Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers

Qin Chen, Bradley F Boeve, Nirubol Tosakulwong, Timothy Lesnick, Danielle Brushaber, Christina Dheel, Julie A Fields, Leah Forsberg, Ralitza M Gavrilova, Debra Gearhart, Dana Haley, Jeffrey L. Gunter, Jonathan Graff-Radford, David T Jones, David S Knopman, Neill R Graff Radford, Ruth Kraft, Maria Isabel Lapid, Rosa V Rademakers, Jeremy SyrjanenZbigniew K Wszolek, Howie Rosen, Adam L. Boxer, Kejal M Kantarci

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Abstract

To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. Methods We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. Results Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/ creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. Conclusion Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

Original languageEnglish (US)
Pages (from-to)E758-E765
JournalNeurology
Volume93
Issue number8
DOIs
StatePublished - Jan 1 2019

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Microtubule-Associated Proteins
Frontal Lobe
Magnetic Resonance Spectroscopy
Creatine
Inositol
Mutation
Frontotemporal Lobar Degeneration
Dementia
Frontotemporal Dementia
Age of Onset
N-acetylaspartate
Proton Magnetic Resonance Spectroscopy
Linear Models
Biomarkers
Demography

ASJC Scopus subject areas

  • Clinical Neurology

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Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers. / Chen, Qin; Boeve, Bradley F; Tosakulwong, Nirubol; Lesnick, Timothy; Brushaber, Danielle; Dheel, Christina; Fields, Julie A; Forsberg, Leah; Gavrilova, Ralitza M; Gearhart, Debra; Haley, Dana; Gunter, Jeffrey L.; Graff-Radford, Jonathan; Jones, David T; Knopman, David S; Graff Radford, Neill R; Kraft, Ruth; Lapid, Maria Isabel; Rademakers, Rosa V; Syrjanen, Jeremy; Wszolek, Zbigniew K; Rosen, Howie; Boxer, Adam L.; Kantarci, Kejal M.

In: Neurology, Vol. 93, No. 8, 01.01.2019, p. E758-E765.

Research output: Contribution to journalArticle

Chen, Qin ; Boeve, Bradley F ; Tosakulwong, Nirubol ; Lesnick, Timothy ; Brushaber, Danielle ; Dheel, Christina ; Fields, Julie A ; Forsberg, Leah ; Gavrilova, Ralitza M ; Gearhart, Debra ; Haley, Dana ; Gunter, Jeffrey L. ; Graff-Radford, Jonathan ; Jones, David T ; Knopman, David S ; Graff Radford, Neill R ; Kraft, Ruth ; Lapid, Maria Isabel ; Rademakers, Rosa V ; Syrjanen, Jeremy ; Wszolek, Zbigniew K ; Rosen, Howie ; Boxer, Adam L. ; Kantarci, Kejal M. / Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers. In: Neurology. 2019 ; Vol. 93, No. 8. pp. E758-E765.
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abstract = "To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. Methods We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. Results Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/ creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. Conclusion Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.",
author = "Qin Chen and Boeve, {Bradley F} and Nirubol Tosakulwong and Timothy Lesnick and Danielle Brushaber and Christina Dheel and Fields, {Julie A} and Leah Forsberg and Gavrilova, {Ralitza M} and Debra Gearhart and Dana Haley and Gunter, {Jeffrey L.} and Jonathan Graff-Radford and Jones, {David T} and Knopman, {David S} and {Graff Radford}, {Neill R} and Ruth Kraft and Lapid, {Maria Isabel} and Rademakers, {Rosa V} and Jeremy Syrjanen and Wszolek, {Zbigniew K} and Howie Rosen and Boxer, {Adam L.} and Kantarci, {Kejal M}",
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T1 - Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers

AU - Chen, Qin

AU - Boeve, Bradley F

AU - Tosakulwong, Nirubol

AU - Lesnick, Timothy

AU - Brushaber, Danielle

AU - Dheel, Christina

AU - Fields, Julie A

AU - Forsberg, Leah

AU - Gavrilova, Ralitza M

AU - Gearhart, Debra

AU - Haley, Dana

AU - Gunter, Jeffrey L.

AU - Graff-Radford, Jonathan

AU - Jones, David T

AU - Knopman, David S

AU - Graff Radford, Neill R

AU - Kraft, Ruth

AU - Lapid, Maria Isabel

AU - Rademakers, Rosa V

AU - Syrjanen, Jeremy

AU - Wszolek, Zbigniew K

AU - Rosen, Howie

AU - Boxer, Adam L.

AU - Kantarci, Kejal M

PY - 2019/1/1

Y1 - 2019/1/1

N2 - To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. Methods We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. Results Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/ creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. Conclusion Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

AB - To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. Methods We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. Results Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/ creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. Conclusion Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

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