Functional signature of conversion of patients with mild cognitive impairment

Pizzi, Stefano Delli; Punzi, Miriam; Sensi, Stefano L.; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.neurobiolaging.2018.10.004

Cited by 35 publications

(28 citation statements)

References 93 publications

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“…The analysis of this spontaneous synaptic activity indicates that aged neurons exhibit an increased frequency of [Ca 2+ ]i transients along with decreased spike amplitudes, two indirect signs of hyperexcitability 28,41 . These findings parallel in vivo observations in hippocampal and cortical neurons of clinical and preclinical models of physiopathological aging 29,[42][43][44] .…”

Section: Age-related Functional and Molecular Changes On Cultured Corsupporting

confidence: 83%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

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Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca 2+ i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that 'aged' neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca 2+ ]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca 2+ ]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease agerelated neuronal dysfunctions. L-CS treatment does not modify NCX activityCeramides can modulate the activity of the plasmalemmal Na + -Ca 2+ exchanger (NCX) 25 , a low capacitance high-affinity system that critically regulates cellular [Ca 2+ ]i. We, therefore, investigated

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Section: Age-related Functional and Molecular Changes On Cultured Corsupporting

confidence: 83%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

Self Cite

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“…fMRI has shown a disruption of brain network organization at different stages of the disease, essentially indicating a progressive disruption of the default mode network, both at the network level (Lim et al, 2014; Jones et al, 2015) and at the local level (Jovicich et al, 2018); being hub regions primarily impaired (Drzezga et al, 2011; Crossley et al, 2014). Furthermore, patients that convert from MCI to AD showed entorhinal/hippocampal hypoconnectivity in comparison to those that did not covert (Delli Pizzi et al, 2019). Interestingly, MCI patients who did not convert to AD or did not show CSF signs of disease showed hyperconnectivity between hippocampal/entorhinal with neocortical/subcortical regions (Delli Pizzi et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, patients that convert from MCI to AD showed entorhinal/hippocampal hypoconnectivity in comparison to those that did not covert (Delli Pizzi et al, 2019). Interestingly, MCI patients who did not convert to AD or did not show CSF signs of disease showed hyperconnectivity between hippocampal/entorhinal with neocortical/subcortical regions (Delli Pizzi et al, 2019). These results are essentially in agreement with those found with electrophysiological techniques in certain frequency bands such as alpha and beta.…”

Section: Discussionmentioning

confidence: 99%

The Importance of the Validation of M/EEG With Current Biomarkers in Alzheimer's Disease

Maestú

Cuesta

Hasan

et al. 2019

Front. Hum. Neurosci.

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Current biomarkers used in research and in clinical practice in Alzheimer's Disease (AD) are the analysis of cerebral spinal fluid (CSF) to detect levels of Aβ42 and phosphorylated-tau, amyloid and FDG-PET, and MRI volumetry. Some of these procedures are still invasive for patients or expensive. Electroencephalography (EEG) and Magnetoencephalography (MEG) are two non-invasive techniques able to detect the early synaptic dysfunction and track the course of the disease. However, in spite of its added value they are not part of the standard of care in clinical practice in dementia. In this paper we review what these neurophysiological techniques can add to the early diagnosis of AD, whether results in both modalities are related to each other or not, as well as the need of its validation against current biomarkers. We discuss their potential implications for the better understanding of the pathophysiological mechanisms of the disease as well as the need of performing simultaneous M/EEG recordings to better understand discrepancies between these two techniques. Finally, more studies are needed studying M/EEG with amyloid and Tau biomarkers.

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“…They were primarily hampered by a small sample size and the limited patient stratification as far as the copper and AD status is concerned. All of these issues and shortcomings can be easily overcome by maximizing the possibility of early intervention recruiting individuals diagnosed as MCI [83][84][85][86][87][88][89][90] and employing non-ceruloplasmin copper as a serum stratification/prognostic biomarker [91,92] and inclusion criterion (higher than 1.6 µmol/L) for eligibility assessment to participate in clinical trials testing zinc therapy.…”

Section: Early Studies On Zinc Therapy In Alzheimer's Diseasementioning

confidence: 99%

Zinc Therapy in Early Alzheimer’s Disease: Safety and Potential Therapeutic Efficacy

et al. 2020

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Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound (‘free’) copper in serum and urine. A subset of patients with Alzheimer’s disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc’s action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.

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Functional signature of conversion of patients with mild cognitive impairment

Cited by 35 publications

References 93 publications

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

The Importance of the Validation of M/EEG With Current Biomarkers in Alzheimer's Disease

Zinc Therapy in Early Alzheimer’s Disease: Safety and Potential Therapeutic Efficacy

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