Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients
Abstract A definitive diagnosis of Alzheimer’s disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-21796-y |
| _version_ | 1797984757459451904 |
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| author | Florin V. Chirila Guang Xu Dan Fontaine Grant Kern Tapan K. Khan Jason Brandt Yoshihiro Konishi Gerhard Nebe-von-Caron Charles L. White Daniel L. Alkon |
| author_facet | Florin V. Chirila Guang Xu Dan Fontaine Grant Kern Tapan K. Khan Jason Brandt Yoshihiro Konishi Gerhard Nebe-von-Caron Charles L. White Daniel L. Alkon |
| author_sort | Florin V. Chirila |
| collection | DOAJ |
| description | Abstract A definitive diagnosis of Alzheimer’s disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55–90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21—all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers—four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy—even with abundant co-morbidity. |
| first_indexed | 2024-04-11T07:06:44Z |
| format | Article |
| id | doaj.art-421842d784514b24b7e8dd3b1b3c8854 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T07:06:44Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-421842d784514b24b7e8dd3b1b3c88542022-12-22T04:38:22ZengNature PortfolioScientific Reports2045-23222022-11-0112111410.1038/s41598-022-21796-yMorphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patientsFlorin V. Chirila0Guang Xu1Dan Fontaine2Grant Kern3Tapan K. Khan4Jason Brandt5Yoshihiro Konishi6Gerhard Nebe-von-Caron7Charles L. White8Daniel L. Alkon9Synaps DxSynaps DxSynaps DxSynaps DxSynaps DxJohns Hopkins Hospital PsychiatryNational Hospital Organization Tottori Medical Center TottoriMologicDepartment of Pathology, The University of Texas Southwestern Medical CenterSynaps DxAbstract A definitive diagnosis of Alzheimer’s disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55–90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21—all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers—four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy—even with abundant co-morbidity.https://doi.org/10.1038/s41598-022-21796-y |
| spellingShingle | Florin V. Chirila Guang Xu Dan Fontaine Grant Kern Tapan K. Khan Jason Brandt Yoshihiro Konishi Gerhard Nebe-von-Caron Charles L. White Daniel L. Alkon Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients Scientific Reports |
| title | Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients |
| title_full | Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients |
| title_fullStr | Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients |
| title_full_unstemmed | Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients |
| title_short | Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients |
| title_sort | morphometric imaging biomarker identifies alzheimer s disease even among mixed dementia patients |
| url | https://doi.org/10.1038/s41598-022-21796-y |
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