Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Wilson, Heather; Politis, Marios; Rabiner, Eugenii A.; Middleton, Lefkos T.

doi:10.3390/cells9122581

Cited by 20 publications

(15 citation statements)

References 365 publications

(430 reference statements)

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“…While there is an understandable focus on in vivo CTE tau identification, measuring the degree and spatial distribution of neuroinflammation [ 100 , 148 – 150 ] and synaptic dysfunction are other potentially interesting PET applications for repetitive head trauma [ 151 – 153 ]. The translocator protein (TSPO) is a mitochondrial membrane protein that is upregulated in activated microglia, astroglia, and macrophages.…”

Section: Future Considerations For Neuroimaging Research In Repetitive Head Traumamentioning

confidence: 99%

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

Asken

Rabinovici

2021

acta neuropathol commun

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Background and Scope of Review Varying severities and frequencies of head trauma may result in dynamic acute and chronic pathophysiologic responses in the brain. Heightened attention to long-term effects of head trauma, particularly repetitive head trauma, has sparked recent efforts to identify neuroimaging biomarkers of underlying disease processes. Imaging modalities like structural magnetic resonance imaging (MRI) and positron emission tomography (PET) are the most clinically applicable given their use in neurodegenerative disease diagnosis and differentiation. In recent years, researchers have targeted repetitive head trauma cohorts in hopes of identifying in vivo biomarkers for underlying biologic changes that might ultimately improve diagnosis of chronic traumatic encephalopathy (CTE) in living persons. These populations most often include collision sport athletes (e.g., American football, boxing) and military veterans with repetitive low-level blast exposure. We provide a clinically-oriented review of neuroimaging data from repetitive head trauma cohorts based on structural MRI, FDG-PET, Aβ-PET, and tau-PET. We supplement the review with two patient reports of neuropathology-confirmed, clinically impaired adults with prior repetitive head trauma who underwent structural MRI, FDG-PET, Aβ-PET, and tau-PET in addition to comprehensive clinical examinations before death. Review Conclusions Group-level comparisons to controls without known head trauma have revealed inconsistent regional volume differences, with possible propensity for medial temporal, limbic, and subcortical (thalamus, corpus callosum) structures. Greater frequency and severity (i.e., length) of cavum septum pellucidum (CSP) is observed in repetitive head trauma cohorts compared to unexposed controls. It remains unclear whether CSP predicts a particular neurodegenerative process, but CSP presence should increase suspicion that clinical impairment is at least partly attributable to the individual’s head trauma exposure (regardless of underlying disease). PET imaging similarly has not revealed a prototypical metabolic or molecular pattern associated with repetitive head trauma or predictive of CTE based on the most widely studied radiotracers. Given the range of clinical syndromes and neurodegenerative pathologies observed in a subset of adults with prior repetitive head trauma, structural MRI and PET imaging may still be useful for differential diagnosis (e.g., assessing suspected Alzheimer’s disease).

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Section: Future Considerations For Neuroimaging Research In Repetitive Head Traumamentioning

confidence: 99%

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

Asken

Rabinovici

2021

acta neuropathol commun

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“…Neuroimaging techniques have been useful for assessing changes in energy metabolism [23,24]. For example, changes in glucose and oxygen consumption can be measured using oxygen or glucose PET and indirectly using fMRI.…”

Section: Decreased Brain Ph In Patients With Schizophreniamentioning

confidence: 99%

Decreased Brain pH and Pathophysiology in Schizophrenia

Park

Choi

Leem

2021

IJMS

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Postmortem studies reveal that the brain pH in schizophrenia patients is lower than normal. The exact cause of this low pH is unclear, but increased lactate levels due to abnormal energy metabolism appear to be involved. Schizophrenia patients display distinct changes in mitochondria number, morphology, and function, and such changes promote anaerobic glycolysis, elevating lactate levels. pH can affect neuronal activity as H+ binds to numerous proteins in the nervous system and alters the structure and function of the bound proteins. There is growing evidence of pH change associated with cognition, emotion, and psychotic behaviors. Brain has delicate pH regulatory mechanisms to maintain normal pH in neurons/glia and extracellular fluid, and a change in these mechanisms can affect, or be affected by, neuronal activities associated with schizophrenia. In this review, we discuss the current understanding of the cause and effect of decreased brain pH in schizophrenia based on postmortem human brains, animal models, and cellular studies. The topic includes the factors causing decreased brain pH in schizophrenia, mitochondria dysfunction leading to altered energy metabolism, and pH effects on the pathophysiology of schizophrenia. We also review the acid/base transporters regulating pH in the nervous system and discuss the potential contribution of the major transporters, sodium hydrogen exchangers (NHEs), and sodium-coupled bicarbonate transporters (NCBTs), to schizophrenia.

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“…The glucose analog 2-[ 18 F]fluoro-2-deoxy-d-glucose ([ 18 F]FDG) is the most frequently used radiotracer to measure cerebral glucose metabolism for the diagnosis of AD in patients. The reduction of brain glucose metabolism correlates well with the degree of cognitive impairment [ 29 ]. Thus, [ 18 F]FDG-PET and NOR test were performed for the in vivo evaluation of glucose metabolism and cognitive function in an AD transgenic mouse model.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes Ameliorate Alzheimer’s Disease Pathology and Improve Cognitive Deficits

Chen

et al. 2021

Biomedicines

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The accumulation of extracellular β-amyloid (Aβ) plaques within the brain is unique to Alzheimer’s disease (AD) and thought to induce synaptic deficits and neuronal loss. Optimal therapies should tackle the core AD pathophysiology and prevent the decline in memory and cognitive functions. This study aimed to evaluate the therapeutic performance of mesenchymal stem cell-derived exosomes (MSC-exosomes), which are secreted membranous elements encapsulating a variety of MSC factors, on AD. A human neural cell culture model with familial AD (FAD) mutations was established and co-cultured with purified MSC-exosomes. 2-[18F]Fluoro-2-deoxy-d-glucose ([18F]FDG) and novel object recognition (NOR) testing were performed before/after treatment to evaluate the therapeutic effect in vivo. The AD-related pathology and the expression of neuronal memory/synaptic plasticity-related genes were also evaluated. The results showed that MSC-exosomes reduced Aβ expression and restored the expression of neuronal memory/synaptic plasticity-related genes in the cell model. [18F]FDG-PET imaging and cognitive assessment revealed a significant improvement in brain glucose metabolism and cognitive function in AD transgenic mice. The phase of neurons and astrocytes in the brain of AD mice were also found to be regulated after treatment with MSC-exosomes. Our study demonstrates the therapeutic mechanism of MSC-exosomes and provides an alternative therapeutic strategy based on cell-free MSC-exosomes for the treatment of AD.

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Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Cited by 20 publications

References 365 publications

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

Decreased Brain pH and Pathophysiology in Schizophrenia

Mesenchymal Stem Cell-Derived Exosomes Ameliorate Alzheimer’s Disease Pathology and Improve Cognitive Deficits

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