Nady Braidy’s research while affiliated with UNSW Sydney and other places

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Publications (259)


Functional Magnetic Resonance Imaging in Alzheimer’s Disease Drug Trials: A Mini-Review
  • Chapter

November 2024

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Nady Braidy

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative pathology that leads to cognitive decline and dementia, particularly in older adults. It disrupts brain structure and function, with neurotoxic amyloid-β (Aβ) plaques being a primary pathological hallmark. Pharmacotherapeutic trials targeting Aβ and other AD pathological features aim to slow disease progression. Functional magnetic resonance imaging (fMRI) is a non-invasive tool that visualizes brain functional activity, aiding in evaluating the efficacy of AD drugs in clinical trials. Objective: This mini-review explores the role of fMRI in evaluating the impact of AD pharmacotherapeutic clinical trials conducted in the past seven years. Methods: Literature was systematically searched using two databases. The risk of bias was assessed with the Revised Cochrane risk-of-bias tool (RoB-2) for randomized clinical trials (RCTs). Results: Four studies using fMRI to investigate AD drug efficacy were included. Cholinesterase, glutamatergic, and sero- tonergic drugs showed significant positive effects on brain functional activity, especially within the default mode network. Functional connectivity (FC) changes due to drug intake were linked to cerebellar and cholinergic decline in AD, correlating with improved global cognition and fMRI task performance. Conclusions: Recent RCTs demonstrate fMRI’s ability to reveal longitudinal FC pattern changes in response to AD drug treat- ments across disease stages. Positive FC changes in distinct brain regions suggest potential compensatory mechanisms from drug intake. However, these drugs have limited efficacy, necessitating further research to enhance specific pharmacological interventions for clinical application.


Supplementation with NAD+ Precursors for Treating Alzheimer’s Disease: A Metabolic Approach

November 2024

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3 Reads

Background: Alzheimer’s disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases. Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR. Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.


Supplementation with NAD+ Precursors for Treating Alzheimer's Disease: A Metabolic Approach

October 2024

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14 Reads

Background: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases. Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR. Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.


Functional Magnetic Resonance Imaging in Alzheimer's Disease Drug Trials: A Mini-Review

October 2024

·

8 Reads

Background: Alzheimer's disease (AD) is a progressive neurodegenerative pathology that leads to cognitive decline and dementia, particularly in older adults. It disrupts brain structure and function, with neurotoxic amyloid-β (Aβ) plaques being a primary pathological hallmark. Pharmacotherapeutic trials targeting Aβ and other AD pathological features aim to slow disease progression. Functional magnetic resonance imaging (fMRI) is a non-invasive tool that visualizes brain functional activity, aiding in evaluating the efficacy of AD drugs in clinical trials. Objective: This mini-review explores the role of fMRI in evaluating the impact of AD pharmacotherapeutic clinical trials conducted in the past seven years. Methods: Literature was systematically searched using two databases. The risk of bias was assessed with the Revised Cochrane risk-of-bias tool (RoB-2) for randomized clinical trials (RCTs). Results: Four studies using fMRI to investigate AD drug efficacy were included. Cholinesterase, glutamatergic, and serotonergic drugs showed significant positive effects on brain functional activity, especially within the default mode network. Functional connectivity (FC) changes due to drug intake were linked to cerebellar and cholinergic decline in AD, correlating with improved global cognition and fMRI task performance. Conclusions: Recent RCTs demonstrate fMRI's ability to reveal longitudinal FC pattern changes in response to AD drug treatments across disease stages. Positive FC changes in distinct brain regions suggest potential compensatory mechanisms from drug intake. However, these drugs have limited efficacy, necessitating further research to enhance specific pharmacological interventions for clinical application.


Biocompatibility and Proteomic Profiling of DMSA-Coated Iron Nanocubes in a Human Glioblastoma Cell Line
  • Article
  • Full-text available

January 2024

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57 Reads

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Chul-Kyu Kim

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[...]

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Nady Braidy

Background: Superparamagnetic iron core iron oxide shell nanocubes have previously shown superior performance in magnetic resonance imaging T2 contrast enhancement compared with spherical nanoparticles. Methods: Iron core iron oxide shell nanocubes were synthesized, stabilized with dimercaptosuccinic acid (DMSA-NC) and physicochemically characterized. Magnetic resonance imaging (MRI) contrast enhancement and biocompatibility were assessed in vitro. Results: DMSA-NC showed a transverse relaxivity of 122.59 mM ⁻¹ ·s ⁻¹ Fe. Treatment with DMSA-NC did not induce cytotoxicity or oxidative stress in U-251 cells, and electron microscopy demonstrated DMSA-NC localization within endosomes and lysosomes in cells following internalization. Global proteomics revealed dysregulation of iron storage, transport, transcription and mRNA processing proteins. Conclusion: DMSA-NC is a promising T2 MRI contrast agent which, in this preliminary investigation, demonstrates favorable biocompatibility with an astrocyte cell model.

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Involvement of single nucleotide polymorphisms of junction adhesion molecule with small vessel vascular dementia

December 2023

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40 Reads

Objectives It is now recognized that blood brain barrier (BBB) leakage occurs in cerebral small vascular disease (CSVD) and plays a significant role in the pathophysiology of vascular dementia. We hypothesized that genetic polymorphisms of junctional adhesion molecule‐A (JAM‐A) (which may result in compromised structure of tight junction proteins that form the BBB) in combination with cerebrovascular risk factors hypertension, lipid disorders, and type 2 diabetes may result in BBB leakage and increase the individual's risk of CSVD‐related dementia. Methods In this case–control study, 97 controls with a mean Mini‐Mental State Exam (MMSE) score of 29 and 38 CSVD‐related vascular dementia participants (mean MMSE score of 19) were recruited. Bloods were collected for the analysis of two common single nucleotide polymorphisms (SNPs) of the JAM‐A genotypes rs790056 and rs2481084 using real‐time polymerase chain reaction (PCR) assay. Medical history of hypertension, hyperlipidemia, and diabetes was collected for all participants. Results Polymorphisms of genotype JAM‐A SNP rs790056 showed statistically significant result when the subgroup with hyperlipidemia was analyzed (OR = 3.130, p = 0.042 for TC + CC genotypes with hyperlipidaemia vs controls). Similar result was found with diabetes (OR = 4.670, p = 0.031 for TC + CC genotypes vs controls). No significant result was found with hypertension. Borderline results of statistical significance were found for JAM‐A SNP rs2481084 with hyperlipidemia (OR = 3.210, p = 0.054 for TC + CC genotypes vs controls) and with diabetes (OR = 3.620, p = 0.069 for TC + CC genotypes vs controls) but not for hypertension. The borderline results might have been due to lack of statistical power because of small sample size. Conclusions These results lend further support that cerebrovascular risk factors interact with genetic polymorphisms of BBB proteins to increase the risk of vascular dementia.


Figure 1. Iron nanoparticles and NP-Ab show biocompatibility. Lactate dehydrogenase release relative to untreated control wells in U-251 cells incubated with different concentrations of nanoparticles for 24 h. Data represent mean ± SD (n = 3-4). LDH: lactate dehydrogenase.
Figure 3. In vitro MRI properties and relaxometry of iron nanoparticles and NP-Ab. (A) MR imaging of iron nanoparticles and NP-Ab phantoms in MilliQ at increasing concentrations from left to right (0 mM, 0.01 mM, 0.02 mM, 0.05 mM, and 0.2 mM Fe). (B) Corresponding curves of the inverse of T2 (R2) versus concentration, where the gradient gives the r2 relaxivity in mM Fe −1 , s −1 .
Characterization of nanoparticles. Size, polydispersity index (PDI), and zeta potential were measured in MilliQ water at 25 • C.
Evaluation of Dimercaptosuccinic Acid-Coated Iron Nanoparticles Immunotargeted to Amyloid Beta as MRI Contrast Agents for the Diagnosis of Alzheimer’s Disease

September 2023

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101 Reads

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5 Citations

Cells

Nanoparticle-based magnetic contrast agents have opened the potential for magnetic resonance imaging (MRI) to be used for early non-invasive diagnosis of Alzheimer’s disease (AD). Accumulation of amyloid pathology in the brain has shown association with cognitive decline and tauopathy; hence, it is an effective biomarker for the early detection of AD. The aim of this study was to develop a biocompatible magnetic nanoparticle targeted to amyloid beta (Aβ) plaques to increase the sensitivity of T2-weighted MRI for imaging of amyloid pathology in AD. We presented novel iron core-iron oxide nanoparticles stabilized with a dimercaptosuccinic acid coating and functionalized with an anti-Aβ antibody. Nanoparticle biocompatibility and cellular internalization were evaluated in vitro in U-251 glioblastoma cells using cellular assays, proteomics, and transmission electron microscopy. Iron nanoparticles demonstrated no significant in vitro cytotoxicity, and electron microscopy results showed their movement through the endocytic cycle within the cell over a 24 h period. In addition, immunostaining and bio-layer interferometry confirmed the targeted nanoparticle’s binding affinity to amyloid species. The iron nanoparticles demonstrated favourable MRI contrast enhancement; however, the addition of the antibody resulted in a reduction in the relaxivity of the particles. The present work shows promising preliminary results in the development of a targeted non-invasive method of early AD diagnosis using contrast-enhanced MRI.




The mammalian stress response, and roles of sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. The SNS releases (1) noradrenaline from the splanchnic nerve (originating from sympathetic chain ganglia) and (2b) Adrenaline from the adrenal medulla [through activation of the sympathomedullary pathway (2a)]. Activation of the HPA axis involves release of corticotropin-releasing hormone (CRH) and other “releasing” hormones [including arginine vasopressin (AVP)] from paraventricular nucleus of hypothalamus (3). The release of CRH, AVP and other hormones acts on the anterior pituitary, resulting in release of β-endorphin (4) and adrenocorticotropin-releasing hormone (ACTH) (5). ACTH acts on the adrenal cortex to promote synthesis and release of glucocorticoid hormones; cortisol in humans and corticosterone in rodents (6). NB: solid line with arrow = act on; dashed line with arrow = release of; solid line = description; solid line with circle = zoom in.
The stress response and its effects on body systems and CVD risk. Chronic stress activation of the HPA axis and SNS activity result in elevations in glvuocorticoids (GC) and catecholamines, and reduced PNS activity. Resultant behavoural/affective outcomes, immuo-inflammatory dysregulation, metabolic and cardiovascular effects collectively favour development of CVD.
The sex-dependent response to psychosocial stress and ischaemic heart disease

April 2023

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1,206 Reads

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19 Citations

Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome—a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.


Citations (60)


... In vitro MRI assessments of DMSA-NCs were conducted as previously described [28] at room temperature (22 • C) on a 9.4T Bruker (Karlsruhe, Germany) BioSpec Avance III 94/20 system equipped with a 72-mm internal diameter quadrature radiofrequency coil and BGA-12S HP gradients with maximum strength 660 mT/m and slew rate 4570 T/m/s. Increasing concentrations (0.1, 0.2, 0.5, 1, 100 and 500 μM) of DMSA-NC in Milli-Q water were prepared and Eppendorf tubes containing the solutions were secured in a rack 3D-printed in house for scanning. ...

Reference:

Biocompatibility and Proteomic Profiling of DMSA-Coated Iron Nanocubes in a Human Glioblastoma Cell Line
Evaluation of Dimercaptosuccinic Acid-Coated Iron Nanoparticles Immunotargeted to Amyloid Beta as MRI Contrast Agents for the Diagnosis of Alzheimer’s Disease

Cells

... Again, the reasons for these phenomena are the influence of female hormones, namely, under stress, estrogen production decreases, the level of the "happiness hormone" serotonin drops, and the amount of the "stress hormone" cortisol increases rapidly. Such physiological processes cause a strong feeling of hunger, resulting in uncontrolled consumption of unhealthy foods high in fat and carbohydrates [18]. ...

The sex-dependent response to psychosocial stress and ischaemic heart disease

... Fruit and vegetable consumption was assessed with a question that asked, "How often in the past week have you eaten (1) Fresh vegetables (not including potatoes); (2) Fresh fruit" with the response options, (i) daily/almost daily; (ii) several times per week; (iii) once a week; (iv) less than once a week; (v) don't know. In line with several previous studies that have used less than weekly as a cut-off point (38,39), in this study those respondents who stated that they ate both fruit and vegetables less than once in the week were categorized as having low fruit and vegetable consumption. ...

The association between dietary patterns, plasma lipid profiles, and inflammatory potential in a vascular dementia cohort

... In 2004, it was found that NAD + can also be synthesized by NRK, which was initially detected in yeast as nicotinamide riboside kinase 1 (NRK1) followed by human homologs NRK1 and NRK2 [58,59]. NRK1 activity is more prone to occur in mammalian tissues; on the other hand, NRK2 is specific to muscle and more significantly predominant in skeletal muscle than cardiac [12,60]. Findings from research on wild-type (WT) mice showed that the modulation effect of NAD + by NR and NMN supplementation is ineffective if the NRK enzyme is absent in the tissue whereas other enzymes for the NAD + synthesis pathway remain active in WT mice [61,62]. ...

Pharmacology of NAD+boosters
  • Citing Chapter
  • January 2023

... As clinical trials concerning NR advance, its therapeutic potential is increasingly being elucidated in a wider scope. 53,54 In existing studies, NR has demonstrated potential therapeutic effects on various diseases, with a particular focus on metabolic, neurodegenerative, and age-related conditions. 22,55 Furthermore, in both animal models and clinical trials related to glaucoma, NAD + has exhibited protective effects on RGCs 24 and preserved visual function in patients with glaucoma. ...

Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders
  • Citing Article
  • December 2022

Drugs & Aging

... For instance, phytochemicals are compounds that have demonstrated a number of biological effects including antioxidants to anti-inflammatory. In this way, they could serve as barrier against the diseases of despair including diabetes, cancer, and cardiovascular diseases [13,40,41]. Hence there is a notable increased research interest in novel natural products among the scientific community [40]. ...

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Phytomedicine

... Public health organisations create and promote particular hashtags or use popular hashtags that can facilitate easy search and discovery of health-related information by users on social media [3]. Hashtag analysis has been broadly used as a tool in research that allows different quantifications [18,19]. Fuster-Casanovas et al. [20] applied network analysis related to #VaccinesWork, promoted by UNICEF, to detect the optimal time to launch the campaigns and investigate the shared main messages and involvement of key leaders that had a significant influence on the dissemination of health information on Twitter [20]. ...

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Phytomedicine

... (3) The introduction of virtual care into the health-care setting has been widely encouraged and, in many applications, sustained post-pandemic. (9)(10)(11)(12) Existing quantitative literature reveals reduced rates of falls in high-risk community-dwelling older adults with the integration of combined telehealth and in-person exercise classes. (2,13) The literature also recognizes the importance of a thorough falls-risk assessment prior to program initiation; (2) however, it is not well understood how effective these assessments are when conducted virtually. ...

Video-based fall prevention education for cognitively impaired inpatients: a pilot study
  • Citing Article
  • July 2022

Asian Journal of Gerontology and Geriatrics

... Durch die gleichzeitig stattfindende Verschiebung des Energiestoffwechsels in Richtung Glykolyse, die zu einer ungünstigen Gesamtausbeute bei der ATP-Produktion führt, wird die Effizienz der zellulären Energieversorgung herabgesetzt [31]. Die Folge sind transiente oder chronische Erschöpfungszustände (Fatigue), wie sie auch typisch für die Erkrankung Myalgische Enzephalomyelitis/Chronic Fatigue Syndrom (ME/CFS) sind [32]. Möglicherweise ist ein NAD + -Mangel und die Dysregulation des NAD-Metaboloms auch Grundlage vieler Symptome (chronische Fatigue, Belastungsintoleranz, neurokognitive Dysfunktion, Myalgie, Kopfschmerz), die im Kontext des Long-/Post-COVID-Syndroms auftreten [33]. ...

The Role of Kynurenine Pathway and NAD + Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Aging and Disease

... Interestingly, although PA and exercise are highly recommended in people with dementia or MCI, few exercise intervention studies have engaged SCD populations [29]. Early management strategies are strongly emphasized for being of utmost importance in preventing brain aging and cognitive degeneration [19,[65][66][67]. Thus, since cognitive decline, mental and physical well-being benefit from exercise interventions in people with MCI or dementia, it is not unreasonable to assume that SCD populations might benefit, too. ...

Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?

Aging and Disease