Abstract

Background: Early-onset Parkinson’s disease (EOPD), diagnosed before age 50, presents unique challenges due to prolonged disease course and higher risk of cognitive decline.

Problem: While motor symptoms are well-studied, longitudinal cognitive trajectories and preservation factors in EOPD remain under-researched. Purpose: This study examines cognitive changes over 36 months in EOPD patients and identifies clinical, genetic, and pharmacological factors associated with cognitive preservation.

Methodology: A prospective longitudinal cohort design tracked 120 EOPD patients (baseline mean age 45.2 years, 52% male) over three years. Cognitive function was assessed every six months using the Montreal Cognitive Assessment (MoCA) and Parkinson’s Disease Cognitive Rating Scale (PD-CRS). Predictors included dopaminergic medication dosage, physical activity, baseline α-synuclein levels, and sirtuin-1 activity.

Key findings: Mixed-effects models showed that 34% of patients maintained stable cognitive scores (preservation group), while 66% declined (>1.5 MoCA points/year). Higher baseline sirtuin-1 activity (β = 0.42, p < 0.01) and regular aerobic exercise (β = 0.38, p < 0.05) predicted preservation. Dopaminergic dose showed no significant effect on cognition.

Conclusion/implications: Sirtuin pathways and lifestyle factors may mediate cognitive preservation in EOPD, supporting targeted non-pharmacological interventions.

Highlights

• Unique axonal architecture dictates high energy demand in dopaminergic neurons.
• Impaired cellular bioenergetics precedes structural loss in Parkinson’s disease.
• Energy metabolism failure contributes to Parkinson’s disease progression.
• Metabolic pathways identified as targets for Parkinson’s disease therapy.

...We highlight evidence suggesting that bioenergetic impairment precedes overt neurodegeneration and contributes to the variability in disease onset, progression, and therapeutic response. We also discuss emerging approaches aimed at strengthening metabolic capacity, including strategies to enhance nicotinamide adenine dinucleotide (NAD^(+)**) availability, support glycolysis and fatty acid oxidation, reduce oxidative stress, and modulate trophic signaling. Understanding how metabolic crisis shapes the trajectory of PD may offer new opportunities for earlier diagnosis and the development of targeted, disease-modifying interventions. Future work comparing metabolic phenotypes across patient subgroups will be essential for advancing precision treatment and clarifying the role of energy dysregulation in disease heterogeneity..."

Summary 

>An imbalance in the NAD+/NADH ratio caused by NAD+ depletion is implicated in various diseases, including metabolic disease, aging, and cancer. The cellular NAD+ content is decreased in cardiovascular diseases and heart failure. Lack of NAD+ in cardiomyocytes leads to mitochondrial dysfunction, increased reactive oxygen species (ROS) production and cell death. The supplementation of NAD+ and its precursors such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) are currently being evaluated in clinical trials. This review mainly focuses on the role of NAD+ in cardiovascular diseases and therapeutics.

Abstract

Background: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive.

Methods: We used APP/PS1 mice and amyloid beta (Aβ)-challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD+) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD+ homeostasis mitigates AD-related vascular and inflammatory pathology.

Results: NAD+ deficiency induced voltage-dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING-IRF3 activation, promoting endothelial senescence and SASP production with NAD+-consuming enzyme CD38 upregulation. Senescent BECs triggered IL-6-dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS-STING signaling, and reduced neuroinflammation, improving vascular function and cognition.

Discussion: Aβ-driven NAD+ deficiency initiates a VDAC1-mtDNA-cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC-microglia crosstalk, highlighting NAD+ restoration as a promising AD therapeutic strategy.

>"As the global population ages rapidly, delaying and preventing age-related diseases have become urgent priorities in public health and biomedical research. During aging, mitochondrial dysfunction is a core molecular hallmark and a common pathogenic mechanism underlying multiple age-related disorders. Age-related mitochondrial dysfunction typically manifests as diminished metabolic capacity, impaired organelle renewal, and disrupted redox homeostasis. These factors interact to form a feedback loop constraining mitochondrial adaptability. Specifically, the interdependent decline in NAD^(+) availability, impaired mitochondrial biogenesis, and excessive oxidative stress render single-pathway interventions ineffective in mitigating systemic functional impairments triggered by aging.

>To address this complex mechanism, this review presents a novel tri-axis anti-aging model encompassing three key compounds: nicotinamide mononucleotide/nicotinamide riboside (NMN/NR), pyrroloquinoline quinone (PQQ), and L-ergothioneine (EGT). Within this framework, NMN/NR serves as a broad NAD^(+)**-dependent regulator of mitochondrial homeostasis, with its most immediate effects on metabolic activation, while PQQ and EGT may further strengthen mitochondrial remodeling and redox resilience, respectively. While each compound has distinct functional emphases, they are highly mechanistically coupled, collectively forming a closed-loop network regulating mitochondrial number, function, and homeostasis. This review synthesizes preclinical and emerging clinical evidence supporting the standalone or combined use of NMN/NR, PQQ, and EGT across various diseases.

>Collectively, by conceptualizing mitochondrial aging as a systemic imbalance rather than isolated molecular defects, this paper highlights a three-axis model of NMN/NR, PQQ, and EGT. This framework offers a theoretical foundation for mitochondrial-targeted anti-aging interventions while laying the groundwork for future clinical research, nutritional interventions, and the development of multi-target combination strategies."