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Drawing of a Brain with neurons and electric impulses

Brain scientists are especially busy researching NAD precursors, because the brain is mostly made of neurons and early results are promising with respect to neuropathy and neurodegenerative disorders, including Alzheimer's, Parkinson's, ALS, and Ataxia.


Here are the studies:

Feb 6, 2023

Neurons - Brain - Parkinson's

Brain Sciences

Could Vitamins Have a Positive Impact on the Treatment of Parkinson’s Disease?



"...Vitamin B3 supplementation has been shown to alleviate various symptoms associated with PD...Mechanistically, vitamin B3 promotes the biosynthesis of the classical enzyme cofactor nicotinamide adenine dinucleotide (NAD) and mediates the release of nicotinamide by poly-ADP ribosylation. This generates an anti-inflammatory response, which alleviates DA-ergic neurodegeneration caused by neuroinflammation. These findings suggest that dietary supplementation with vitamin B3 may ameliorates oxidative stress and neuroinflammation, which would therefore prevent the death of DA-ergic neurons..."

Jan 26, 2023

Brain - Alzheimer's Disease

Translational Neurodegeneration

Combined Metabolic Activators Improves Cognitive Functions in Alzheimer’s Disease

Yulug, Burak


We designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMAs improves cognitive functions in AD patients...We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.

Dec 14, 2022

Brain - Neurons - Neurodegeneration - Inflammation - Alzheimer's

Aging Cell

Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin

Vreones, Michael


We report the first study examining [extracellular vesicles enriched for neuronal origin or "NEV"] NEV biomarkers in response to oral NR supplementation. Our primary analysis of NAD+ and NADH in NEVs suggests an increase in neuronal NAD+ concentration in response to oral NR supplementation....We demonstrate that oral NR supplementation [in humans] increases NAD+ levels in NEVs ...These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans.

Nov 17, 2022

Brain - Alzheimer's - Neuroinflammation - Metabolism - Diabetes

Scientific Reports

Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer’s disease with metabolic syndrome

Tyagi, Alpna


Mitochondrial dysfunction, insulin resistance, metabolic dysregulation and neuroinflammation that contribute to cognitive decline in Alzheimer's Disease...The findings of this study suggest that SIRT3 is a potential therapeutic target for the treatment of AD. Sirtuins, including SIRT3, require NAD+ as a cosubstrate. Administration of NR, a precursor of NAD+, leads to increase in the cellular level of NAD+. In this study, we demonstrate that NR increases the levels of IDE as well as neprilysin and decreases the levels of BACE1 in vivo. Interestingly, NR also increases the levels of SIRT3, probably by autoregulation. NR has been reported to reverse insulin resistance and glucose intolerance in a mouse model for type 2 diabetes. NR has been shown to be effective in reducing neuroinflammation and improve cognition in Alzheimer’s mouse models. Therefore, NR-based treatment can be considered for the treatment of AD with comorbidities.

Oct 20, 2022

Brain - Neurodegeneration - Mitochondria - Parkinsons - Alzheimers - ALS

International Journal of Molecular Sciences

Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation

Mantle, David


We have selected a number of neurodegenerative disorders that are known to involve mitochondrial dysfunction in their pathogenesis. We have further selected a number of nutrients that have a key role in mitochondrial function. We then correlated data on the deficiency (Table 1) and supplementation of these nutrients (Table 2) in the said neurodegenerative disorders. In this review, we have therefore provided a rationale for a combination of CoQ10, B-vitamins/NADH, l-carnitine, vitamin D, and alpha-lipoic acid to support the future treatment of these neurodegenerative disorders.

Aug 7, 2022

Brain - Aging - Cognitive Decline - Alzheimers - Stroke


Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts

Campbell, Jared


A large body of preclinical research supports the potential effectiveness of NAD+ precursor supplementation for preserving cognitive health across a variety of disease contexts, with the strongest evidence presented for Alzheimer’s disease and other forms of dementia.

Jul 22, 2022

Brain - Cancer - NRH

Cancers (Basel)

Overcoming Temozolomide Resistance in Glioblastoma via Enhanced NAD+ Bioavailability and Inhibition of Poly-ADP-Ribose Glycohydrolase

Li, Jianfeng


Using the NAD precursor NRH to raise NAD levels in an incurable type of brain cancer (Glioblastoma multiforme or GBM) significantly increased the effectiveness of a type of chemotherapy (Temozolomide or TMZ) that is commonly used to treat GBM.

Jul 18, 2022

Brain - Ataxia


Nicotinamide Riboside for Ataxia Telangiectasia: Report of an Early Treated Individual

Steinbruecker, Katja


We here present the effect of nicotinamide riboside in another individual with ataxia…Given the absence of adverse effects, we strongly encourage to consider nicotinamide riboside in all individuals with ataxia telangiectasia.

Jul 7, 2022

Brain - Oxytocin - Autism

Frontiers in Neuroscience

Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside

Higashida, Harohiro


...It has recently been found that gavage application of a precursor of nicotinamide adenine dinucleotide, nicotinamide riboside, for 12 days can increase brain Oxytocin (OT) in mice. Here, we review the evaluation of the new concept that RAGE is involved in the regulation of OT dynamics at the interface between the brain, blood, and intestine in the living body...

Mar 1, 2022

Brain - Parkinson's Disease

Cell Metabolism

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease

Brage, Brakedal


We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous magnetic resonance spectroscopy—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.

Jan 19, 2022

Brain - Neurons - Alzheimer's

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Liang, Yuquing


Dec 1, 2021

Brain - Ataxia

Movement Disorders

Nicotinamide Riboside Improves Ataxia Scores and Immunoglobulin Levels in Ataxia Telangiectasia

Veenhuis, Stefanie


24 patients with Ataxia telangiectasia (A-T) were treated with NR during four consecutive months. The effects of NR on ataxia, dysarthria, quality of life, and laboratory parameters were analyzed. During treatment, ataxia scores improved; mean total Scale for the Assessment and Rating of Ataxia and International Cooperative Ataxia Rating Scale scores decreased to 2.4 and 10.1 points, respectively. After NR withdrawal, ataxia scores worsened.

Nov 10, 2021

Brain - Alzheimer's Disease

Cell & Bioscience

Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD + and ATP

Yang, Tingpeng


...Downregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.

Sep 21, 2021

Aging - Brain - Ataxia - Stem Cells - Bone Marrow - Inflammation

Aging Cell

NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs

Zong, Le


Our data suggest that NR administration in compromised hematopoietic systems (NAD+ depleted system) drives cell-intrinsic changes of the HSC compartment together with an overall reduction in circulating inflammatory cytokines. However, once the aged system has been exposed to NR, the effects of removing the supplementation may have undesirable consequences. Thus, once a deficient system is exposed to NAD+ supplementation, to maintain the benefits we have demonstrated, the regimen may need to be sustained long-term...Our results showed significant alterations in lineage commitment of HSCs after NR treatment, with enhanced lymphoid potential. This correlated with changes in inflammatory cytokines and transcriptional alterations of the HSCs. While transplantation of aged NR-treated HSCs reproduced the enhanced lymphoid output seen in the transcriptional profiles, the changes in potential are not sustained after NR withdrawal in the aged mice, and the rebound phenotype appear to exacerbate aging phenotypes. Our results highlight the importance of the duration of NR exposure and the timing of initial exposure to derive robust, balanced lineage outputs from HSCs.

Sep 14, 2021

Brain - Alzheimer's Disease

Proceedings of the National Academy of Science

NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING

Hou, Yujun


...Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of Alzheimer's Disease (AD), but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons...Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS–STING elevation was observed in the AD mice and normalized by NR treatment...NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS–STING in neuroinflammation and cellular senescence in AD.

Sep 1, 2021

Brain - Neurons

Mechanisms of Aging and Development

Risks and rewards of targeting NAD+ homeostasis in the brain

Li, Catherine


Strategies to correct declining nicotinamide adenine dinucleotide (NAD+) levels in neurological disease and biological ageing are promising therapeutic candidates. These strategies include supplementing with NAD+ precursors, small molecule activation of NAD+ biosynthetic enzymes, and treatment with small molecule inhibitors of NAD+ consuming enzymes such as CD38, SARM1 or members of the PARP family. While these strategies have shown efficacy in animal models of neurological disease, each of these has the mechanistic potential for adverse events that could preclude their preclinical use. Here, we discuss the implications of these strategies for treating neurological diseases, including potential off-target effects that may be unique to the brain.

Aug 4, 2021

Brain - Parkinson's Disease


Combined Metabolic Activators Improve Cognitive Functions without Altering Motor Scores in Parkinson’s Disease

Yulug, Burak


The neuropathologic hallmarks of Parkinson’s disease (PD) are associated with mitochondrial dysfunction and metabolic abnormalities. We have reported that the Combined Metabolic Activators (CMA), consisting of L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate can be used in treating metabolic abnormalities. These metabolic activators are the precursors of nicotinamide adenine dinucleotide (NAD+) and glutathione (GSH) and used in activation of mitochondrial and global metabolism...Here, we designed a randomized, double-blinded, placebo-controlled, phase-2 study in PD patients with CMA administration. We found that the cognitive functions in PD patients is significantly improved 21% in the CMA group, whereas it is improved only 11% in the placebo group after 84 days of CMA administration. We also found that the administration of CMA did not affect motor functions in PD patients. We performed a comprehensive multi-omics analysis of plasma proteins and metabolites, and revealed the molecular mechanism associated with the treatment of the patients. In conclusion, our results show that treating PD patients with CMAs leads to enhanced cognitive function, as recently reported in AD patients.

Aug 3, 2021

Brain - Alzheimer's Disease

Frontiers in Cell and Developmental Biology

NAD+ in Alzheimer’s Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo

Wang, Xinshi


Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer’s disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients’ phenotypes.

Jun 17, 2021

Neurons - Brain - Parkinson's - Niacin

Frontiers in Aging Neuroscience

Niacin Enhancement for Parkinson’s Disease: An Effectiveness Trial

Chong, Raymond


We previously reported that individuals with Parkinson’s disease (PD) present with lower vitamin B3 levels compared to controls. It may be related to carbidopa interaction, defective tryptophan metabolism, and stresses of night sleep disorder...These results suggest that niacin enhancement has the potential to maintain or improve quality of life in PD and slow disease progression.

May 9, 2021

Brain - Neuroinflammation

Journal of Neurochemistry

Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD+

Roboon, Jureepon


Neuroinflammation is initiated by activation of the brain’s innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer’s disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone-induced demyelination, neuroinflammation and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level...These results suggest that CD38-mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain.

NAD Research - Brain

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