Augmented Cheung Glutamatergic Regimen as a Candidate for Investigation in Amyotrophic Lateral Sclerosis

Letter to the EditorAugmented Cheung Glutamatergic Regimen as a Candidate for Investigation in Amyotrophic Lateral SclerosisDear Editor,Depressive symptoms are increasingly recognized as part of the early clinical picture of amyotrophic lateral sclerosis (ALS), and in some patients they appear before clear motor signs emerge [1]. That pattern raises the possibility that ALS and major depressive disorder may share some underlying biology. In recent work, synaptic pruning was identified as the only gene set consistently enriched in both disorders, despite a near-zero overall genetic correlation [2]. A later transcriptome-wide association study using Project MinE ALS summary statistics also found depletion of oxidative phosphorylation pathways, especially complex I subunits such as NDUFA2, together with compensatory upregulation of mitochondrial NAD⁺-related genes including NMNAT3 and SIRT5 [3]. Taken together, these findings support a four-tier pruning-mitochondrial-autophagy continuum model.Against this background, I would like to suggest that an augmented version of the Cheung Glutamatergic Regimen (CGR) may merit exploratory study in ALS (Figure 1). The core oral regimen combines low-dose dextromethorphan, prolonged by CYP2D6 inhibition, with piracetam to enhance activity-dependent plasticity. This component is intended to address Tier 1 pruning vulnerability through mTOR- and BDNF-linked synaptogenesis. The proposed augmentation adds daily nicotinamide mononucleotide (NMN) for NAD⁺ support, intermittent, or pulsed, senolytics such as fisetin or dasatinib plus quercetin, and ongoing N-acetylcysteine (NAC) [4].This multi-target approach fits the proposed cascade in a fairly direct way. NMN targets Tier 2 mitochondrial compensation and energy failure, which was highlighted by the recent TWAS findings. In SOD1-G93A mice, dietary NMN was reported to modestly delay motor decline, improve neuromuscular junction function, and extend healthspan [5]. NAC may help buffer oxidative stress and glutamate excitotoxicity, while pulsed senolytics are intended to reduce the burden of the senescence-associated secretory phenotype, which could otherwise amplify glial-mediated damage. It is also worth noting that dextromethorphan-quinidine combinations are already used in ALS for pseudobulbar affect, which offers some reassurance about tolerability when doses are adjusted [6]. Figure 1. The four-tier pruning–mitochondrial–autophagy continuum and mechanistic mapping of the augmented Cheung Glutamatergic Regimen (CGR) in amyotrophic lateral sclerosis. (A) The pathological cascade proceeds from shared microglial pruning vulnerability (Tier 1, blue) through mitochondrial bioenergetic stress with compensatory NAD⁺ upregulation (Tier 2, amber), autophagy collapse with senescence-associated inflammatory amplification (Tier 3, pink), to motor neuron loss and clinical disease (Tier 4, lavender). The red dashed feedback arrow (left) illustrates the SASP-driven complement re-pruning loop from Tier 3 back to Tier 1, which pulsed senolytics are intended to interrupt (green inhibition bar). (B) Each CGR component is aligned to its primary therapeutic target tier. Green boxes denote the core CGR (plasticity rescue via low-dose dextromethorphan, CYP2D6 inhibition, and piracetam); yellow boxes denote the augmentation arm (daily NMN, ongoing NAC, pulsed senolytics); the grey box indicates predicted clinical outcomes. Solid arrows indicate established mechanistic targets; the dashed arrow at Tier 4 indicates projected outcomes. (C) Horizontal bar chart of key TWAS Z-scores from S-PrediXcan analysis of Project MinE ALS GWAS data across 14 GTEx tissues, illustrating the Tier 2 imbalance: OXPHOS depletion driven by NDUFA2 downregulation (red, complex I) against compensatory upregulation of NAD⁺ synthesis (NMNAT3) and sirtuin genes (SIRT5, SIRT1) (green)—the direct target of daily NMN supplementation. CGR = Cheung Glutamatergic Regimen; DXM = dextromethorphan; NMN = nicotinamide mononucleotide; NAC = N-acetylcysteine; D+Q = dasatinib + quercetin; NMJ = neuromuscular junction; SASP = senescence-associated secretory phenotype; OXPHOS = oxidative phosphorylation; GSH = glutathione; PARP = poly(ADP-ribose) polymerase; TWAS = transcriptome-wide association study.At the same time, the limitations of this proposal should be stated clearly. No human data currently exist for this specific combination in ALS. Earlier trials of NAC monotherapy did not show a consistent survival benefit [7], and senolytic agents remain at an early stage of development in neurodegenerative disease. Any future study would therefore need careful safety monitoring, particularly for drug interactions and bulbar function. Such work may be most informative in stratified patients with high pruning-related genetic risk or evidence of NAD⁺ dysregulation.Even so, the mechanistic fit between the four-tier model and the components of the augmented CGR is noteworthy. Small open-label pilot studies, followed by properly controlled trials, could help clarify whether this practical oral strategy has any meaningful effect on disease progression or on prodromal neuropsychiatric symptoms.Ngo Cheung, MBBS, FHKAM(Psychiatry) Cheung Ngo Medical Limited Hong Kong SAR, China Email: info@cheungngomedical.com Tel: 98768323 DeclarationsEthics approval and consent to participate: Not applicable.Consent for publication: Not applicable.Availability of data and materials: Not applicable.Competing interests: The author declares no competing interests.Funding: None.Authors' contributions: NC conceived the idea, drafted the letter, and approved the final version.Acknowledgements: Not applicable.Authors' informationNgo Cheung, MBBS, FHKAM(Psychiatry)Cheung Ngo Medical LimitedHong Kong SAR, ChinaEmail: info@cheungngomedical.comTel: +852 98768323 ReferencesHeidari ME, Nadali J, Parouhan A, et al. 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