Clinicopathologic and <sup>11</sup>C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum

Melissa E. Murray, Val J. Lowe, Neill R. Graff-Radford, Amanda M. Liesinger, Ashley Cannon, Scott A. Przybelski, Bhupendra Rawal, Joseph E. Parisi, Ronald C. Petersen, Kejal Kantarci, Owen A. Ross, Ranjan Duara, David S. Knopman, Clifford R. Jack, Dennis W. Dickson

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing-Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing-Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem <sup>11</sup>C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of <sup>11</sup>C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. <sup>11</sup>C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical <sup>11</sup>C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted <sup>11</sup>C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to <sup>11</sup>C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with <sup>11</sup>C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The <sup>11</sup>C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

Original languageEnglish (US)
Pages (from-to)1370-1381
Number of pages12
JournalBrain
Volume138
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

Fingerprint

Amyloid
Alzheimer Disease
Cerebral Amyloid Angiopathy
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Pittsburgh
Alzheimer's Disease
Autopsy
Guidelines
Amyloid Plaques
Brain
Age of Onset
Positron-Emission Tomography
Cerebellum
Cerebrospinal Fluid
Microscopy
Biomarkers

Keywords

  • Alzheimer's disease
  • Braak tangle stage
  • neuropathology
  • Pittsburgh compound B
  • Thal amyloid phase

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Murray, M. E., Lowe, V. J., Graff-Radford, N. R., Liesinger, A. M., Cannon, A., Przybelski, S. A., ... Dickson, D. W. (2015). Clinicopathologic and <sup>11</sup>C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. Brain, 138(5), 1370-1381. https://doi.org/10.1093/brain/awv050

Clinicopathologic and <sup>11</sup>C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. / Murray, Melissa E.; Lowe, Val J.; Graff-Radford, Neill R.; Liesinger, Amanda M.; Cannon, Ashley; Przybelski, Scott A.; Rawal, Bhupendra; Parisi, Joseph E.; Petersen, Ronald C.; Kantarci, Kejal; Ross, Owen A.; Duara, Ranjan; Knopman, David S.; Jack, Clifford R.; Dickson, Dennis W.

In: Brain, Vol. 138, No. 5, 01.05.2015, p. 1370-1381.

Research output: Contribution to journalArticle

Murray, ME, Lowe, VJ, Graff-Radford, NR, Liesinger, AM, Cannon, A, Przybelski, SA, Rawal, B, Parisi, JE, Petersen, RC, Kantarci, K, Ross, OA, Duara, R, Knopman, DS, Jack, CR & Dickson, DW 2015, 'Clinicopathologic and <sup>11</sup>C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum', Brain, vol. 138, no. 5, pp. 1370-1381. https://doi.org/10.1093/brain/awv050
Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA et al. Clinicopathologic and <sup>11</sup>C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. Brain. 2015 May 1;138(5):1370-1381. https://doi.org/10.1093/brain/awv050
Murray, Melissa E. ; Lowe, Val J. ; Graff-Radford, Neill R. ; Liesinger, Amanda M. ; Cannon, Ashley ; Przybelski, Scott A. ; Rawal, Bhupendra ; Parisi, Joseph E. ; Petersen, Ronald C. ; Kantarci, Kejal ; Ross, Owen A. ; Duara, Ranjan ; Knopman, David S. ; Jack, Clifford R. ; Dickson, Dennis W. / Clinicopathologic and <sup>11</sup>C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. In: Brain. 2015 ; Vol. 138, No. 5. pp. 1370-1381.
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AU - Murray, Melissa E.

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AU - Przybelski, Scott A.

AU - Rawal, Bhupendra

AU - Parisi, Joseph E.

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AU - Ross, Owen A.

AU - Duara, Ranjan

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AU - Dickson, Dennis W.

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N2 - Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing-Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing-Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2.

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