Serum glial fibrillary acidic protein is a marker of disease severity in 1 frontotemporal lobar degeneration

46 Objective: To assess the diagnostic and prognostic value of serum glial fibrillary acidic protein 47 (GFAP) in a large cohort of patients with frontotemporal lobar degeneration (FTLD). 48 Methods: In this retrospective study, performed on 406 participants, we measured serum GFAP 49 concentration with an ultrasensitive Single molecule array (Simoa) method in FTLD, Alzheimer’s 50 disease (AD) and healthy ageing. We assessed the role of GFAP as marker of disease severity by 51 analysing the correlation with clinical variables, neurophysiological data and cross-sectional brain 52 imaging. Moreover, we evaluated the role of serum GFAP as a prognostic marker of disease 53 survival. 54 Results: We observed significantly higher levels of serum GFAP in patients with FTLD 55 syndromes, except progressive supranuclear palsy (PSP), compared with healthy controls, but not 56 compared with AD patients. In FTLD, serum GFAP levels correlated with measures of cognitive 57 dysfunction and disease severity, and were associated with indirect measures of GABAergic deficit. 58 Serum GFAP concentration was not a significant predictor of survival. 59 Conclusions: Serum GFAP is a marker of disease severity in FTLD. 60

[1]  G. Frisoni,et al.  Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer’s disease , 2022, Revista brasileira de psiquiatria.

[2]  G. Frisoni,et al.  Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia , 2020, Journal of Neurology, Neurosurgery, and Psychiatry.

[3]  Nick C Fox,et al.  White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study , 2019, NeuroImage: Clinical.

[4]  G. Perea,et al.  GABAergic‐astrocyte signaling: A refinement of inhibitory brain networks , 2019, Glia.

[5]  K. Fliessbach,et al.  Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase , 2018, Journal of Neurology, Neurosurgery, and Psychiatry.

[6]  Nick C Fox,et al.  Plasma tau is increased in frontotemporal dementia , 2018, Journal of Neurology, Neurosurgery, and Psychiatry.

[7]  G. Binetti,et al.  The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort. , 2017, Journal of Alzheimer's disease : JAD.

[8]  B. Barres,et al.  Reactive Astrocytes: Production, Function, and Therapeutic Potential. , 2017, Immunity.

[9]  Murray Grossman,et al.  Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria , 2017, Movement disorders : official journal of the Movement Disorder Society.

[10]  M. Jorge Cardoso,et al.  Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia , 2016, Neurology.

[11]  S. Ourselin,et al.  Neurofilament light chain: a biomarker for genetic frontotemporal dementia , 2016, Annals of clinical and translational neurology.

[12]  K. Blennow,et al.  CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis , 2016, The Lancet Neurology.

[13]  B. Borroni,et al.  White matter hyperintensities characterize monogenic frontotemporal dementia with granulin mutations , 2016, Neurobiology of Aging.

[14]  N. Tomita,et al.  Glial fibrillar acidic protein in the cerebrospinal fluid of Alzheimer's disease, dementia with Lewy bodies, and frontotemporal lobar degeneration , 2016, Journal of neurochemistry.

[15]  Harald Sontheimer,et al.  Glia as drivers of abnormal neuronal activity , 2015, Nature Neuroscience.

[16]  A. Strafella,et al.  TMS and drugs revisited 2014 , 2015, Clinical Neurophysiology.

[17]  Henrik Zetterberg,et al.  Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction , 2015, PloS one.

[18]  S. Rossi,et al.  Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee , 2015, Clinical Neurophysiology.

[19]  Sterling C. Johnson,et al.  Extracting and summarizing white matter hyperintensities using supervised segmentation methods in Alzheimer's disease risk and aging studies , 2014, Human brain mapping.

[20]  Nick C Fox,et al.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. , 2011, Brain : a journal of neurology.

[21]  B. Miller,et al.  Classification of primary progressive aphasia and its variants , 2011, Neurology.

[22]  R. Lodi,et al.  Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia , 2010, Movement disorders : official journal of the Movement Disorder Society.

[23]  Julie S. Snowden,et al.  Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype , 2006, Acta Neuropathologica.

[24]  J. Rothwell,et al.  Short latency inhibition of human hand motor cortex by somatosensory input from the hand , 2000, The Journal of physiology.

[25]  L. Rosengren,et al.  Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple‐system atrophy compared with Parkinson's disease , 1998, Movement disorders : official journal of the Movement Disorder Society.

[26]  J. Rothwell,et al.  Interaction between intracortical inhibition and facilitation in human motor cortex. , 1996, The Journal of physiology.

[27]  C. Marsden,et al.  Corticocortical inhibition in human motor cortex. , 1993, The Journal of physiology.

[28]  M. Hallett,et al.  Human motor evoked responses to paired transcranial magnetic stimuli. , 1992, Electroencephalography and clinical neurophysiology.

[29]  K. Chiappa,et al.  Magnetic stimulation , 1991, Neurology.

[30]  P. Lewczuk,et al.  Glial Fibrillary Acidic Protein in Serum is Increased in Alzheimer's Disease and Correlates with Cognitive Impairment. , 2019, Journal of Alzheimer's disease : JAD.

[31]  B. Borroni,et al.  Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum. , 2016, Journal of Alzheimer's disease : JAD.

[32]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.