Poly(GP), neurofilament and grey matter deficits in <i>C9orf72</i> expansion carriers

Meeter, Lieke H.H.; Gendron, Tania F.; Sias, Ana C.; Jiskoot, Lize C.; Russo, Silvia; Kaat, Laura Donker; Papma, Janne M.; Panman, Jessica L.; Ende, Emma L. van der; Dopper, Elise G.P.; Franzen, Sanne; Graff, Caroline; Boxer, Adam L.; Rosen, Howard J.; Sánchez‐Valle, Raquel; Galimberti, Daniela; Pijnenburg, Yolande A.L.; Benussi, Luisa; Ghidoni, Roberta; Borroni, Barbara; Laforce, Robert; Campo, Marta Del; Teunissen, Charlotte E.; Minkelen, Rick van; Rojas, Julio C.; Coppola, Giovanni; Geschwind, Dan; Rademakers, Rosa; Karydas, Anna; Öijerstedt, Linn; Scarpini, Elio; Binetti, Giuliano; Padovani, Alessandro; Cash, David M.; Dick, Katrina M.; Bocchetta, Martina; Miller, Bruce L.; Rohrer, Jonathan D.; Petrucelli, Leonard; Swieten, John C. van; Lee, Suzee E.

doi:10.1002/acn3.559

Cited by 51 publications

(67 citation statements)

References 55 publications

(82 reference statements)

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“…The association between plasma NfL levels and FA values in the majority of tracts affected by the disease process is in line with both cross-sectional and longitudinal studies in the FTD spectrum showing that levels of NfL are increased with disease severity and associated with poorer prognosis (7,10,11,18,36,40). Although it is not the primary outcome of the present study, the association between NfL levels and disease severity holds also in our cohort has revealed by a positive association between NfL and FTLD-CDR sum of boxes (Spearman's rho = 0.7; p < 0.001).…”

Section: Discussionsupporting

confidence: 82%

Plasma neurofilament light protein correlates with diffusion tensor imaging metrics in frontotemporal dementia

Spotorno

Lindberg

Nilsson

et al. 2020

Preprint

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AbstractNeurofilaments are structural components of neurons and are particularly abundant in highly myelinated axons. The levels of neurofilament light chain (NfL) in both cerebrospinal fluid (CSF) and plasma have been related to degeneration in several neurodegenerative conditions including frontotemporal dementia (FTD) and NfL is currently considered as the most promising diagnostic and prognostic fluid biomarker in FTD. Although the location and function of filaments in the healthy nervous system suggests a link between increased NfL and white matter degeneration, such a claim has not been fully elucidated in vivo, especially in the context of FTD. The present study provides evidence of an association between the plasma levels of NfL and white matter involvement in behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The results of both voxel-wise and tract specific analysis showed that increased plasma NfL concentration is associated with a reduction in fractional anisotropy (FA) in a widespread set of white matter tracts including the superior longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic radiation and the dorsal cingulum bundle. Plasma NfL concentration also correlated with cortical thinning in a portion of the right medial prefrontal cortex and of the right lateral orbitofrontal cortex. These results support the hypothesis that blood NfL levels reflect the global level of neurodegeneration in bvFTD and help to advance our understanding of the association between this blood biomarker for FTD and the disease process.

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Section: Discussionsupporting

confidence: 82%

Plasma neurofilament light protein correlates with diffusion tensor imaging metrics in frontotemporal dementia

Spotorno

Lindberg

Nilsson

et al. 2020

Preprint

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“…Twenty-six studies compared CSF NfL concentration in 1827 FTD cases and 1113 cognitively unimpaired controls, with a ROM of 3.41 (95% CI 2.96-3.93, P , 0.0001; Fig. 3A) [16][17][18][20][21][22][26][27][28]31,32,35,36,38,[44][45][46][54][55][56][57][58][59][60][61][62]. Four studies investigated 113 FTD cases and 110 MCI controls [9,22,43,44], with no observable difference in CSF NfL concentration (ROM 5 1.87, 95% CI 0.88-3.98, P 5 0.077; Fig.…”

Section: Nfl In Ftdmentioning

confidence: 99%

The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta‐analysis

Forgrave

Huei‐Ming

Best

et al. 2019

Alz & Dem Diag Ass & Dis Mo

113

134

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Introduction A systematic review and meta‐analysis was performed regarding the diagnostic performance of neurofilament light chain (NfL) in CSF and blood. Methods A database search was conducted for NfL biomarker studies in the context of Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) compared with controls (i.e., cognitively unimpaired, mild cognitive impairment, or disease mimics). Results In groups with a sufficient number of studies, the performance of NfL in blood and CSF was similar. Compared with disease mimics, we observed that CSF NfL had strong discriminatory power for ALS, modest discriminatory power for FTD, and no discriminatory power for AD. NfL provided the greatest separation between ALS and cognitively unimpaired controls in both the blood and CSF, followed by FTD (CSF and blood), then AD (blood and CSF). Discussion Comparable performance of CSF and blood NfL in many groups demonstrates the promise of NfL as a noninvasive biomarker of neurodegeneration; however, its utility in clinically meaningful scenarios requires greater scrutiny. Toward clinical implementation, a more comprehensive understanding of NfL concentrations in disease subtypes with overlapping phenotypes and at defined stages of disease, and the development of a harmonization program, are warranted.

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“…As clinical trials in genetic FTD are fast approaching, robust biomarkers that allow accurate measurement of disease onset and progression are becoming increasingly important. In particular, many trials will focus on the presymptomatic stage of disease where neuropathological alterations are already present2 and yet few biomarkers have been shown to be abnormal in this phase 3–5…”

Section: Introductionmentioning

confidence: 99%

“…Cerebrospinal fluid (CSF) or plasma/serum progranulin levels in GRN mutation carriers4 6 and CSF (poly)GP dipeptide repeat concentrations in C9orf72 expansion carriers5 7 8 are markers of specific protein abnormalities in genetic FTD, but both are abnormal from early in the presymptomatic period (and potentially from birth). In contrast, neurofilament light chain (NfL) is a marker of neuronal death and axonal degeneration (measurable in CSF3 9 10 as well as both plasma11 and serum12 13) that is not specific to FTD14 and has only been shown to be abnormal in the very late presymptomatic period prior to conversion to the symptomatic phase 3.…”

Section: Introductionmentioning

confidence: 99%

Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia

Heller

Foiani

Moore

et al. 2020

J Neurol Neurosurg Psychiatry

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121

128

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BackgroundThere are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.MethodsPlasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures.ResultsPlasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe.ConclusionsRaised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.

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Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Cited by 51 publications

References 55 publications

Plasma neurofilament light protein correlates with diffusion tensor imaging metrics in frontotemporal dementia

Plasma neurofilament light protein correlates with diffusion tensor imaging metrics in frontotemporal dementia

The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta‐analysis

Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia

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