Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging

A. Benussi; S. Gazzina; E. Premi; M. Cosseddu; S. Archetti; V. Dell'Era; V. Cantoni; M.S. Cotelli; A. Alberici; A. Micheli; L. Benussi; R. Ghidoni; A. Padovani; B. Borroni

doi:10.1016/j.neurobiolaging.2018.12.018

Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging

A. Benussi, S. Gazzina, E. Premi, M. Cosseddu, S. Archetti, V. Dell'Era, V. Cantoni, M.S. Cotelli, A. Alberici, A. Micheli, L. Benussi, R. Ghidoni, A. Padovani, B. Borroni

Centro San Giovanni di Dio - Fatebenefratelli

Research output: Contribution to journal › Article › peer-review

Abstract

Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms. © 2019 Elsevier Inc.

Original language	English
Pages (from-to)	133-140
Number of pages	8
Journal	Neurobiol. Aging
Volume	76
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.12.018
Publication status	Published - 2019

Keywords

Biomarkers
C9orf72
Frontotemporal dementia
GRN
Transcranial magnetic stimulation
adult
Article
brain atrophy
brain tissue
C9orf72 gene
cognitive defect
female
follow up
frontotemporal dementia
gene
gene mutation
GRN gene
heterozygote
human
major clinical study
male
middle aged
neurotransmission
priority journal
tissue structure
white matter lesion
aged
atrophy
brain
genetics
mutation
pathology
pathophysiology
psychology
transcranial magnetic stimulation
biological marker
C9orf72 protein, human
fungichromin
GRN protein, human
guanine nucleotide exchange C9orf72
macrolide
polyene
Adult
Aged
Atrophy
Brain
C9orf72 Protein
Female
Frontotemporal Dementia
Heterozygote
Humans
Macrolides
Male
Middle Aged
Mutation
Polyenes
Progranulins
Transcranial Magnetic Stimulation

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10.1016/j.neurobiolaging.2018.12.018

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060748961&doi=10.1016%2fj.neurobiolaging.2018.12.018&partnerID=40&md5=9ee772e175ad693d1fb91c0de6bc9106

Cite this

Benussi, A., Gazzina, S., Premi, E., Cosseddu, M., Archetti, S., Dell'Era, V., Cantoni, V., Cotelli, M. S., Alberici, A., Micheli, A., Benussi, L., Ghidoni, R., Padovani, A., & Borroni, B. (2019). Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging. Neurobiol. Aging, 76, 133-140. https://doi.org/10.1016/j.neurobiolaging.2018.12.018

Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia : Neurobiology of Aging. / Benussi, A.; Gazzina, S.; Premi, E.; Cosseddu, M.; Archetti, S.; Dell'Era, V.; Cantoni, V.; Cotelli, M.S.; Alberici, A.; Micheli, A.; Benussi, L.; Ghidoni, R.; Padovani, A.; Borroni, B.

In: Neurobiol. Aging, Vol. 76, 2019, p. 133-140.

Research output: Contribution to journal › Article › peer-review

Benussi, A, Gazzina, S, Premi, E, Cosseddu, M, Archetti, S, Dell'Era, V, Cantoni, V, Cotelli, MS, Alberici, A, Micheli, A, Benussi, L , Ghidoni, R, Padovani, A & Borroni, B 2019, 'Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging', Neurobiol. Aging, vol. 76, pp. 133-140. https://doi.org/10.1016/j.neurobiolaging.2018.12.018

@article{031584bd970f4f948eda7e3961edcef5,

title = "Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging",

abstract = "Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms. {\textcopyright} 2019 Elsevier Inc.",

keywords = "Biomarkers, C9orf72, Frontotemporal dementia, GRN, Transcranial magnetic stimulation, adult, Article, brain atrophy, brain tissue, C9orf72 gene, cognitive defect, female, follow up, frontotemporal dementia, gene, gene mutation, GRN gene, heterozygote, human, major clinical study, male, middle aged, neurotransmission, priority journal, tissue structure, white matter lesion, aged, atrophy, brain, genetics, mutation, pathology, pathophysiology, psychology, transcranial magnetic stimulation, biological marker, C9orf72 protein, human, fungichromin, GRN protein, human, guanine nucleotide exchange C9orf72, macrolide, polyene, Adult, Aged, Atrophy, Brain, C9orf72 Protein, Female, Frontotemporal Dementia, Heterozygote, Humans, Macrolides, Male, Middle Aged, Mutation, Polyenes, Progranulins, Transcranial Magnetic Stimulation",

author = "A. Benussi and S. Gazzina and E. Premi and M. Cosseddu and S. Archetti and V. Dell'Era and V. Cantoni and M.S. Cotelli and A. Alberici and A. Micheli and L. Benussi and R. Ghidoni and A. Padovani and B. Borroni",

note = "Cited By :6 Export Date: 10 February 2020 CODEN: NEAGD Correspondence Address: Borroni, B.; Clinica Neurologica, Universit{\`a} degli Studi di Brescia, P.le Spedali Civili 1, Italy; email: bborroni@inwind.it Chemicals/CAS: fungichromin, 6834-98-6; Biomarkers; C9orf72 Protein; C9orf72 protein, human; fungichromin; GRN protein, human; Macrolides; Polyenes; Progranulins Funding details: GR-2013-02357415 Funding text 1: This study was supported by grants from {"}AIRAlzh Onlus{"} and {"}ANCC-COOP{"} issued to VC; Italian Ministry of Health (Ricerca Corrente) issued to LB and RG; and partially supported by a grant from the Italian Ministry of Health (GR-2013-02357415) issued to MC. Authors' contribution: AB and BB designed the study. AB, SG, EP, MC, SA, VD, VC, MSC, AA, AM, LB, RG, AP, and BB recruited patients. AB, SG, EP, MC, and BB performed experiments and analyzed the data. AB, SG, EP, and BB evaluated the data and cowrote the article. AB, SG, EP, MC, SA, VD, VC, MSC, AA, AM, LB, RG, AP, and BB contributed to revising the article for intellectual content. Appendix A References: Bastos, A.M., Usrey, W.M., Adams, R.A., Mangun, G.R., Fries, P., Friston, K.J., Canonical microcircuits for predictive coding (2012) Neuron, 76, pp. 695-711; Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Morris, J.C., Clinical and biomarker changes in dominantly inherited Alzheimer's disease (2012) N. Engl. J. Med., 367, pp. 795-804; Benussi, A., Cosseddu, M., Filareto, I., Dell'Era, V., Archetti, S., Sofia Cotelli, M., Micheli, A., Borroni, B., Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia (2016) Ann. Neurol., 80, pp. 472-476; Benussi, A., Dell'Era, V., Cantoni, V., Ferrari, C., Caratozzolo, S., Rozzini, L., Alberici, A., Borroni, B., Discrimination of atypical parkinsonisms with transcranial magnetic stimulation (2018) Brain Stimul., 11, pp. 366-373; Benussi, A., Di Lorenzo, F., Dell'Era, V., Cosseddu, M., Alberici, A., Caratozzolo, S., Cotelli, M.S., Borroni, B., Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia (2017) Neurology, 89, pp. 665-672; Benussi, A., Padovani, A., Borroni, B., Phenotypic heterogeneity of monogenic frontotemporal dementia (2015) Front. Aging Neurosci., 7, p. 171; Burrell, J.R., Hornberger, M., Vucic, S., Kiernan, M.C., Hodges, J.R., Apraxia and motor dysfunction in corticobasal syndrome (2014) PLoS One, 9, p. e92944; Burrell, J.R., Kiernan, M.C., Vucic, S., Hodges, J.R., Motor Neuron dysfunction in frontotemporal dementia (2011) Brain, 134, pp. 2582-2594; Ernst, T., Chang, L., Melchor, R., Mehringer, C.M., Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H-1 MR spectroscopy (1997) Radiology, 203, pp. 829-836; Farokhian, F., Beheshti, I., Sone, D., Matsuda, H., Comparing CAT12 and VBM8 for detecting brain morphological abnormalities in temporal lobe epilepsy (2017) Front. Neurol., 8, p. 428; Ferrer, I., Neurons and their dendrites in frontotemporal dementia (1999) Dement Geriatr. Cogn. Disord., 10, pp. 55-60; Frasson, E., Bertolasi, L., Bertasi, V., Fusina, S., Bartolomei, L., Vicentini, S., Rizzuto, N., Priori, A., Paired transcranial magnetic stimulation for the early diagnosis of corticobasal degeneration (2003) Clin. Neurophysiol., 114, pp. 272-278; Galimberti, D., Fumagalli, G.G., Fenoglio, C., Cioffi, S.M.G., Arighi, A., Serpente, M., Borroni, B., Scarpini, E., Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study (2018) Neurobiol. Aging, 62. , 245.e9–245.e12; Gazzina, S., Benussi, A., Premi, E., Paternic{\`o}, D., Cristillo, V., Dell'Era, V., Cosseddu, M., Borroni, B., Neuroanatomical correlates of transcranial magnetic stimulation in presymptomatic granulin mutation carriers (2018) Brain Topogr., 31, pp. 488-497; Geevasinga, N., Menon, P., Nicholson, G.A., Ng, K., Howells, J., Kril, J.J., Yiannikas, C., Vucic, S., Cortical function in asymptomatic carriers and patients with C9orf72Amyotrophic lateral sclerosis (2015) JAMA Neurol., 72, p. 1268; Geschwind, D.H., Robidoux, J., Alarc{\'o}n, M., Miller, B.L., Wilhelmsen, K.C., Cummings, J.L., Nasreddine, Z.S., Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia (2001) Ann. Neurol., 50, pp. 741-746; Ghidoni, R., Benussi, L., Glionna, M., Franzoni, M., Binetti, G., Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration (2008) Neurology, 71, pp. 1235-1239; Ghidoni, R., Stoppani, E., Rossi, G., Piccoli, E., Albertini, V., Paterlini, A., Glionna, M., Benussi, L., Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study (2012) Neurodegener. Dis., 9, pp. 121-127; Gorno-Tempini, M.L., Hillis, A.E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S.F., Ogar, J.M., Grossman, M., Classification of primary progressive aphasia and its variants (2011) Neurology, 76, pp. 1006-1014; Hughes, L.E., Ghosh, B.C.P., Rowe, J.B., Reorganisation of brain networks in frontotemporal dementia and progressive supranuclear palsy (2013) Neuroimage Clin., 2, pp. 459-468; Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Marsden, C.D., Corticocortical inhibition in human motor cortex (1993) J. Physiol., 471, pp. 501-519; Kurth, F., Gaser, C., Luders, E., A 12-step user guide for analyzing voxel-wise gray matter asymmetries in statistical parametric mapping (SPM) (2015) Nat. Protoc., 10, pp. 293-304; Le Ber, I., Camuzat, A., Hannequin, D., Pasquier, F., Guedj, E., Rovelet-Lecrux, A., Hahn-Barma, V., Brice, A., Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study (2008) Brain, 131, pp. 732-746; Levenga, J., Krishnamurthy, P., Rajamohamedsait, H., Wong, H., Franke, T.F., Cain, P., Sigurdsson, E.M., Hoeffer, C.A., Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments (2013) Acta Neuropathol. Commun., 1, p. 34; Meeter, L.H.H., Patzke, H., Loewen, G., Dopper, E.G.P., Pijnenburg, Y.A.L., van Minkelen, R., van Swieten, J.C., Progranulin levels in plasma and cerebrospinal fluid in granulin mutation carriers (2016) Dement Geriatr. Cogn. Disord. Extra, 6, pp. 330-340; Murley, A.G., Rowe, J.B., Neurotransmitter deficits from frontotemporal lobar degeneration (2018) Brain, 141, pp. 1263-1285; Pal, P.K., Gunraj, C.A., Li, J.Y., Lang, A.E., Chen, R., Reduced intracortical and interhemispheric inhibitions in corticobasal syndrome (2008) J. Clin. Neurophysiol., 25, pp. 304-312; Paternic{\`o}, D., Premi, E., Gazzina, S., Cosseddu, M., Alberici, A., Archetti, S., Cotelli, M.S., Borroni, B., White matter hyperintensities characterize monogenic frontotemporal dementia with granulin mutations (2016) Neurobiol. Aging, 38, pp. 176-180; Pietroboni, A.M., Fumagalli, G.G., Ghezzi, L., Fenoglio, C., Cortini, F., Serpente, M., Cantoni, C., Scarpini, E., Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred (2011) J. Alzheimers Dis., 24, pp. 253-259; Procter, A.W., Qurne, M., Francis, P.T., Neurochemical features of frontotemporal dementia (1999) Dement. Geriatr. Cogn. Disord., 10, pp. 80-84; Rascovsky, K., Hodges, J.R., Knopman, D., Mendez, M.F., Kramer, J.H., Neuhaus, J., van Swieten, J.C., Miller, B.L., Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia (2011) Brain, 134, pp. 2456-2477; Rohrer, J.D., Guerreiro, R., Vandrovcova, J., Uphill, J., Reiman, D., Beck, J., Authier, A., Rossor, M.N., The heritability and genetics of frontotemporal lobar degeneration (2009) Neurology, 73, pp. 1451-1456; Rohrer, J.D., Nicholas, J.M., Cash, D.M., Van Swieten, J., Dopper, E., Jiskoot, L., van Minkelen, R., Binetti, G., Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis (2015) Lancet Neurol., 14, pp. 253-262; Rossini, P.M., Burke, D., Chen, R., Cohen, L.G., Daskalakis, Z., Di Iorio, R., Di Lazzaro, V., Ziemann, U., 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. 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year = "2019",

doi = "10.1016/j.neurobiolaging.2018.12.018",

language = "English",

volume = "76",

pages = "133--140",

journal = "Neurobiol. Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia

T2 - Neurobiology of Aging

AU - Benussi, A.

AU - Gazzina, S.

AU - Premi, E.

AU - Cosseddu, M.

AU - Archetti, S.

AU - Dell'Era, V.

AU - Cantoni, V.

AU - Cotelli, M.S.

AU - Alberici, A.

AU - Micheli, A.

AU - Benussi, L.

AU - Ghidoni, R.

AU - Padovani, A.

AU - Borroni, B.

N1 - Cited By :6 Export Date: 10 February 2020 CODEN: NEAGD Correspondence Address: Borroni, B.; Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili 1, Italy; email: bborroni@inwind.it Chemicals/CAS: fungichromin, 6834-98-6; Biomarkers; C9orf72 Protein; C9orf72 protein, human; fungichromin; GRN protein, human; Macrolides; Polyenes; Progranulins Funding details: GR-2013-02357415 Funding text 1: This study was supported by grants from "AIRAlzh Onlus" and "ANCC-COOP" issued to VC; Italian Ministry of Health (Ricerca Corrente) issued to LB and RG; and partially supported by a grant from the Italian Ministry of Health (GR-2013-02357415) issued to MC. Authors' contribution: AB and BB designed the study. AB, SG, EP, MC, SA, VD, VC, MSC, AA, AM, LB, RG, AP, and BB recruited patients. AB, SG, EP, MC, and BB performed experiments and analyzed the data. AB, SG, EP, and BB evaluated the data and cowrote the article. AB, SG, EP, MC, SA, VD, VC, MSC, AA, AM, LB, RG, AP, and BB contributed to revising the article for intellectual content. Appendix A References: Bastos, A.M., Usrey, W.M., Adams, R.A., Mangun, G.R., Fries, P., Friston, K.J., Canonical microcircuits for predictive coding (2012) Neuron, 76, pp. 695-711; Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Morris, J.C., Clinical and biomarker changes in dominantly inherited Alzheimer's disease (2012) N. Engl. J. Med., 367, pp. 795-804; Benussi, A., Cosseddu, M., Filareto, I., Dell'Era, V., Archetti, S., Sofia Cotelli, M., Micheli, A., Borroni, B., Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia (2016) Ann. Neurol., 80, pp. 472-476; Benussi, A., Dell'Era, V., Cantoni, V., Ferrari, C., Caratozzolo, S., Rozzini, L., Alberici, A., Borroni, B., Discrimination of atypical parkinsonisms with transcranial magnetic stimulation (2018) Brain Stimul., 11, pp. 366-373; Benussi, A., Di Lorenzo, F., Dell'Era, V., Cosseddu, M., Alberici, A., Caratozzolo, S., Cotelli, M.S., Borroni, B., Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia (2017) Neurology, 89, pp. 665-672; Benussi, A., Padovani, A., Borroni, B., Phenotypic heterogeneity of monogenic frontotemporal dementia (2015) Front. Aging Neurosci., 7, p. 171; Burrell, J.R., Hornberger, M., Vucic, S., Kiernan, M.C., Hodges, J.R., Apraxia and motor dysfunction in corticobasal syndrome (2014) PLoS One, 9, p. e92944; Burrell, J.R., Kiernan, M.C., Vucic, S., Hodges, J.R., Motor Neuron dysfunction in frontotemporal dementia (2011) Brain, 134, pp. 2582-2594; Ernst, T., Chang, L., Melchor, R., Mehringer, C.M., Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H-1 MR spectroscopy (1997) Radiology, 203, pp. 829-836; Farokhian, F., Beheshti, I., Sone, D., Matsuda, H., Comparing CAT12 and VBM8 for detecting brain morphological abnormalities in temporal lobe epilepsy (2017) Front. Neurol., 8, p. 428; Ferrer, I., Neurons and their dendrites in frontotemporal dementia (1999) Dement Geriatr. Cogn. Disord., 10, pp. 55-60; Frasson, E., Bertolasi, L., Bertasi, V., Fusina, S., Bartolomei, L., Vicentini, S., Rizzuto, N., Priori, A., Paired transcranial magnetic stimulation for the early diagnosis of corticobasal degeneration (2003) Clin. Neurophysiol., 114, pp. 272-278; Galimberti, D., Fumagalli, G.G., Fenoglio, C., Cioffi, S.M.G., Arighi, A., Serpente, M., Borroni, B., Scarpini, E., Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study (2018) Neurobiol. Aging, 62. , 245.e9–245.e12; Gazzina, S., Benussi, A., Premi, E., Paternicò, D., Cristillo, V., Dell'Era, V., Cosseddu, M., Borroni, B., Neuroanatomical correlates of transcranial magnetic stimulation in presymptomatic granulin mutation carriers (2018) Brain Topogr., 31, pp. 488-497; Geevasinga, N., Menon, P., Nicholson, G.A., Ng, K., Howells, J., Kril, J.J., Yiannikas, C., Vucic, S., Cortical function in asymptomatic carriers and patients with C9orf72Amyotrophic lateral sclerosis (2015) JAMA Neurol., 72, p. 1268; Geschwind, D.H., Robidoux, J., Alarcón, M., Miller, B.L., Wilhelmsen, K.C., Cummings, J.L., Nasreddine, Z.S., Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia (2001) Ann. Neurol., 50, pp. 741-746; Ghidoni, R., Benussi, L., Glionna, M., Franzoni, M., Binetti, G., Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration (2008) Neurology, 71, pp. 1235-1239; Ghidoni, R., Stoppani, E., Rossi, G., Piccoli, E., Albertini, V., Paterlini, A., Glionna, M., Benussi, L., Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study (2012) Neurodegener. Dis., 9, pp. 121-127; Gorno-Tempini, M.L., Hillis, A.E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S.F., Ogar, J.M., Grossman, M., Classification of primary progressive aphasia and its variants (2011) Neurology, 76, pp. 1006-1014; Hughes, L.E., Ghosh, B.C.P., Rowe, J.B., Reorganisation of brain networks in frontotemporal dementia and progressive supranuclear palsy (2013) Neuroimage Clin., 2, pp. 459-468; Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Marsden, C.D., Corticocortical inhibition in human motor cortex (1993) J. Physiol., 471, pp. 501-519; Kurth, F., Gaser, C., Luders, E., A 12-step user guide for analyzing voxel-wise gray matter asymmetries in statistical parametric mapping (SPM) (2015) Nat. Protoc., 10, pp. 293-304; Le Ber, I., Camuzat, A., Hannequin, D., Pasquier, F., Guedj, E., Rovelet-Lecrux, A., Hahn-Barma, V., Brice, A., Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study (2008) Brain, 131, pp. 732-746; Levenga, J., Krishnamurthy, P., Rajamohamedsait, H., Wong, H., Franke, T.F., Cain, P., Sigurdsson, E.M., Hoeffer, C.A., Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments (2013) Acta Neuropathol. Commun., 1, p. 34; Meeter, L.H.H., Patzke, H., Loewen, G., Dopper, E.G.P., Pijnenburg, Y.A.L., van Minkelen, R., van Swieten, J.C., Progranulin levels in plasma and cerebrospinal fluid in granulin mutation carriers (2016) Dement Geriatr. Cogn. Disord. Extra, 6, pp. 330-340; Murley, A.G., Rowe, J.B., Neurotransmitter deficits from frontotemporal lobar degeneration (2018) Brain, 141, pp. 1263-1285; Pal, P.K., Gunraj, C.A., Li, J.Y., Lang, A.E., Chen, R., Reduced intracortical and interhemispheric inhibitions in corticobasal syndrome (2008) J. Clin. Neurophysiol., 25, pp. 304-312; Paternicò, D., Premi, E., Gazzina, S., Cosseddu, M., Alberici, A., Archetti, S., Cotelli, M.S., Borroni, B., White matter hyperintensities characterize monogenic frontotemporal dementia with granulin mutations (2016) Neurobiol. Aging, 38, pp. 176-180; Pietroboni, A.M., Fumagalli, G.G., Ghezzi, L., Fenoglio, C., Cortini, F., Serpente, M., Cantoni, C., Scarpini, E., Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred (2011) J. Alzheimers Dis., 24, pp. 253-259; Procter, A.W., Qurne, M., Francis, P.T., Neurochemical features of frontotemporal dementia (1999) Dement. Geriatr. Cogn. 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PY - 2019

Y1 - 2019

N2 - Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms. © 2019 Elsevier Inc.

AB - Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms. © 2019 Elsevier Inc.

KW - Biomarkers

KW - C9orf72

KW - Frontotemporal dementia

KW - GRN

KW - Transcranial magnetic stimulation

KW - adult

KW - Article

KW - brain atrophy

KW - brain tissue

KW - C9orf72 gene

KW - cognitive defect

KW - female

KW - follow up

KW - frontotemporal dementia

KW - gene

KW - gene mutation

KW - GRN gene

KW - heterozygote

KW - human

KW - major clinical study

KW - male

KW - middle aged

KW - neurotransmission

KW - priority journal

KW - tissue structure

KW - white matter lesion

KW - aged

KW - atrophy

KW - brain

KW - genetics

KW - mutation

KW - pathology

KW - pathophysiology

KW - psychology

KW - transcranial magnetic stimulation

KW - biological marker

KW - C9orf72 protein, human

KW - fungichromin

KW - GRN protein, human

KW - guanine nucleotide exchange C9orf72

KW - macrolide

KW - polyene

KW - Adult

KW - Aged

KW - Atrophy

KW - Brain

KW - C9orf72 Protein

KW - Female

KW - Frontotemporal Dementia

KW - Heterozygote

KW - Humans

KW - Macrolides

KW - Male

KW - Middle Aged

KW - Mutation

KW - Polyenes

KW - Progranulins

KW - Transcranial Magnetic Stimulation

U2 - 10.1016/j.neurobiolaging.2018.12.018

DO - 10.1016/j.neurobiolaging.2018.12.018

M3 - Article

VL - 76

SP - 133

EP - 140

JO - Neurobiol. Aging

JF - Neurobiol. Aging

SN - 0197-4580

ER -

Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia: Neurobiology of Aging

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