FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis

Hugo Botha; William G. Mantyh; Melissa E. Murray; David S. Knopman; Scott A. Przybelski; Heather J. Wiste; Jonathan Graff-Radford; Keith A. Josephs; Christopher G. Schwarz; Walter K. Kremers; Bradley F. Boeve; Ronald C. Petersen; Mary M. Machulda; Joseph E. Parisi; Dennis W. Dickson; Val Lowe; Clifford R. Jack; David T. Jones

doi:10.1093/brain/awy049

FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis

Hugo Botha, William G. Mantyh, Melissa E. Murray, David S. Knopman, Scott A. Przybelski, Heather J. Wiste, Jonathan Graff-Radford, Keith A. Josephs, Christopher G. Schwarz, Walter K. Kremers, Bradley F. Boeve, Ronald C. Petersen, Mary M. Machulda, Joseph E. Parisi, Dennis W. Dickson, Val Lowe, Clifford R. Jack, David T. Jones

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

61 Scopus citations

Abstract

Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis May account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of ¹⁸ F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating 4 0) with amnestic presentations 5 75 years who had MRI and PET imaging with ¹⁸ F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem ¹⁸ F-FDG-PET were screened and those with TDP-43-negative Alzheimer’s disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer’s disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and May serve as a biomarker for hippocampal sclerosis.

Original language	English (US)
Pages (from-to)	1201-1217
Number of pages	17
Journal	Brain
Volume	141
Issue number	4
DOIs	https://doi.org/10.1093/brain/awy049
State	Published - Apr 2018
Externally published	Yes

Bibliographical note

Funding Information:
This research was supported by NIH grants P50 AG016574, U01 AG006786, R01 AG11378, R01 AG041851, R01 AG011378, RO1 AG034676, R01 AG37491 and RO1 NS097495; the Robert Wood Johnson Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Liston Family Foundation; the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program; the GHR Foundation; Foundation Dr. Corinne Schuler (Geneva, Switzerland); the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, and the Mayo Foundation for Medical Education and Research.

Funding Information:
This research was supported by NIH grants P50 AG016574, U01 AG006786, R01 AG11378, R01 AG041851, R01 AG011378, RO1 AG034676, R01 AG37491 and RO1 NS097495; the Robert Wood Johnson Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Liston Family Foundation; the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program; the GHR Foundation; Foundation Dr. Corinne Schuler (Geneva, Switzerland); the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, and the Mayo Foundation for Medical Education and Research. We would like to greatly thank AVID Radiopharmaceuticals, Inc., for their support in supplying AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work.

Publisher Copyright:
© The Author(s) (2018).

Keywords

Alzheimer’s disease
FDG-PET
Hippocampal sclerosis
TDP-43
Tau-PET

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Botha, H., Mantyh, W. G., Murray, M. E., Knopman, D. S., Przybelski, S. A., Wiste, H. J., Graff-Radford, J., Josephs, K. A., Schwarz, C. G., Kremers, W. K., Boeve, B. F., Petersen, R. C., Machulda, M. M., Parisi, J. E., Dickson, D. W., Lowe, V., Jack, C. R., & Jones, D. T. (2018). FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis. Brain, 141(4), 1201-1217. https://doi.org/10.1093/brain/awy049

Botha, H, Mantyh, WG, Murray, ME, Knopman, DS, Przybelski, SA, Wiste, HJ, Graff-Radford, J, Josephs, KA, Schwarz, CG, Kremers, WK, Boeve, BF, Petersen, RC, Machulda, MM, Parisi, JE, Dickson, DW, Lowe, V, Jack, CR & Jones, DT 2018, 'FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis', Brain, vol. 141, no. 4, pp. 1201-1217. https://doi.org/10.1093/brain/awy049

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title = "FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis",

abstract = " Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis May account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18 F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating 4 0) with amnestic presentations 5 75 years who had MRI and PET imaging with 18 F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18 F-FDG-PET were screened and those with TDP-43-negative Alzheimer{\textquoteright}s disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer{\textquoteright}s disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and May serve as a biomarker for hippocampal sclerosis.",

keywords = "Alzheimer{\textquoteright}s disease, FDG-PET, Hippocampal sclerosis, TDP-43, Tau-PET",

author = "Hugo Botha and Mantyh, {William G.} and Murray, {Melissa E.} and Knopman, {David S.} and Przybelski, {Scott A.} and Wiste, {Heather J.} and Jonathan Graff-Radford and Josephs, {Keith A.} and Schwarz, {Christopher G.} and Kremers, {Walter K.} and Boeve, {Bradley F.} and Petersen, {Ronald C.} and Machulda, {Mary M.} and Parisi, {Joseph E.} and Dickson, {Dennis W.} and Val Lowe and Jack, {Clifford R.} and Jones, {David T.}",

note = "Funding Information: This research was supported by NIH grants P50 AG016574, U01 AG006786, R01 AG11378, R01 AG041851, R01 AG011378, RO1 AG034676, R01 AG37491 and RO1 NS097495; the Robert Wood Johnson Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Liston Family Foundation; the Robert H. and Clarice Smith and Abigail van Buren Alzheimer{\textquoteright}s Disease Research Program; the GHR Foundation; Foundation Dr. Corinne Schuler (Geneva, Switzerland); the Alexander Family Alzheimer{\textquoteright}s Disease Research Professorship of the Mayo Clinic, and the Mayo Foundation for Medical Education and Research. Funding Information: This research was supported by NIH grants P50 AG016574, U01 AG006786, R01 AG11378, R01 AG041851, R01 AG011378, RO1 AG034676, R01 AG37491 and RO1 NS097495; the Robert Wood Johnson Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Liston Family Foundation; the Robert H. and Clarice Smith and Abigail van Buren Alzheimer{\textquoteright}s Disease Research Program; the GHR Foundation; Foundation Dr. Corinne Schuler (Geneva, Switzerland); the Alexander Family Alzheimer{\textquoteright}s Disease Research Professorship of the Mayo Clinic, and the Mayo Foundation for Medical Education and Research. We would like to greatly thank AVID Radiopharmaceuticals, Inc., for their support in supplying AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work. Publisher Copyright: {\textcopyright} The Author(s) (2018).",

year = "2018",

month = apr,

doi = "10.1093/brain/awy049",

language = "English (US)",

volume = "141",

pages = "1201--1217",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "4",

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TY - JOUR

T1 - FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis

AU - Botha, Hugo

AU - Mantyh, William G.

AU - Murray, Melissa E.

AU - Knopman, David S.

AU - Przybelski, Scott A.

AU - Wiste, Heather J.

AU - Graff-Radford, Jonathan

AU - Josephs, Keith A.

AU - Schwarz, Christopher G.

AU - Kremers, Walter K.

AU - Boeve, Bradley F.

AU - Petersen, Ronald C.

AU - Machulda, Mary M.

AU - Parisi, Joseph E.

AU - Dickson, Dennis W.

AU - Lowe, Val

AU - Jack, Clifford R.

AU - Jones, David T.

N1 - Funding Information: This research was supported by NIH grants P50 AG016574, U01 AG006786, R01 AG11378, R01 AG041851, R01 AG011378, RO1 AG034676, R01 AG37491 and RO1 NS097495; the Robert Wood Johnson Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Liston Family Foundation; the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program; the GHR Foundation; Foundation Dr. Corinne Schuler (Geneva, Switzerland); the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, and the Mayo Foundation for Medical Education and Research. Funding Information: This research was supported by NIH grants P50 AG016574, U01 AG006786, R01 AG11378, R01 AG041851, R01 AG011378, RO1 AG034676, R01 AG37491 and RO1 NS097495; the Robert Wood Johnson Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Liston Family Foundation; the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program; the GHR Foundation; Foundation Dr. Corinne Schuler (Geneva, Switzerland); the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, and the Mayo Foundation for Medical Education and Research. We would like to greatly thank AVID Radiopharmaceuticals, Inc., for their support in supplying AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work. Publisher Copyright: © The Author(s) (2018).

PY - 2018/4

Y1 - 2018/4

N2 - Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis May account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18 F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating 4 0) with amnestic presentations 5 75 years who had MRI and PET imaging with 18 F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18 F-FDG-PET were screened and those with TDP-43-negative Alzheimer’s disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer’s disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and May serve as a biomarker for hippocampal sclerosis.

AB - Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis May account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18 F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating 4 0) with amnestic presentations 5 75 years who had MRI and PET imaging with 18 F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18 F-FDG-PET were screened and those with TDP-43-negative Alzheimer’s disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer’s disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and May serve as a biomarker for hippocampal sclerosis.

KW - Alzheimer’s disease

KW - FDG-PET

KW - Hippocampal sclerosis

KW - TDP-43

KW - Tau-PET

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JO - Brain

JF - Brain

IS - 4

ER -

FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis

Abstract

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