Neurofilament light chain as novel blood biomarker of disturbed neuroaxonal integrity in patients with ketamine dependence

Abstract

Objectives: Chronic and heavy ketamine use has been associated with persistent neurocognitive impairment and structural brain abnormalities. Blood levels of neurofilament light chain (NFL) was recently proposed as a measure of axonal integrity in several neuropsychiatric disorders. We aimed to characterise the axonal neurotoxicity of chronic ketamine use and its relationship to relevant clinical outcomes. Methods: We enrolled 65 treatment-seeking ketamine-dependent patients (55 males and 10 females) and 60 healthy controls (51 males and 9 females). Blood NFL levels measured by single molecule array (SiMoA) immunoassay. We compared NFL levels between groups and used regression analyses to identify clinical variables related to NFL levels. Results: Ketamine-dependent patients had significantly higher NFL levels compared to controls (p < 0.001). A multivariate regression showed that age (p < 0.05) and lifetime history of major depressive disorder (MDD) (p < 0.01) predicted high NFL blood levels in patients. Subsequent group comparisons showed that specifically ketamine-dependent patients with a lifetime history of MDD had significantly increased NFL levels than those without (p < 0.05). Conclusions: These results suggest substantial neuroaxonal alterations following chronic and heavy ketamine use. The pronounced increase of NFL levels in the MDD subgroup warrants further investigation of a potential neuroaxonal vulnerability of depressed patients to ketamine.

Brain-derived neurotrophic factor protects serotonergic neurons against 3,4-methylenedioxymethamphetamine (“Ecstasy”) induced cytoskeletal damage

“…Consequently, NFs and particularly the neurofilament light chain (NfL) subunit recently emerged as promising in-vivo markers of active brain pathology in several neuropsychiatric disorders, including multiple sclerosis, neurodegenerative diseases, traumatic brain injuries, and depression (Barro et al 2018 ; Khalil et al 2018 ; Bavato et al 2021 ). Our recent work also reported elevated NfL levels in subjects with ketamine dependence and in chronic cocaine users, confirming its sensitivity to drug-induced neurotoxicity (Liu, et al 2021 ; Bavato, et al 2022 ). Thus, NfL represents an ideal translational biomarker of drug-induced brain pathology, which could be applied in both preclinical and clinical settings.…”

A longitudinal investigation of blood neurofilament light chain levels in chronic cocaine users

“…Higher NfL levels have previously been described in patients with MDD and in a sample of treatment-seeking ketamine users with a history of MDD. 13,14 However, in this study, we specifically excluded subjects with current major depressive episodes. Thus, the lack of associations between NfL levels and depressive symptoms in the present study is consistent with the view that neuroaxonal pathology in MDD is strongly stage-dependent.…”

“…14,19,20 Our recent work also reported elevated NfL levels in patients with chronic ketamine addiction, demonstrating its sensitivity to substance-related brain pathology. 13 Although cocaine use has been associated with several structural brain changes, this is the first study to investigate its impact on NfL levels. We compared the NfL levels of a sample of 35 CU with 35 healthy controls (HC) at baseline.…”

“…Moreover, cocaine adulteration with neurotoxic compounds (e.g., the anthelmintic levamisole), 10,11 concomitant use of other illicit substances or alcohol, 12 and comorbidity with psychiatric disorders (e.g., depression) [12][13][14][15] might influence brain integrity in chronic cocaine users (CU) independently of cocaine intake itself. Considering the limitations of current diagnostic methods, which are mostly limited to cost-intensive neuroimaging measures, the introduction of new markers of active brain pathology may help clarify crucial questions on substance-induced brain pathology and provide new monitoring tools for physicians working in addiction medicine.…”

“…14,19,20 Our recent work also reported elevated NfL levels in patients with chronic ketamine addiction, demonstrating its sensitivity to substance-related brain pathology. 13…”