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Cited by 183Functional Brain Connectivity StudiesDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

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Gradual Disturbances of the Amplitude of Low-Frequency Fluctuations (ALFF) and Fractional ALFF in Alzheimer Spectrum

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Yang, Liu, Yan, Yan, Wang, Yonghao, Hu, Xiaochen, Lu, Jie, Chan, Piu, Yan, Tianyi, Han, Ying·2018·Frontiers in Neuroscience
DOI 10.3389/fnins.2018.00975PMC PMC6306691
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Abstract

Background: Alzheimer’s disease (AD) is a common neurodegenerative disease in which the brain undergoes alterations for decades before symptoms become obvious. Subjective cognitive decline (SCD) have self-complain of persistent decline in cognitive function especially in memory but perform normally on standard neuropsychological tests. SCD with the presence of AD pathology is the transitional stage 2 of Alzheimer’s continuum, earlier than the prodromal stage, mild cognitive impairment (MCI), which seems to be the best target to research AD. In this study, we aimed to detect the transformational patterns of the intrinsic brain activity as the disease burden got heavy. Method: In this study, we enrolled 44 SCD, 55 amnestic MCI (aMCI), 47 AD dementia (d-AD) patients and 57 normal controls (NC) in total. A machine learning classification was utilized to detect identification accuracies between groups by using ALFF, fALFF, and fusing ALFF with fALFF features. Then, we measured the amplitude of the low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) levels in three frequency bands (classic: 0.01-0.1 Hz; slow-5: 0.01–0.027 Hz; and slow-4: 0.027–0.073 Hz) and compared alterations in patients with NC. Results: In the machine learning verification, the identification accuracy of SCD, aMCI, d-AD from NC was higher when fused ALFF and fALFF features (76.44%, 81.94%, and 91.83%, respectively) than only using ALFF or fALFF features. Several brain regions showed significant differences in ALFF/fALFF within these bands among four groups: brain regions presented decreasing trend of values, including the Cingulum_Mid_R (aal), bilateral inferior cerebellum lobe, bilateral precuneus, and the Cingulum_Ant_R (aal); increasing trend of values were detected in the Hippocampus_L (aal), Frontal_Mid_Orb_R (aal), Frontal_Sup_R (aal) and Paracentral_Lobule_R (aal) as disease progressed. The normalized ALFF/fALFF values of these features were significantly correlated with the neuropsychological test scores. Conclusions: This study revealed gradual disturbances in intrinsic brain activity as the disease progressed: the normal objective performance in SCD may be dependent on compensation; as disease advanced, the cognitive function gradually impaired and decompensated in aMCI, severer in d-AD. Our results indicated that the ALFF and fALFF may help detect the underlying pathological mechanism in AD continuum.

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Figures

FIGURE 1 Receiver operating characteristic (ROC) curve of ALFF, fALFF, and ALFF combined with fALFF. TPR, true positive rate; FPR, false positive rate; NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease.
FIGURE 1 Receiver operating characteristic (ROC) curve of ALFF, fALFF, and ALFF combined with fALFF. TPR, true positive rate; FPR, false positive rate; NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease.CC BY · PubMed Central
FIGURE 2 Significant differences of ALFF/fALFF among NC, SCD, aMCI, and d-AD under different frequency bands. The results were obtained by ANCOVA analysis adjusted with mean age, gender, education, mean GM volume and mean FD (P < 0.001, cluster level < 0.05, GRF correction) by DPABI_V3.0_171210.
FIGURE 2 Significant differences of ALFF/fALFF among NC, SCD, aMCI, and d-AD under different frequency bands. The results were obtained by ANCOVA analysis adjusted with mean age, gender, education, mean GM volume and mean FD (P < 0.001, cluster level < 0.05, GRF correction) by DPABI_V3.0_171210.CC BY · PubMed Central
FIGURE 3 Decreased ALFF and fALFF patterns tendency in patient groups. ∗ represents significant level P < 0.05, ∗∗ means significant level P < 0.01, and ∗∗∗ means significant level P < 0.001. L., left; R., right; R.PCUN, Precuneus_R (aal); R.Cere8, Cerebelum_8_R (aal); R.MCG, Cingulum_Mid_R (aal); L.PCUN, Precuneus_L (aal); R.ACG, Cingulum_Ant_R (aal). ALFF analysis in full band (0.01–0.1 Hz); a4, ALFF analysis in slow-4 band (0.027–0.073 Hz); a5, ALFF analysis in slow-5 band (0.01–0.027 Hz); f, fALFF analysis in full band; f4, fALFF analysis in slow-4 band; f5, fALFF analysis in slow-5 band.
FIGURE 3 Decreased ALFF and fALFF patterns tendency in patient groups. ∗ represents significant level P < 0.05, ∗∗ means significant level P < 0.01, and ∗∗∗ means significant level P < 0.001. L., left; R., right; R.PCUN, Precuneus_R (aal); R.Cere8, Cerebelum_8_R (aal); R.MCG, Cingulum_Mid_R (aal); L.PCUN, Precuneus_L (aal); R.ACG, Cingulum_Ant_R (aal). ALFF analysis in full band (0.01–0.1 Hz); a4, ALFF analysis in slow-4 band (0.027–0.073 Hz); a5, ALFF analysis in slow-5 band (0.01–0.027 Hz); f, fALFF analysis in full band; f4, fALFF analysis in slow-4 band; f5, fALFF analysis in slow-5 band.CC BY · PubMed Central
FIGURE 4 Increased ALFF and fALFF patterns tendency in patient groups. ∗ represents significant level P < 0.05, ∗∗ means significant level P < 0.01, and ∗∗∗ means significant level P < 0.001. L., left; R., right; L.HIP, Hippocampus_L (aal); R.ORBmid, Frontal_Mid_Orb_R (aal); R.FROsup, Frontal_Sup_R (aal); R.PCL, Paracentral_Lobule_R. a, ALFF analysis in full band (0.01–0.1 Hz); a4, ALFF analysis in slow-4 band (0.027–0.073 Hz); a5, ALFF analysis in slow-5 band (0.01–0.027 Hz); f, fALFF analysis in full band; f4, fALFF analysis in slow-4 band; f5, fALFF analysis in slow-5 band.
FIGURE 4 Increased ALFF and fALFF patterns tendency in patient groups. ∗ represents significant level P < 0.05, ∗∗ means significant level P < 0.01, and ∗∗∗ means significant level P < 0.001. L., left; R., right; L.HIP, Hippocampus_L (aal); R.ORBmid, Frontal_Mid_Orb_R (aal); R.FROsup, Frontal_Sup_R (aal); R.PCL, Paracentral_Lobule_R. a, ALFF analysis in full band (0.01–0.1 Hz); a4, ALFF analysis in slow-4 band (0.027–0.073 Hz); a5, ALFF analysis in slow-5 band (0.01–0.027 Hz); f, fALFF analysis in full band; f4, fALFF analysis in slow-4 band; f5, fALFF analysis in slow-5 band.CC BY · PubMed Central
FIGURE 5 The correlation between mALFF values of the Hippocampus_L (aal) and Cerebelum_8_R (aal) in full band and recognition of AVLT scores. The column 1 showed corresponding anatomic location of the left hippocampus and Cerebelum_8_R (aal) in the brain. The column 2 displayed significant differences of mALFF values of these two regions in full band among four groups obtained by post hoc test (Bonferroni correction, P < 0.05). ∗ represents significant level P < 0.05; ∗∗ means significant level P < 0.01; ∗∗∗ means significant level P < 0.001. The column 3 were scatter plots demonstrating the negative correlation between the Hippocampus_L (aal) and Cerebelum_8_R (aal) and recognition of AVLT scores (Bonferroni correction, P < 0.05/5). Corresponding correlation coefficient “r” and significant level “p” were marked. NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease; mALFF, the normalized amplitude of the low-frequency fluctuation; AVLT, the auditory verbal learning test.
FIGURE 5 The correlation between mALFF values of the Hippocampus_L (aal) and Cerebelum_8_R (aal) in full band and recognition of AVLT scores. The column 1 showed corresponding anatomic location of the left hippocampus and Cerebelum_8_R (aal) in the brain. The column 2 displayed significant differences of mALFF values of these two regions in full band among four groups obtained by post hoc test (Bonferroni correction, P < 0.05). ∗ represents significant level P < 0.05; ∗∗ means significant level P < 0.01; ∗∗∗ means significant level P < 0.001. The column 3 were scatter plots demonstrating the negative correlation between the Hippocampus_L (aal) and Cerebelum_8_R (aal) and recognition of AVLT scores (Bonferroni correction, P < 0.05/5). Corresponding correlation coefficient “r” and significant level “p” were marked. NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease; mALFF, the normalized amplitude of the low-frequency fluctuation; AVLT, the auditory verbal learning test.CC BY · PubMed Central
FIGURE 6 The correlation between mALFF values of the Cingulum_Mid_R (aal) in slow-4 band and delayed recall of AVLT/MMSE scores. The row 1, column 1 showed the corresponding anatomic location of the right median cingulate and paracingulate gyri in the brain. The row 1, column 2 displayed significant differences of mALFF values of this region in slow-4 band among four groups obtained by post hoc test (Bonferroni correction, P < 0.05). ∗∗∗ means significant level P < 0.001. The row 2 were scatter plots demonstrating the positive correlation between the right median cingulate and paracingulate gyri and delayed recall of AVLT/MMSE scores (Bonferroni correction, P < 0.05/5). Corresponding correlation coefficient “r” and significant level “p” were marked. NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease; AVLT, the auditory verbal learning test; MMSE, the Mini–Mental State Examination.
FIGURE 6 The correlation between mALFF values of the Cingulum_Mid_R (aal) in slow-4 band and delayed recall of AVLT/MMSE scores. The row 1, column 1 showed the corresponding anatomic location of the right median cingulate and paracingulate gyri in the brain. The row 1, column 2 displayed significant differences of mALFF values of this region in slow-4 band among four groups obtained by post hoc test (Bonferroni correction, P < 0.05). ∗∗∗ means significant level P < 0.001. The row 2 were scatter plots demonstrating the positive correlation between the right median cingulate and paracingulate gyri and delayed recall of AVLT/MMSE scores (Bonferroni correction, P < 0.05/5). Corresponding correlation coefficient “r” and significant level “p” were marked. NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease; AVLT, the auditory verbal learning test; MMSE, the Mini–Mental State Examination.CC BY · PubMed Central
FIGURE 7 The correlation between mALFF values of the Cerebelum_8_L (aal) in slow-5 band and delayed recall/recognition of AVLT scores. The row 1, column 1 showed the corresponding anatomic location of Cerebelum_8_L (aal) in the brain. The row 1, column 2 described corresponding group comparison obtained by post hoc test (Bonferroni correction, P < 0.05). ∗∗∗ means significant level P < 0.001. The row 2 showed negative correlation between this region and delayed recall/recognition of AVLT scores (Bonferroni correction, P < 0.05/5). Corresponding correlation coefficient “r” and significant level “p” were marked. NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease; AVLT, the auditory verbal learning test.
FIGURE 7 The correlation between mALFF values of the Cerebelum_8_L (aal) in slow-5 band and delayed recall/recognition of AVLT scores. The row 1, column 1 showed the corresponding anatomic location of Cerebelum_8_L (aal) in the brain. The row 1, column 2 described corresponding group comparison obtained by post hoc test (Bonferroni correction, P < 0.05). ∗∗∗ means significant level P < 0.001. The row 2 showed negative correlation between this region and delayed recall/recognition of AVLT scores (Bonferroni correction, P < 0.05/5). Corresponding correlation coefficient “r” and significant level “p” were marked. NC, normal controls; SCD, subjective cognitive decline; aMCI, amnestic mild cognitive impairment; d-AD, dementia of Alzheimer’s disease; AVLT, the auditory verbal learning test.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Guo, 2007, Norm of auditory verbal learning test in the normal aged in Chinese community., Chin. J. Clin. Psychol., 15, 132
  2. Zhang, 1999, The minimental state examination in the Chinese residents population aged 55 years and over in the urban and rural areas of Beijing., Chin. J. Neurol., 32, 149, 10.3760/j.issn:1006-7876.1999.03.006 · DOI
  3. Zhao, 2012, Amplitude of low-frequency fluctuation in patients with alzheimer’s disease based on resting-state functional MRI., J. China Med. Univ., 41, 329

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Metadata

Authors
Yang, L., Yan, Y., Wang, Y., Hu, X., Lu, J., Chan, P., Yan, T., & Han, Y.
Affiliations
  • Beijing Institute of Technology (CN)
  • University of Cologne (DE)
  • Capital Medical University (CN)
Corresponding author
  • Yan, Tianyi
  • Han, Ying
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2018-12-20
Volume
12
Pages
975-975
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2018.00975
PMC
PMC6306691
OpenAlex
W2904195085
Cited by
182
References
74
Citations by year
2026: 9 · 2025: 22 · 2024: 16 · 2023: 27 · 2022: 36 · 2021: 37 · 2020: 20 · 2019: 14
FWCI
10.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (61633018, 81430037, 81471731, 31371007, 81671776, 61727807, 81522021)
  • Beijing Municipal Natural Science Foundation (7132147)
  • Beijing Municipal Science and Technology Commission (Z161100002616020)
  • Beijing Nova Program (Z171100001117057)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • 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
Keywords
Alzheimer's disease, subjective cognitive decline, amnestic mild cognitive impairment, Alzheimer's dementia, amplitude of low-frequency fluctuation, fractional ALFF, intrinsic brain activity, machine learning classification, disease progression, hippocampus, precuneus, cingulum, neuropsychological test performance, early detection of Alzheimer's disease, mild cognitive impairment

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