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Cited by 116Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsFunctional Brain Connectivity Studies

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Involvement of the precuneus/posterior cingulate cortex is significant for the development of Alzheimer’s disease: a pet (THK5351, PiB) and resting fMRI study.

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Yokoi, Takamasa, Watanabe, Hirohisa, Yamaguchi, Hiroshi, Bagarinao, Epifanio, Masuda, Michihito, Imai, Kazunori, Ogura, Aya, Ohdake, Reiko, Kawabata, Kazuya, Hara, Kazuhiro, Riku, Yuichi, Ishigaki, Shinsuke, Katsuno, Masahisa, Miyao, Shinichi, Kato, Katsuhiko, Naganawa, Shinji, Harada, Ryuichi, Okamura, Nobuyuki, Yanai, Kazuhiko, Yoshida, Mari, Sobue, Gen·2018·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2018.00304PMC PMC6182068
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Abstract

Background: Imaging studies in Alzheimer’s disease have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption, and cognitive decline. We compared the spatial retention patterns of 18F-THK5351 and resting state network disruption in patients with early Alzheimer’s disease and healthy controls. Methods: We enrolled 23 11C-Pittsburgh compound B (PiB)-positive patients with early Alzheimer’s disease and 24 11C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and 18F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in Alzheimer’s disease and healthy controls. Findings: SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex, right and left dorsolateral prefrontal cortex which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating Alzheimer’s disease from healthy controls. There was a significant relationship between the intensity of the 18F-THK5351 covariation pattern and cognitive scores in Alzheimer’s disease. The spatial patterns of 18F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the precuneus/posterior cingulate cortex network. Seed-based connectivity analysis from the precuneus/posterior cingulate cortex showed significant decrease in connectivity over widespread brain regions in Alzheimer’s disease patients. An evaluation of an autopsied Alzheimer’s disease patient with Braak V showed that 18F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B and astrogliosis in the precuneus/posterior cingulate cortex. Interpretation: We identified an Alzheimer’s disease-specific spatial pattern of 18F-THK5351 retention in the precuneus/posterior cingulate cortex, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in Alzheimer’s disease.

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Figures

Figure 1 Decreased gray matter volume in early Alzheimer’s disease (AD). The hot spots indicate sites where gray matter’s volume significantly decreased in AD (family-wise error cluster level correction (FWEc) at p < 0.05).
Figure 1 Decreased gray matter volume in early Alzheimer’s disease (AD). The hot spots indicate sites where gray matter’s volume significantly decreased in AD (family-wise error cluster level correction (FWEc) at p < 0.05).CC BY · PubMed Central
Figure 2 Spatial distributions of THK5351 covariation pattern using scaled subprofile modeling/principal component analysis (SSM/PCA). AD-related THK5351 distribution pattern (ADRTP; A): SSM/PCA identified a principal component 1 (PC1), which indicates AD-related THK5351 covariation pattern (ADRTP). The hot areas represent PC1. Common distribution pattern of THK5351 between healthy control (HC) and AD (B): SSM/PCA identified PC2, which indicates that the accumulation sites common to early AD patients and HC. The hot areas represent PC2.
Figure 2 Spatial distributions of THK5351 covariation pattern using scaled subprofile modeling/principal component analysis (SSM/PCA). AD-related THK5351 distribution pattern (ADRTP; A): SSM/PCA identified a principal component 1 (PC1), which indicates AD-related THK5351 covariation pattern (ADRTP). The hot areas represent PC1. Common distribution pattern of THK5351 between healthy control (HC) and AD (B): SSM/PCA identified PC2, which indicates that the accumulation sites common to early AD patients and HC. The hot areas represent PC2.CC BY · PubMed Central
Figure 3 PC1 and subject score, ADRTP. Panel (A) shows ADRTP. This figure indicates the ratio of each PC with the total subject voxel variance of data. Panel (B) shows subject score relative to PC1 which showed 82.6% sensitivity and 79.1% specificity in discriminating AD from HC. Panel (C) shows the relationship between the Addenbrooke’s Cognitive Examination Revised (ACE-R) and the ADRTP subject scores of early AD patients, Clinical Dementia Rating 1.0 (CDR 1.0) and CDR 0.5. Blue triangles indicate CDR0.5, and green circles indicate CDR1.0. Panel (D) represents the relationship between ACE-R and the ADRTP subject scores of early AD patients, CDR1.0. Green circles indicate CDR1.0.
Figure 3 PC1 and subject score, ADRTP. Panel (A) shows ADRTP. This figure indicates the ratio of each PC with the total subject voxel variance of data. Panel (B) shows subject score relative to PC1 which showed 82.6% sensitivity and 79.1% specificity in discriminating AD from HC. Panel (C) shows the relationship between the Addenbrooke’s Cognitive Examination Revised (ACE-R) and the ADRTP subject scores of early AD patients, Clinical Dementia Rating 1.0 (CDR 1.0) and CDR 0.5. Blue triangles indicate CDR0.5, and green circles indicate CDR1.0. Panel (D) represents the relationship between ACE-R and the ADRTP subject scores of early AD patients, CDR1.0. Green circles indicate CDR1.0.CC BY · PubMed Central
Figure 4 Relationship between THK5351 retention and canonical resting state networks (RSNs). Panel (A) shows the similarity of the THK5351 retention pattern and each canonical RSN. Panel (B) is the result of independent component analysis (ICA). The green areas indicate each canonical network, and the blue areas indicate decreased connectivity, as identified by ICA of resting-state functional MRI data (FWE at p < 0.05).
Figure 4 Relationship between THK5351 retention and canonical resting state networks (RSNs). Panel (A) shows the similarity of the THK5351 retention pattern and each canonical RSN. Panel (B) is the result of independent component analysis (ICA). The green areas indicate each canonical network, and the blue areas indicate decreased connectivity, as identified by ICA of resting-state functional MRI data (FWE at p < 0.05).CC BY · PubMed Central
Figure 5 Seed-based connectivity of the precuneus/posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC). This figure shows seed-based connectivity analysis from ROIs located in the precuneus/PCC (A–C), and DLPFC (D–F). (A,D) HC (B,E) early AD; (C) intrinsic connectivity of precuneus/PCC significantly decreased to the hot areas (FWEc p < 0.05, cluster defining threshold, p = 0.001, cluster size = 170). (F) Intrinsic connectivity of DLPFC significantly decreased to the hot areas (FWEc p < 0.05, cluster defining threshold, p = 0.001, cluster size = 220).
Figure 5 Seed-based connectivity of the precuneus/posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC). This figure shows seed-based connectivity analysis from ROIs located in the precuneus/PCC (A–C), and DLPFC (D–F). (A,D) HC (B,E) early AD; (C) intrinsic connectivity of precuneus/PCC significantly decreased to the hot areas (FWEc p < 0.05, cluster defining threshold, p = 0.001, cluster size = 170). (F) Intrinsic connectivity of DLPFC significantly decreased to the hot areas (FWEc p < 0.05, cluster defining threshold, p = 0.001, cluster size = 220).CC BY · PubMed Central
Figure 6 Comparative study among THK5351, tau, monoamine oxidase-B (MAO-B) and astrogliosis findings of the precuneus/posterior cingulate gyrus (PCC) and parahippocampal gyrus in autopsy cases with AD. Panel (A) shows the results of 3H-THK5351 autoradiography. In vitro autoradiogram of 3H-THK5351 in brain sections of the parahippocampal gyrus and precuneus/PCC from an 81-year-old control (Braak II) and an 87-year-old AD patient (Braak V) in the absence and presence of the MAO-B inhibitor lazabemide. 3H-THK5351 bindings in the parahippocampal gyrus and precuneus/PCC was more evident in a patient with Braak’s stage V (Case 1) than in a healthy control with Braak’s stage II (Control 1). After treatment with lazabemide (+lazabemide) as a MAO-B inhibitor, 3H-THK5351 bindings remained detectable in the parahippocampus and precuneus/PCC in Case 1 with Braak’s stage V but was scarce in Control 1 with Braak’s stage II. Panel (B) demonstrates the results of immunostaining of tau, MAO-B, and glial fibrillary acidic protein (GFAP). Anti-tau antibody (AT8), anti-MAO-B antibody and GFAP immunohistochemistry revealed marked immunostaining in an AD case, compared to a healthy control. Tau, MAO-B and GFAP accumulation were more evident in Braak’s stage V than in Braak’s stage II patients. Panel (C) is the result of double immunofluorescence for GFAP and MAO-B. Tissue sections double stained with anti-MAO-B antibody and anti-GFAP antibody in a Braak’s stage V parahippocampal gyrus, and the PCC/precuneus. GFAP and MAO-B were colocalized in the astrocyte. Anti-GFAP immunohistochemistry diffusely labeled the cytoplasm and processed of astrocytes, which contained MAO-B immunopositive granules.
Figure 6 Comparative study among THK5351, tau, monoamine oxidase-B (MAO-B) and astrogliosis findings of the precuneus/posterior cingulate gyrus (PCC) and parahippocampal gyrus in autopsy cases with AD. Panel (A) shows the results of 3H-THK5351 autoradiography. In vitro autoradiogram of 3H-THK5351 in brain sections of the parahippocampal gyrus and precuneus/PCC from an 81-year-old control (Braak II) and an 87-year-old AD patient (Braak V) in the absence and presence of the MAO-B inhibitor lazabemide. 3H-THK5351 bindings in the parahippocampal gyrus and precuneus/PCC was more evident in a patient with Braak’s stage V (Case 1) than in a healthy control with Braak’s stage II (Control 1). After treatment with lazabemide (+lazabemide) as a MAO-B inhibitor, 3H-THK5351 bindings remained detectable in the parahippocampus and precuneus/PCC in Case 1 with Braak’s stage V but was scarce in Control 1 with Braak’s stage II. Panel (B) demonstrates the results of immunostaining of tau, MAO-B, and glial fibrillary acidic protein (GFAP). Anti-tau antibody (AT8), anti-MAO-B antibody and GFAP immunohistochemistry revealed marked immunostaining in an AD case, compared to a healthy control. Tau, MAO-B and GFAP accumulation were more evident in Braak’s stage V than in Braak’s stage II patients. Panel (C) is the result of double immunofluorescence for GFAP and MAO-B. Tissue sections double stained with anti-MAO-B antibody and anti-GFAP antibody in a Braak’s stage V parahippocampal gyrus, and the PCC/precuneus. GFAP and MAO-B were colocalized in the astrocyte. Anti-GFAP immunohistochemistry diffusely labeled the cytoplasm and processed of astrocytes, which contained MAO-B immunopositive granules.CC BY · PubMed Central

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Authors
Yokoi, T., Watanabe, H., Yamaguchi, H., Bagarinao, E., Masuda, M., Imai, K., Ogura, A., Ohdake, R., Kawabata, K., Hara, K., Riku, Y., Ishigaki, S., Katsuno, M., Miyao, S., Kato, K., Naganawa, S., Harada, R., Okamura, N., Yanai, K., Yoshida, M., & Sobue, G.
Affiliations
  • Nagoya University (JP)
  • Brain & Mind Research Center, Nagoya University (JP)
  • Meitetsu Hospital (JP)
  • Tohoku University (JP)
  • Tohoku Medical and Pharmaceutical University (JP)
  • Aichi Medical University (JP)
Corresponding author
Sobue, Gen
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2018-10-05
Volume
10
Pages
304-304
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2018.00304
PMC
PMC6182068
OpenAlex
W2895455599
Cited by
116
References
73
Citations by year
2026: 5 · 2025: 20 · 2024: 18 · 2023: 14 · 2022: 24 · 2021: 15 · 2020: 8 · 2019: 10 · 2018: 1
FWCI
6.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
  • Nagoya University Repository (NAGOYA Repository) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (26117002, 80569781)
  • Ministry of Health, Labour and Welfare
  • Japan Society for the Promotion of Science (18K07367, 18H02771, 26117002, 26117001, 26117004)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
Alzheimer's disease, precuneus, posterior cingulate cortex, 18F-THK5351, tau PET, [11C]PIB, resting-state functional connectivity, intrinsic functional connectivity, seed-based functional connectivity, early Alzheimer's disease, tau deposition, dorsolateral prefrontal cortex, Braak staging, astrocyte activation

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