Neurofilament light chain and retinal layers' determinants and association: A population‐based study

Garzone, Davide; Finger, Robert P.; Mauschitz, Matthias M.; Santos, Marina Lima Silva; Breteler, Monique M.B.; Aziz, N. Ahmad

doi:10.1002/acn3.51522

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…Conditional analysis on the kidney function showed that the association of our lead SNP rs7203642 became less significant (P = 3.51x10 -6 ). The association of blood NfL levels with variants in UMOD is supported by results from earlier studies reporting the association between increased blood NfL levels and decreased kidney function, which may be due to aging, cardiovascular risk factors, and diabetes mellitus (37)(38)(39)(40). The observation of higher blood levels of NfL in children with chronic kidney disease (41) contradicts the role of cardiovascular diseases and diabetes as the sole drivers of blood NfL levels.…”

Section: Discussionmentioning

confidence: 59%

Genome-wide Association Study Meta-analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Ahmad

Imtiaz

Mishra

et al. 2022

Preprint

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Background: Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders. Methods: To identify the genetic variations underlying blood NfL levels, we conducted an ancestry-specific meta-analyses of genome-wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African-American ancestry. In the post-GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD-regression, and genetic risk score (GRS) association analysis with neurological traits. Results: In the European ancestry GWAS meta-analysis, we identified two genome-wide significant (P < 5x10-8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African-American ancestry GWAS meta-analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta-analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer's disease(AD) (rg = 0.32, P = 1.74x10-6), total-tau (rg = 2.01, P = 1.03x10-6), amyloid-beta (Aβ-40 (rg = 0.80, P = 6.92x10-6), and Aβ-42 (rg = 1.03, P = 4.39x10-5). A higher genetic risk score based on NfL-associated genetic variants was also related to increased plasma levels of total-tau (P = 1.97x10-4), Aβ-40 (P = 2.24x10-5), Aβ-42 (P = 2.92x10-4) in the Rotterdam Study. Conclusion: This large-scale GWAS meta-analysis revealed multiple novel genetic loci of NFL levels in blood in participants from European and African-American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ-42, and total-tau may indicate a common underlying pathway of neurodegeneration.

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Section: Discussionmentioning

confidence: 59%

Genome-wide Association Study Meta-analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Ahmad

Imtiaz

Mishra

et al. 2022

Preprint

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“…Neuronal damage, due to aging or other pathologies, might lead to neuronal death which is reflected in degeneration of both retinal and cerebral structures. Retinal neurodegeneration therefore also likely reflects central neurodegeneration, independently of visual pathway decay (Garzone et al, 2022 ). Studies investigating retinal changes in brain diseases with predominant visual involvement and including more granular measures of visual function could further elucidate this relationship.…”

Section: Discussionmentioning

confidence: 99%

“…From V1, visual information is then carried forward through the ventral (parietal) and dorsal (temporal) streams for further integration and multimodal processing (Mishkin et al, 1983 ). In particular, retinal thinning in the inner neuronal layers (including GCL, the inner plexiform layer [IPL], and RNFL), which can be assessed noninvasively with spectral domain—optical coherence tomography (SD‐OCT), is attributed to neurodegeneration and likely reflects neuronal damage accrued with age and other pathologies (Garzone et al, 2022 ; Mauschitz et al, 2018 ; Pfeiffer et al, 2020 ). Indeed, retinal neurodegeneration has been associated with both global and regional brain atrophy, as well as cognitive impairment (Hernowo et al, 2011 , 2014 ; Ward et al, 2020 ; Mutlu et al, 2017 ).…”

Section: Objectivesmentioning

confidence: 99%

Visual impairment and retinal and brain neurodegeneration: A population‐based study

Garzone

Finger

Mauschitz

et al. 2023

Human Brain Mapping

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Visual impairment and retinal neurodegeneration are intrinsically connected and both have been associated with cognitive impairment and brain atrophy, but the underlying mechanisms remain unclear. To investigate whether transneuronal degeneration is implicated, we systematically assessed the relation between visual function and retinal, visual pathway, hippocampal and brain degeneration. We analyzed baseline data from 3316 eligible Rhineland Study participants with visual acuity (VA), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) data available. Regional volumes, cortical volume, and fractional anisotropy (FA) were derived from T1‐weighted and diffusion‐weighted 3 T MRI scans. Statistical analyses were performed using multivariable linear regression and structural equation modeling. VA and ganglion cell layer (GCL) thinning were both associated with global brain atrophy (SD effect size [95% CI] −0.090 [−0.118 to −0.062] and 0.066 [0.053–0.080], respectively), and hippocampal atrophy (−0.029 [−0.055 to −0.003] and 0.114 [0.087–0.141], respectively). The effect of VA on whole brain and hippocampal volume was partly mediated by retinal neurodegeneration. Similarly, the effect of retinal neurodegeneration on brain and hippocampal atrophy was mediated through intermediate visual tracts, accounting for 5.2%–23.9% of the effect. Visual impairment and retinal neurodegeneration were robustly associated with worse brain atrophy, FA, and hippocampal atrophy, partly mediated through disintegration of intermediate visual tracts. Our findings support the use of OCT‐derived retinal measures as markers of neurodegeneration, and indicate that both general and transneuronal neurodegeneration along the visual pathway, partly reflecting visual impairment, account for the association between retinal neurodegeneration and brain atrophy.

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“…Plasma‐L levels and inner retinal atrophy have been reported as NF exponentially with age. In this context, inner retinal atrophy may reflect neuroaxonal damage associated with elevated plasma NF‐L levels (Garzone et al, 2022). NF‐L and associated neurofilament proteins may be significantly associated with inflammatory and vascular proteins.…”

Section: Discussionmentioning

confidence: 99%

Intermediate filament proteins are reliable immunohistological biomarkers to help diagnose multiple tissue‐specific diseases

Doğanyiğit

Eroğlu

Okan

2023

Anat Histol Embryol

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Cytoskeletal networks are proteins that effectively maintain cell integrity and provide mechanical support to cells by actively transmitting mechanical signals. Intermediate filaments, which are from the cytoskeleton family and are 10 nanometres in diameter, are unlike actin and microtubules, which are highly dynamic cytoskeletal elements. Intermediate filaments are flexible at low strain, harden at high strain and resist breaking. For this reason, these filaments fulfil structural functions by providing mechanical support to the cells through their different strain‐hardening properties. Intermediate filaments are suitable in that cells both cope with mechanical forces and modulate signal transmission. These filaments are composed of fibrous proteins that exhibit a central α‐helical rod domain with a conserved substructure. Intermediate filament proteins are divided into six groups. Type I and type II include acidic and basic keratins, type III, vimentin, desmin, peripheralin and glial fibrillary acidic protein (GFAP), respectively. Type IV intermediate filament group includes neurofilament proteins and a fourth neurofilament subunit, α‐internexin proteins. Type V consists of lamins located in the nucleus, and the type VI group consists of lens‐specific intermediate filaments, CP49/phakinin and filen. Intermediate filament proteins show specific immunoreactivity in differentiating cells and mature cells of various types. Various carcinomas such as colorectal, urothelial and ovarian, diseases such as chronic pancreatitis, cirrhosis, hepatitis and cataract have been associated with intermediate filaments. Accordingly, this section reviews available immunohistochemical antibodies to intermediate filament proteins. Identification of intermediate filament proteins by methodological methods may contribute to the understanding of complex diseases.

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Neurofilament light chain and retinal layers' determinants and association: A population‐based study

Cited by 5 publications

References 17 publications

Genome-wide Association Study Meta-analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Genome-wide Association Study Meta-analysis of Neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Visual impairment and retinal and brain neurodegeneration: A population‐based study

Intermediate filament proteins are reliable immunohistological biomarkers to help diagnose multiple tissue‐specific diseases

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