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Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease.
Jett, S, Boneu, C, Zarate, C, Carlton, C, Kodancha, V, Nerattini, M, Battista, M, Pahlajani, S, Williams, S, Dyke, JP, et al
Frontiers in aging neuroscience. 2023;:1183228
Abstract
Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used 18F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. 31Phosphorus-magnetic resonance spectroscopy (31P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the 31P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of 31P-MRS measures as biomarkers for the early detection of AD.
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A tale of two systems: Lessons learned from female mid-life aging with implications for Alzheimer's prevention & treatment.
Mishra, A, Wang, Y, Yin, F, Vitali, F, Rodgers, KE, Soto, M, Mosconi, L, Wang, T, Brinton, RD
Ageing research reviews. 2022;:101542
Abstract
Neurological aging is frequently viewed as a linear process of decline, whereas in reality, it is a dynamic non-linear process. The dynamic nature of neurological aging is exemplified during midlife in the female brain. To investigate fundamental mechanisms of midlife aging that underlie risk for development of Alzheimer's disease (AD) in late life, we investigated the brain at greatest risk for the disease, the aging female brain. Outcomes of our research indicate that mid-life aging in the female is characterized by the emergence of three phases: early chronological (pre-menopause), endocrinological (peri-menopause) and late chronological (post-menopause) aging. The endocrinological aging program is sandwiched between early and late chronological aging. Throughout the three stages of midlife aging, two systems of biology, metabolic and immune, are tightly integrated through a network of signaling cascades. The network of signaling between these two systems of biology underlie an orchestrated sequence of adaptative starvation responses that shift the brain from near exclusive dependence on a single fuel, glucose, to utilization of an auxiliary fuel derived from lipids, ketone bodies. The dismantling of the estrogen control of glucose metabolism during mid-life aging is a critical contributor to the shift in fuel systems and emergence of dynamic neuroimmune phenotype. The shift in fuel reliance, puts the largest reservoir of local fatty acids, white matter, at risk for catabolism as a source of lipids to generate ketone bodies through astrocytic beta oxidation. APOE4 genotype accelerates the tipping point for emergence of the bioenergetic crisis. While outcomes derived from research conducted in the female brain are not directly translatable to the male brain, the questions addressed in a female centric program of research are directly applicable to investigation of the male brain. Like females, males with AD exhibit deficits in the bioenergetic system of the brain, activation of the immune system and hallmark Alzheimer's pathologies. The drivers and trajectory of mechanisms underlying neurodegeneration in the male brain will undoubtedly share common aspects with the female in addition to factors unique to the male. Preclinical and clinical evidence indicate that midlife endocrine aging can also be a transitional bridge to autoimmune disorders. Collectively, the data indicate that endocrinological aging is a critical period "tipping point" in midlife which can initiate emergence of the prodromal stage of late-onset-Alzheimer's disease. Interventions that target both immune and metabolic shifts that occur during midlife aging have the potential to alter the trajectory of Alzheimer's risk in late life. Further, to achieve precision medicine for AD, chromosomal sex is a critical variable to consider along with APOE genotype, other genetic risk factors and stage of disease.
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Antibacterial and Anti-Inflammatory Activity of an Antimicrobial Peptide Synthesized with D Amino Acids.
Brunetti, J, Carnicelli, V, Ponzi, A, Di Giulio, A, Lizzi, AR, Cristiano, L, Cresti, L, Cappello, G, Pollini, S, Mosconi, L, et al
Antibiotics (Basel, Switzerland). 2020;(12)
Abstract
The peptide SET-M33 is a molecule synthesized in tetra-branched form which is being developed as a new antibiotic against Gram-negative bacteria. Its isomeric form with D amino acids instead of the L version (SET-M33D) is also able to kill Gram-positive bacteria because of its higher resistance to bacterial proteases (Falciani et al., PLoS ONE, 2012, 7, e46259). Here we report the strong in vitro activity of SET-M33D (MIC range 0.7-6.0 µM) against multiresistant pathogens of clinical interest, including Gram-positives Staphylococcus aureus, Staphylococcus saprophyticus, and Enterococcus faecalis, and various Gram-negative enterobacteriaceae. SET-M33D antibacterial activity is also confirmed in vivo against a MRSA strain of S. aureus with doses perfectly compatible with clinical use (5 and 2.5 mg/Kg). Moreover, SET-M33D strongly neutralized lipopolysaccharide (LPS) and lipoteichoic acid (LTA), thus exerting a strong anti-inflammatory effect, reducing expression of cytokines, enzymes, and transcription factors (TNF-α, IL6, COX-2, KC, MIP-1, IP10, iNOS, NF-κB) involved in the onset and evolution of the inflammatory process. These results, along with in vitro and in vivo toxicity data and the low frequency of resistance selection reported here, make SET-M33D a strong candidate for the development of a new broad spectrum antibiotic.
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Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area.
Mosconi, L, Walters, M, Sterling, J, Quinn, C, McHugh, P, Andrews, RE, Matthews, DC, Ganzer, C, Osorio, RS, Isaacson, RS, et al
BMJ open. 2018;8(3):e019362
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Alzheimer’s disease (AD) is the most common form of dementia, affecting nearly 34 million people worldwide. It has been estimated that one in every three cases of AD may be attributable to diet and lifestyle factors. The aim of this study was to investigate the effects of lifestyle and vascular-related risk factors for AD. Researchers studied the brain scans of 116 healthy adults aged 30-60 years. They collected information on factors related to lifestyle, such as diet, physical activity and intellectual enrichment. They also looked at markers for vascular risk such as body mass index (BMI), cholesterol and homocysteine, as well as cognitive function. The researchers found that a Mediterranean-style diet and good insulin sensitivity were both associated with a healthier brain structure. A better score for intellectual enrichment and lower BMI were both associated with better cognition. They concluded that adopting a Mediterranean-style diet and maintaining a healthy weight might reduce the risk of developing AD.
Abstract
OBJECTIVE To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN Cross-sectional, observational. SETTING Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS Adherence to a Mediterranean-style diet (MeDi) and insulin sensitivity were both positively associated with MRI-based cortical thickness (diet: βs≥0.26, insulin sensitivity βs≥0.58, P≤0.008). After accounting for vascular risk, EC in turn explained variance in memory (P≤0.001). None of the other lifestyle and vascular risk variables were associated with brain thickness. In addition, the path associations between intellectual enrichment and better cognition were significant (βs≥0.25 P≤0.001), as were those between overweight and lower cognition (βs≥-0.22, P≤0.01). CONCLUSIONS In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.
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Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer's Disease Prevention.
Schelke, MW, Attia, P, Palenchar, DJ, Kaplan, B, Mureb, M, Ganzer, CA, Scheyer, O, Rahman, A, Kachko, R, Krikorian, R, et al
Frontiers in aging neuroscience. 2018;:96
Abstract
Alzheimer's disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease-modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms-dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity-involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases.
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Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.
Berkowitz, CL, Mosconi, L, Rahman, A, Scheyer, O, Hristov, H, Isaacson, RS
The journal of prevention of Alzheimer's disease. 2018;(4):245-252
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Abstract
Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.
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FDG- and amyloid-PET in Alzheimer's disease: is the whole greater than the sum of the parts?
Mosconi, L, McHugh, PF
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.... 2011;(3):250-64
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Abstract
The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring prior to the onset of clinical symptoms, when the potential for preservation of function is at the greatest. In vivo brain imaging is a promising tool for the early detection of AD through visualization of abnormalities in brain structure, function and histopathology. Currently, positron emission tomography (PET) imaging with amyloid-beta (Aβ) tracers and 2-[(18)F]fluoro-2-Deoxy-D-glucose (FDG) is largely utilized in the diagnosis of AD. This paper reviews brain Aβ- and FDG-PET studies in AD patients as well as in non-demented individuals at risk for AD. We then discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Aβ-PET to improve the early detection of AD.
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[L-acetylcarnitine treatment on fragile X patients hyperactive behaviour].
Calvani, M, D'Iddio, S, de Gaetano, A, Mariotti, P, Mosconi, L, Pomponi, MG, Tabolacci, E, Torrioli, MG, Vernacotola, S, Neri, G
Revista de neurologia. 2001;:S65-70
Abstract
Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome (FXS), the most common inherited disease causing mental retardation. Therapeutical approaches are actually based on Central Nervous System (CNS) stimulants lacking a well defined rationale and efficacy while they further decrease the patient's limited attention span. A pilot study on 17 fragile X male treated with L-acetylcarnitine (LAC) over one year, showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Questionnaire. LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity. LAC is a small, hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters. Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis. The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS. The exogenous administration of LAC may affect brain activity in FXS by: I) modulation of fuel partitioning for energy production, which at the mithocondrial level is associated with the Kreb's cycle metabolic role in neurotransmitter synthesis; II) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids; III) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS. Based on the above premises an explorative, double-blind, placebo controlled, multicenter study is ongoing. A total population of 160 children from nine European centers will be enrolled. The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Questionnaire.