YKL-40 changes are not detected in post-mortem brain of patients with Alzheimer’s disease and frontotemporal lobar degeneration

Hok‐A‐Hin, Yanaika S.; Hoozemans, Jeroen J.M.; Hu, William T.; Wouters, Dorine; Howell, J. Christina; Rábano, Alberto; Flier, Wiesje M. van der; Pijnenburg, Yolande A.L.; Teunissen, Charlotte E.; Campo, Marta Del

doi:10.1186/s13195-022-01039-y

Cited by 9 publications

(5 citation statements)

References 78 publications

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“…In this study, in GM, extensive CHI3L1 immunopositivity was observed in astrocytes in lesion- and near-lesion areas, and in granular cytoplasmic structures in pyramidal neurons (Figure 1). This is a similar pattern to what has recently been reported in Alzheimer's disease cortex ( Hok-A-Hin et al, 2022 ). Although very faintly CHI3L1 + neurons were detected in control brains, they were significantly more frequent in the MS brains, in the lesions, in near-lesion- and normal-appearing areas, compared to the control brains (Figure 2(C)).…”

Section: Discussionsupporting

confidence: 91%

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis

Ahmad,

Wergeland,

Oveland

et al. 2023

ASN Neuro

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Elevated levels of Chitinase-3-like protein-1 (CHI3L1) in cerebrospinal fluid have previously been linked to inflammatory activity and disease progression in multiple sclerosis (MS) patients. This study aimed to investigate the presence of CHI3L1 in the brains of MS patients and in the cuprizone model in mice (CPZ), a model of toxic/metabolic demyelination and remyelination in different brain areas. In MS gray matter (GM), CHI3L1 was detected primarily in astrocytes and in a subset of pyramidal neurons. In neurons, CHI3L1 immunopositivity was associated with lipofuscin-like substance accumulation, a sign of cellular aging that can lead to cell death. The density of CHI3L1-positive neurons was found to be significantly higher in normal-appearing MS GM tissue compared to that of control subjects ( p = .014). In MS white matter (WM), CHI3L1 was detected in astrocytes located within lesion areas, as well as in perivascular normal-appearing areas and in phagocytic cells from the initial phases of lesion development. In the CPZ model, the density of CHI3L1-positive cells was strongly associated with microglial activation in the WM and choroid plexus inflammation. Compared to controls, CHI3L1 immunopositivity in WM was increased from an early phase of CPZ exposure. In the GM, CHI3L1 immunopositivity increased later in the CPZ exposure phase, particularly in the deep GM region. These results indicate that CHI3L1 is associated with neuronal deterioration, pre-lesion pathology, along with inflammation in MS.

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Section: Discussionsupporting

confidence: 91%

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis

Ahmad,

Wergeland,

Oveland

et al. 2023

ASN Neuro

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“… 5 The function was largely unknown, and expression in FTD brain tissue was low and mostly confined to the blood vessels, which was puzzling and did not provide insight into how the validated increase of CH3L1 in CSF relates to brain pathology. 6 The findings of Hinsinger similarly show low expression of CH3L1 in neuronal cells, yet higher expression in plasmablasts, and no overlap between CH3L1 and CD138 expression in MS tissue of the 2 studied patients. The CH3L1-CD138 connection thus appears important for MS and could be a potential therapeutic target, but clearly needs to be studied further.…”

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confidence: 58%

Proteomics Analysis Moves the Needle by Generating Clinical Diagnostic Markers

Teunissen

2024

Neurol Neuroimmunol Neuroinflamm

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“…In addition to YKL40 increases in CSF, our data showed YKL40 is highly increased in brain tissues of symptomatic GRN mutation carriers, aligning with previous findings [ 43 , 50 , 51 ]. Notably, one study reported no significant increases in YKL40 in brain samples from patients with FTD, despite observing elevated levels in paired premortem CSF [ 52 ], but these subjects also had different underlying genotypes or had a different clinical diagnosis (FTLD-Tau; FTLD with amyotrophic lateral sclerosis, FTLD-ALS; and dementia with Lewy body, DLB). The precise role of YKL40 in FTD pathogenesis and its correlation with clinical metrics remain insufficiently characterized.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

Hsiao-Nakamoto,

Chiu,

VandeVrede

et al. 2024

Preprint

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Frontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes: GRN, C9orf72, or MAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage. Methods We conducted a comprehensive investigation of biomarkers indicative of lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations in GRN, C9orf72, or MAPT, as well as asymptomatic GRN mutation carriers. We also assessed the longitudinal changes of biomarkers in GRN mutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomatic GRN carriers. Results We confirmed glucosylsphingosine (GlcSph), a lysosomal biomarker regulated by progranulin, was elevated in the plasma from GRN mutation carriers, both symptomatic and asymptomatic. GlcSph and other lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomatic GRN carriers, and all symptomatic groups, except the symptomatic C9orf72 mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomatic MAPT mutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD-SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD-SB in symptomatic GRN and MAPT mutation carriers. Conclusions In conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients with GRN mutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.

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YKL-40 changes are not detected in post-mortem brain of patients with Alzheimer’s disease and frontotemporal lobar degeneration

Cited by 9 publications

References 78 publications

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis

Proteomics Analysis Moves the Needle by Generating Clinical Diagnostic Markers

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

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