Plasma Glial Fibrillary Acidic Protein and Neurofilament-Light for the Diagnostic and Prognostic Evaluation of Frontotemporal Dementia

Abstract Background: Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. The Study of Glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may be helpful to better understand the different neurodegenerative diseases. We investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament (pNfL) and their combination in frontotemporal dementia (FTD) and Alzheimer’s disease (AD). We studied their clinical utility in predicting disease progression. Methods: We measured pGFAP and pNfL concentrations in 72 FTD, 56 AD and 83 cognitively normal participants (CN) using Single Molecule Array technology. Of 211 participants, 199 had CSF and 122 had MRI. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation with CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated analyzing cognitive decline between group comparisons by tertile. Results: Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all p<0.01). The combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (combination AUC 0.78; pGFAP AUC 0.7; pNfL AUC 0.61, all p<0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all p<0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, HR 3.82, p<0.005) and AD (1.20 points annually, HR 2.26, p<0.005).Conclusions: pGFAP and pNfL differed in FTD and AD, their combination could be useful to distinguish the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.

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Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia

Translational Neurodegeneration ◽

10.1186/s40035-021-00275-w ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Nuole Zhu ◽

Miguel Santos-Santos ◽

Ignacio Illán-Gala ◽

Victor Montal ◽

Teresa Estellés ◽

...

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Cognitive Decline ◽

Frontotemporal Dementia ◽

Cortical Thickness ◽

Light Chain ◽

Diagnostic Performance ◽

Acidic Protein ◽

Neurofilament Light Chain ◽

Neurofilament Light

Abstract Background Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and their clinical utility in predicting disease progression. Methods pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile. Results Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005). Conclusions pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.

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Absence of attack-independent neuroaxonal injury in MOG antibody-associated disease: Longitudinal assessment of serum neurofilament light chain

Multiple Sclerosis Journal ◽

10.1177/13524585211063756 ◽

2021 ◽

pp. 135245852110637

Author(s):

Jae-Won Hyun ◽

So Yeon Kim ◽

Yeseul Kim ◽

Na Young Park ◽

Ki Hoon Kim ◽

...

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Single Molecule ◽

Light Chain ◽

Myelin Oligodendrocyte Glycoprotein ◽

Acidic Protein ◽

Healthy Controls ◽

Longitudinal Assessment ◽

Neurofilament Light Chain ◽

Neurofilament Light

To evaluate the occurrence of attack-independent neuroaxonal and astrocytic damage in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) levels were longitudinally measured in 102 sera using a single-molecule array assay. Sera from 15 adults with relapsing MOGAD with available longitudinal samples for the median 24-month follow-up and 26 age-/sex-matched healthy controls were analyzed. sNfL levels were significantly elevated in all clinical attacks, where the levels decreased below or close to cut-off value within 6 months after attacks. sNfL levels were consistently low during inter-attack periods. In contrast, sGFAP levels did not increase in most clinical attacks and remained low during follow-up. Significant neuroaxonal damage was observed at clinical attacks, while attack-independent neuroaxonal and astrocytic injury was absent in MOGAD.

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Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline

Neurology ◽

10.1212/wnl.0000000000010946 ◽

2020 ◽

Vol 95 (23) ◽

pp. e3093-e3103

Author(s):

Corinne Pettigrew ◽

Anja Soldan ◽

Jiangxia Wang ◽

Mei-Cheng Wang ◽

Karissa Arthur ◽

...

Keyword(s):

Cognitive Decline ◽

Risk Score ◽

Synergistic Effects ◽

Vascular Risk Factor ◽

Rate Of Change ◽

Csf Biomarkers ◽

Vascular Risk ◽

Cognitively Normal ◽

T Tau

ObjectiveTo determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time.MethodsAt baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of β-amyloid (Aβ)1–42, total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aβ1–42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years).ResultsThere was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate −0.022, 95% confidence interval [CI] −0.043 to −0.002, p = 0.03) and AD biomarkers (estimate −0.060, 95% CI −0.096 to −0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aβ1–42, t-tau, or p-tau.ConclusionsThe results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.

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Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity

Multiple Sclerosis Journal ◽

10.1177/1352458518819380 ◽

2018 ◽

Vol 26 (2) ◽

pp. 210-219 ◽

Cited By ~ 16

Author(s):

Heidi Högel ◽

Eero Rissanen ◽

Christian Barro ◽

Markus Matilainen ◽

Marjo Nylund ◽

...

Keyword(s):

Multiple Sclerosis ◽

Nervous System ◽

Glial Fibrillary Acidic Protein ◽

Disease Progression ◽

Disease Severity ◽

Single Molecule ◽

Progressive Disease ◽

Disease Duration ◽

Acidic Protein ◽

Csf Levels

Background: Cerebrospinal fluid (CSF) levels of two soluble biomarkers, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), have been shown to associate with multiple sclerosis (MS) disease progression. Now, both biomarkers can be detected reliably in serum, and importantly, their serum levels correlate well with their CSF levels. Objective: To evaluate the usability of serum GFAP measurement as a biomarker of progressive disease and disease severity in MS. Methods: Clinical course, Expanded Disability Status Scale (EDSS), disease duration, patient age and magnetic resonance imaging (MRI) parameters were reviewed in 79 MS patients in this cross-sectional hospital-based study. Serum samples were collected for measurement of GFAP and NfL concentrations using single molecule array (Simoa) assay. A cohort of healthy controls was evaluated for comparison. Results: Higher serum concentrations of both GFAP and NfL were associated with higher EDSS, older age, longer disease duration, progressive disease course and MRI pathology. Conclusion: Earlier studies have demonstrated that GFAP, unlike NfL, is not increased in association with acute focal inflammation-related nervous system damage. Our work suggests that GFAP serum level associates with disease progression in MS and could potentially serve as an easily measurable biomarker of central nervous system (CNS) pathology related to disease progression in MS.

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Cognitive reserve moderates the impact of subcortical gray matter atrophy on neuropsychological status in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515579443 ◽

2015 ◽

Vol 22 (1) ◽

pp. 36-42 ◽

Cited By ~ 39

Author(s):

Claire M Modica ◽

Niels Bergsland ◽

Michael G Dwyer ◽

Deepa P Ramasamy ◽

Ellen Carl ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Decline ◽

Cognitive Processing ◽

Gray Matter ◽

Cognitive Reserve ◽

Cognitive Outcome ◽

Brain Reserve ◽

The Impact ◽

Normal Controls

Background: Cognitive decline is characterized in multiple sclerosis (MS), but the rate and severity vary. The reserve hypothesis proposes that baseline neurological differences impact cognitive outcome in neurodegenerative disease. Objective: To elucidate how brain reserve and cognitive reserve influence subcortical gray matter (SCGM) atrophy and cognitive decline in MS over 3 years. Methods: Seventy-one MS patients and 23 normal controls underwent magnetic resonance imaging and cognitive assessment at baseline and 3-year follow-up. The influence of reserve on cognitive processing speed (CPS) and memory was examined. Results: SCGM volume and cognitive scores were lower in MS than normal controls ( P⩽0.001). Accounting for baseline, comparison of follow-up means yielded a difference between groups in SCGM volume ( P<0.001) but not cognition (NS). Cognitive reserve ( P=0.005), but not brain reserve, contributed to CPS, with only low cognitive reserve MS subjects showing decline in CPS ( P=0.029). SCGM change predicted CPS outcome in MS with low cognitive reserve ( P=0.002) but not high cognitive reserve. There were no effects in the domain of memory. Conclusions: SCGM atrophy occurs in normal controls, but significantly more so in MS. While CPS did not change in normal controls, low cognitive reserve was associated with CPS decline in MS. High cognitive reserve protect MS patients from cognitive decline related to SCGM atrophy.

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Abstract WP495: Sex Differences in Cognitive Decline: A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, NOMAS

Stroke ◽

10.1161/str.51.suppl_1.wp495 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Deborah A Levine ◽

Alden L Gross ◽

Emily M Briceño ◽

Nicholas Tilton ◽

Mohammed U Kabeto ◽

...

Keyword(s):

Sex Differences ◽

Executive Function ◽

Cognitive Decline ◽

Cognitive Assessment ◽

Cohort Analysis ◽

Cognitive Outcome ◽

Health Study ◽

Cardiovascular Health Study ◽

Global Cognition

Background: Sex differences in dementia risk are unclear but some have found greater risk for women. We hypothesized that women have greater cognitive decline than men, after adjusting for potential confounders. Objective: Determine associations between sex and cognitive decline. Methods: We pooled data from 19,378 participants free of stroke and dementia (mean [SD] age 59.8 [10.4] years at first cognitive assessment), of whom 8,654 (44.7%) were men and 3,852 (19.9%) were black, from 5 longitudinal cohorts between 1971 and 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Linear mixed-effects models measured changes in each continuous cognitive outcome over time by sex, adjusted for demographics, education, vascular risk factors, and age*follow-up time, race*follow-up time, systolic blood pressure*follow-up time, and use of antihypertensive medication*follow-up time interaction terms. Cognitive outcomes were set to a t-score metric (mean 50, standard deviation [SD] 10) at a participant’s first cognitive assessment; a 1-point difference represents a 0.1 SD difference in the distribution of cognition across the 5 cohorts. Median follow-up was 12.4 (IQR: 5.9, 21.0) years. Results: Women had significantly higher baseline performance than men in global cognition, executive function, and memory (adjusted differences in intercepts, 2.09 to 2.15 points; all P<0.001) ( Figure ). Compared with men, women had significantly faster declines in global cognition, executive function, and memory (adjusted differences in slopes, 0.04 to 0.06 points per year faster; P <0.001) ( Figure ). Conclusion: These results are consistent with women having greater cognitive reserve but faster cognitive decline than men.

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Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies

Psychological Medicine ◽

10.1017/s0033291704003897 ◽

2004 ◽

Vol 35 (3) ◽

pp. 307-315 ◽

Cited By ~ 76

Author(s):

HELENE VERDOUX ◽

RAJAA LAGNAOUI ◽

BERNARD BEGAUD

Keyword(s):

General Population ◽

Cognitive Decline ◽

Epidemiological Studies ◽

Cognitive Outcome ◽

Public Health Issue ◽

Hand Search ◽

Increased Risk ◽

Benzodiazepine Use

Background. A major public health issue is to determine whether long-term benzodiazepine use may induce cognitive deficits persisting after withdrawal. The aim of the present review was to examine findings from prospective studies carried out in general population samples exploring whether exposure to benzodiazepines is associated with an increased risk of incident cognitive decline.Method. Using a MEDLINE search and a hand-search of related references in selected papers, we retrieved original studies published in peer-reviewed journals that explored in general population samples the association between benzodiazepine exposure and change in cognitive performance between baseline and follow-up assessment.Results. Six papers met the inclusion criteria. Two studies reported a lower risk of cognitive decline in former or ever users, two found no association whatever the category of user, and three found an increased risk of cognitive decline in benzodiazepine users.Conclusions. The discrepant findings obtained by studies examining the link between benzodiazepine exposure and risk of cognitive decline may be due to methodological differences, especially regarding the definitions of exposure and cognitive outcome. As a large proportion of subjects are exposed to benzodiazepines, a small increase in the risk of cognitive decline may have marked deleterious consequences for the health of the general population. This issue needs to be explored further by pharmaco-epidemiological studies.

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Serum glial fibrillary acidic protein and S100 calcium-binding protein B correlates cerebral vessel reactivity following carotid artery stenting

10.21203/rs.3.rs-701268/v1 ◽

2021 ◽

Author(s):

Xiaofan Yuan ◽

Lei Guo ◽

Jianhong Wang ◽

Duozi Wang ◽

Shu Yang ◽

...

Keyword(s):

Carotid Artery ◽

Glial Fibrillary Acidic Protein ◽

Calcium Binding ◽

Carotid Artery Stenting ◽

Acidic Protein ◽

Serum Concentrations ◽

Mean Flow ◽

Cerebral Vessel ◽

Post Operation

Abstract Using detection markers in serum has the advantages of simplicity, repeatability and the capability. This study combined the use of serum glial fibrillary acidic protein (GFAP) and S100B protein (S100B) with imaging tools to confirm the role of serum biomarkers in evaluating the cerebral vessel reactivity after carotid artery stenting (CAS). After CAS, the serum concentrations of GFAP and S100B increased to the peak at 24 hours after operation, and then gradually decreased. The mean flow velocity (MFV) (pre-operation, post-operation, 30 days follow-up: 47.65 ± 17.24 cm/s, 62.37 ± 18.25 cm/s, 70.29 ± 16.89 cm/s; P < 0.05) and pulsatility index (PI) (pre-operation, post-operation, 30 days follow-up: 0.78 ± 0.21, 0.98 ± 0.19, 1.02 ± 0.20; P < 0.05) increased significantly in the ipsilateral middle cerebral artery after CAS. At the 30-day follow-up, the cerebrovascular reserve (CVR) (post-operation, 30 days follow-up: 27.47 ± 12.13 cm/s, 31.92 ± 10.94 cm/s; P < 0.05) improved significantly. In patients with different degrees of stenosis, the more severe the stenosis in the carotid artery, the more obvious the improvement of CVR at the 30 days of follow-up (CVR changes: 11.08 ± 7.95 cm/s, Kendall’s tau-b = 0.645, P < 0.001). And the serum concentrations of GFAP (r = – 0.629, P < 0.0001) and S100B (r = − 0.604, P < 0.0001) correlated negatively with CVR at 30 days after CAS. Therefore, we recommend using the biomarkers GFAP and S100B associated with imaging tools such as transcranial Doppler (TCD) and Magnetic resonance imaging (MRI) to evaluate the cerebral vessel reactivity following CAS.

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Glial Fibrillary Acidic Protein and CD57 Immunolocalization in Cell Block Preparations Is a Useful Adjunct in the Diagnosis of Pleomorphic Adenoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/2007-131-1373-gfapac ◽

2007 ◽

Vol 131 (9) ◽

pp. 1373-1377 ◽

Cited By ~ 1

Author(s):

Sejal S. Shah ◽

Vishal S. Chandan ◽

David C. Wilbur ◽

Kamal K. Khurana

Keyword(s):

Salivary Gland ◽

Glial Fibrillary Acidic Protein ◽

Pleomorphic Adenoma ◽

Fine Needle Aspiration ◽

Needle Aspiration ◽

Acidic Protein ◽

Cell Block ◽

Cytologic Diagnosis ◽

Fine Needle

Abstract Context.—The cytologic distinction between pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) can be diagnostically challenging in aspirate smears. Hence a cytologic diagnosis of “atypical cytology” with a differential diagnosis including PA and ACC is occasionally rendered in a subset of salivary gland fine-needle aspirations. Objective.—To evaluate the role of glial fibrillary acidic protein (GFAP) and CD57 expression in cell block material obtained during fine-needle aspiration procedure in differentiating PA from ACC. Design.—We performed GFAP and CD57 immunostains on formalin-fixed, paraffin-embedded cell block sections of 26 salivary gland fine-needle aspiration cases with the following cytologic diagnoses: (1) PA (10 cases); (2) atypical cytology, cannot exclude ACC (8 cases); and (3) ACC (8 cases). Results.—All 10 (100%) cases with cytologic diagnoses of PA were positive for GFAP, and 8 (80%) of 10 cases were positive for CD57; tissue follow-up confirmed the diagnosis of PA in all cases. All 8 (100%) cases with cytologic diagnosis of ACC were negative for both GFAP and CD57; tissue follow-up confirmed the diagnoses of ACC in all cases. Of the 8 cases with diagnoses of atypical cytology, 4 (50%) were negative and 4 (50%) were positive for both GFAP and CD57. Subsequent tissue follow-up in these cases revealed 4 cases of ACC (all negative for GFAP and CD57) and 4 cases of PA (all positive for GFAP and CD57). Conclusions.—Our results show that positive staining for GFAP and CD57 serves as a useful adjunct for the diagnosis of PA and helps to reduce the uncertainty in challenging cases.

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Plasma Glial Fibrillary Acidic Protein Detects Alzheimer Pathology and Predicts Future Conversion to Alzheimer Dementia in Patients With Mild Cognitive Impairment

10.21203/rs.3.rs-118286/v1 ◽

2020 ◽

Author(s):

Claudia Cicognola ◽

Shorena Janelidze ◽

Joakim Hertze ◽

Henrik Zetterberg ◽

Kaj Blennow ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Glial Fibrillary Acidic Protein ◽

Acidic Protein ◽

Alzheimer Dementia ◽

Total Tau ◽

Subsequent Conversion ◽

Astroglial Activation ◽

T Tau

Abstract IntroductionPlasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer’s disease (AD) pathology in the form of AD-related amyloid-b (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort.Method160 MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau. Plasma GFAP was measured at baseline and follow-up using Simoa technology.ResultsBaseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/total tau (T-tau) with an AUC of 0.79 (95% CI 0.72-0.86) and 0.80 (95% CI 0.72-0.86), respectively. Combination with APOE ε4 status improved the diagnostic accuracy for abnormal CSF Aβ42/40 status (AUC=0.86, p=0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77-0.91), which was not significantly improved when combined with APOE ε4 or age. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to AD dementia were significantly steeper than for Aβ-negative (p=0.007) and stable MCI (p<0.0001).ConclusionPlasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia.

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