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.

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IntroductionTo explore the combined diagnostic value of plasma Lewy body-associated proteins (p-Asyn at ser129, total α-syn, and oligomeric α-syn) for the diagnosis of PD versus healthy controls (HCs) and other PD syndromes (PDs), as well as clinical characteristics prediction.MethodsThis study included 145 participants: 79 patients with PD, 24 patients with PDs, and 42 HCs. A panel of plasma levels of p-Asyn, total α-syn, and oligomeric α-syn was measured by enzyme-linked immunosorbent assay (ELISA). The primary outcome was the discriminative accuracy of the combined three plasma biomarkers for PD.ResultsThe mean age was 65.43 (SD, 7.467) in the control group, 64.49 (SD, 8.224) in participants with PD, and 69.25 (SD, 7.952) in PDs. The plasma Lewy body-associated protein levels were significantly higher in patients with PD than in age-matched HCs, However, there was no difference in patients with PD and PDs. Of note, a combination of plasma p-Asyn, total α-syn, and oligomeric α-syn was a better biomarker for discriminating PD from HCs, with an AUC of 0.8552 (p < 0.0001, 95%CI, 0.7635–0.9409), which was significantly higher than plasma p-Asyn (ΔAUC, 0.1797), total α-syn (ΔAUC, 0.0891) and oligomeric α-syn (ΔAUC, 0.1592) alone. Meanwhile, Lewy body-associated proteins had no connections between different motor stages and dementia performances.ConclusionOur results suggested that plasma Lewy body-associated proteins, may serve as a non-invasive biomarker to aid the diagnosis of PD from HCs. In addition, increased plasma Lewy body-associated proteins were not associated with the progression of motor and non-motor symptoms.

It is noteworthy that despite many efforts to screen biochemical plasma markers for PD diagnosis, there is still not an accepted and validated surrogate biomarker. To decipher the role of the mitophagy-associated proteins (MAPs) in idiopathic PD subjects and investigate whether the diagnosis is related to MAP levels and whether the levels predict motor and cognitive progression. This prospective study totally enrolled 150 PD patients. 71 age-matched controls (CN) alongside 41 PDs in two cohorts: modeling cohort (cohort 1), including 121 PD, 52 CN, and 29 PDs; validated cohort (cohort 2), including 29 PD, 19 CN, and 12 PDs. The MAPs (PINK1, Parkin, PGAM5, BNIP3, and p-TBK1) and a-synuclein-related proteins (ASPs: total a-synuclein, phosphorylated a-synuclein, and a-synuclein oligomer) levels were measured using an electrochemiluminescence immunoassay. MAPs are elevated in the plasma of PD patients. The PINK1, Parkin, and PGAM5 displayed the top three measurable increase trends in amplitude compared to BNIP3 and p-TBK1. Moreover, the AUCs of PINK1, PGAM5, and Parkin were ranked the top three MAP candidates in diagnosis accuracy for PD from CN, but the MAPs hard to differentiate the PD from PDs. In addition, Plasma PINK1 positively correlated with total UPDRS, UPDRS part III, and H-Y stage, with no significant correlations with HAMA, HAMD, and RBD scores. As expected, higher plasma PINK1-Parkin levels and prominent diagnostic accuracy in A-synuclein (+) subjects than in A-synuclein (-) subjects. These results uncover that plasma MAPs (PINK1, Parkin, and PGAM5) may be potentially useful target biomarkers for PD diagnosis. Studies on larger cohorts would be required to test whether elevated plasma MAP levels are related to PD risk or prediction.

ObjectivesThe ATN's different modalities (fluids and neuroimaging) for each of the Aβ (A), tau (T), and neurodegeneration (N) elements are used for the biological diagnosis of Alzheimer's disease (AD). We aim to identify which ATN category achieves the highest potential for diagnosis and predictive accuracy of longitudinal cognitive decline.MethodsBased on the availability of plasma ATN biomarkers (plasma‐derived Aβ42/40, p‐tau181, NFL, respectively), CSF ATN biomarkers (CSF‐derived Aβ42/Aβ40, p‐tau181, NFL), and neuroimaging ATN biomarkers (18F‐florbetapir (FBP) amyloid‐PET, 18F‐flortaucipir (FTP) tau‐PET, and fluorodeoxyglucose (FDG)‐PET), a total of 2340 participants were selected from ADNI.ResultsOur data analysis indicates that the area under curves (AUCs) of CSF‐A, neuroimaging‐T, and neuroimaging‐N were ranked the top three ATN candidates for accurate diagnosis of AD. Moreover, neuroimaging ATN biomarkers display the best predictive ability for longitudinal cognitive decline among the three categories. To note, neuroimaging‐T correlates well with cognitive performances in a negative correlation manner. Meanwhile, participants in the “N” element positive group, especially the CSF‐N positive group, experience the fastest cognitive decline compared with other groups defined by ATN biomarkers. In addition, the voxel‐wise analysis showed that CSF‐A related to tau accumulation and FDG–PET indexes more strongly in subjects with MCI stage. According to our analysis of the data, the best three ATN candidates for a precise diagnosis of AD are CSF‐A, neuroimaging‐T, and neuroimaging‐N.ConclusionsCollectively, our findings suggest that plasma, CSF, and neuroimaging biomarkers differ considerably within the ATN framework; the most accurate target biomarkers for diagnosing AD were the CSF‐A, neuroimaging‐T, and neuroimaging‐N within each ATN modality. Moreover, neuroimaging‐T and CSF‐N both show excellent ability in the prediction of cognitive decline in two different dimensions.