alzheimer's (AD) is associated quantifiable structural and functional connectivity changes the brain. AD dysregulation of Aβ tau metabolism progressively disrupt normal synaptic function, leading to loss synapses, decreased hippocampal density early atrophy. Advances brain imaging techniques living have enabled transition from clinical signs symptoms-based diagnosis biomarkers-based diagnosis, techniques, quantitative EEG, body fluids sampling. The hippocampus has a central role semantic episodic memory processing. This function critically dependent on intrahippocampal connections many cortical regions, including perirhinal entorhinal cortex, parahippocampal association regions temporal parietal lobes, prefrontal cortex. Therefore, reflected altered intrinsic networks (aka large-scale networks), memory, default mode, salience networks. narrative review discusses recent critical issues related detecting AD-associated markers high-risk or neuropsychologically diagnosed subjective impairment mild impairment.

Language: Английский

---