0d320dd42995bb4f4e9a0f980ef06762 293857.pdf e34c1dd4dc7eca7b1c2cfb4655a281931d3fcdee 293857.pdf 8a10ed19cc1bea2ac7e1e4bf100ff47ef69dbeeb148c4658d21dcf238e2601b3 293857.pdf Title: Use of Ordered Beta Regression Unveils Cognitive Flexibility Index and Longitudinal Cognitive Training Signatures in Normal and Alzheimer’s Disease Pathological Aging Subject: Generalized linear mixed models (GLMMs) are a cornerstone data analysis strategy in behavioral research because of their robustness in handling non-normally distributed variables. Recently, their integration with ordered beta regression (OBR), a novel statistical tool for managing percentage data, has opened new avenues for analyzing continuous response data. Here, we applied this combined approach to investigate nuanced differences between the 3xTg-AD model of Alzheimer’s disease (AD) and their C57BL/6 non-transgenic (NTg) counterparts with normal aging in a 5-day Morris Water Maze (MWM) test protocol. Our longitudinal study included 22 3xTg-AD mice and 15 NTg mice (both male and female) assessed at 12 and 16 months of age. By identifying and analyzing multiple swimming strategies during three different paradigms (cue, place task, and removal), we uncovered genotypic differences in all paradigms. Thus, the NTg group exhibited a higher percentage of direct search behaviors, while an association between circling episodes and 3xTg-AD animals was found. Furthermore, we also propose a novel metric—the “Cognitive Flexibility Index”—which proved sensitive in detecting sex-related differences. Overall, our integrated GLMMs-OBR approach provides a comprehensive insight into mouse behavior in the MWM test, shedding light on the effects of aging and AD pathology. Keywords: behavioral studies; data analysis; Alzheimer’s disease; aging; Morris Water Maze; search strategies; cognitive flexibility Author: Daniel Alveal-Mellado and Lydia Giménez-Llort Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Tue May 21 07:50:10 2024 CEST ModDate: Tue May 21 08:33:11 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1662259 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 LJWUZI+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 JTFYAE+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 XWQMSA+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 MWHIBA+VnURWPalladioL Type 1 Custom yes yes yes 32 0 SLUQMQ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 48 0 QMDDXF+CMSY10 Type 1 Builtin yes yes yes 68 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 81 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 85 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 89 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 93 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 100 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 122 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 126 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 130 0 BCDHEE+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 134 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 141 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 148 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 159 0 RHQYUV+CMBSY10 Type 1 Builtin yes yes yes 164 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 187 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 191 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 195 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 199 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 206 0 LWLIVD+EURM10 Type 1 Builtin yes yes yes 226 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-06-18 02:41:28 CEST RepresentationInformation: 293857.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-06-17 09:32:16 CEST Size: 1662259 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 469 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Animals Destination: subsection.2.1 Item: Title: Morris Water Maze Protocol Destination: subsection.2.2 Children: Item: Title: Classical MWM Test Analysis Destination: subsubsection.2.2.1 Item: Title: Swimming Strategy Classification Destination: subsubsection.2.2.2 Item: Title: Variables Associated with Swimming Strategies Destination: subsubsection.2.2.3 Item: Title: Statistical Analysis Destination: subsection.2.3 Item: Title: Results Destination: section.3 Children: Item: Title: Survival Analysis Destination: subsection.3.1 Item: Title: Classical MWM Test Analysis Destination: subsection.3.2 Children: Item: Title: CUE Stage Destination: subsubsection.3.2.1 Item: Title: PT Stage Destination: subsubsection.3.2.2 Item: Title: RM Stage Destination: subsubsection.3.2.3 Item: Title: Swimming Strategy Analysis Destination: subsection.3.3 Children: Item: Title: Search Strategies Destination: subsubsection.3.3.1 Item: Title: Non-Search Strategies Destination: subsubsection.3.3.2 Item: Title: Cognitive Flexibility Destination: subsubsection.3.3.3 Item: Title: Discussion Destination: section.4 Children: Item: Title: Classical MWM Test Analysis Destination: subsection.4.1 Item: Title: Relevant Swimming Strategies Destination: subsection.4.2 Item: Title: Importance of Non-Search Strategies Destination: subsection.4.3 Item: Title: Cognitive Flexibility Destination: subsection.4.4 Item: Title: Retest Effect Destination: subsection.4.5 Item: Title: Limitations Destination: subsection.4.6 Item: Title: Future Directions Destination: subsection.4.7 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.6 Info: Title: Use of Ordered Beta Regression Unveils Cognitive Flexibility Index and Longitudinal Cognitive Training Signatures in Normal and Alzheimer’s Disease Pathological Aging Author: Daniel Alveal-Mellado and Lydia Giménez-Llort Subject: Generalized linear mixed models (GLMMs) are a cornerstone data analysis strategy in behavioral research because of their robustness in handling non-normally distributed variables. Recently, their integration with ordered beta regression (OBR), a novel statistical tool for managing percentage data, has opened new avenues for analyzing continuous response data. Here, we applied this combined approach to investigate nuanced differences between the 3xTg-AD model of Alzheimer’s disease (AD) and their C57BL/6 non-transgenic (NTg) counterparts with normal aging in a 5-day Morris Water Maze (MWM) test protocol. Our longitudinal study included 22 3xTg-AD mice and 15 NTg mice (both male and female) assessed at 12 and 16 months of age. By identifying and analyzing multiple swimming strategies during three different paradigms (cue, place task, and removal), we uncovered genotypic differences in all paradigms. Thus, the NTg group exhibited a higher percentage of direct search behaviors, while an association between circling episodes and 3xTg-AD animals was found. Furthermore, we also propose a novel metric the “Cognitive Flexibility Index” which proved sensitive in detecting sex-related differences. Overall, our integrated GLMMs-OBR approach provides a comprehensive insight into mouse behavior in the MWM test, shedding light on the effects of aging and AD pathology. 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