5150690ba7bbf61a8e22e995d5459f59 pmc_34199476.pdf 4c101b4260d6ff06f50cdf0bd7a9f5b78c438c0e pmc_34199476.pdf dbd53bc9589f9bd4d94f5152da2e9ca5c9ea2fa47d6499079fb705fd25988270 pmc_34199476.pdf Title: Survival Bias and Crosstalk between Chronological and Behavioral Age: Age- and Genotype-Sensitivity Tests Define Behavioral Signatures in Middle-Aged, Old, and Long-Lived Mice with Normal and AD-Associated Aging Subject: New evidence refers to a high degree of heterogeneity in normal but also Alzheimer’s disease (AD) clinical and temporal patterns, increased mortality, and the need to find specific end-of-life prognosticators. This heterogeneity is scarcely explored in very old male AD mice models due to their reduced survival. In the present work, using 915 (432 APP23 and 483 C57BL/6 littermates) mice, we confirmed the better survival curves in male than female APP23 mice and respective wildtypes, providing the chance to characterize behavioral signatures in middle-aged, old, and long-lived male animals. The sensitivity of a battery of seven paradigms for comprehensive screening of motor (activity and gait analysis), neuropsychiatric and cognitive symptoms was analyzed using a cohort of 56 animals, composed of 12-, 18- and 24-month-old male APP23 mice and wildtype littermates. Most variables analyzed detected age-related differences. However, variables related to coping with stress, thigmotaxis, frailty, gait, and poor cognition better discriminated the behavioral phenotype of male APP23 mice through the three old ages compared with controls. Most importantly, non-linear age- and genotype-dependent behavioral signatures were found in long-lived animals, suggesting crosstalk between chronological and biological/behavioral ages useful to study underlying mechanisms and distinct compensations through physiological and AD-associated aging. Keywords: survival; aging; Alzheimer’s disease; heterogeneity; long-life; gait analysis; cognition; BPSD Author: Lydia Giménez-Llort, Daniela Marin-Pardo, Paula Marazuela and Mar Hernández-Guillamón Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jun 8 03:24:28 2021 CEST ModDate: Tue Jun 8 03:30:25 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3360580 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- KORLVE+VnURWPalladioL Type 1 Custom yes yes no 10 0 YIWMUC+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 VSJRNC+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 YUQUUQ+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 ZZTQUO+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 58 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 62 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 66 0 QMDDXF+CMSY10 Type 1 Builtin yes yes no 81 0 AKBLLA+PalatinoLinotype TrueType WinAnsi yes yes no 99 0 AKBLPB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 102 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 165 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:12:53 CEST RepresentationInformation: pmc_34199476.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:14:17 CEST Size: 3360580 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 508 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: Experimental Design Destination: subsection.2.2 Item: Title: Behavioral Assessments Destination: subsection.2.3 Children: Item: Title: Day 1. Corner and Open-Field Tests (CT and OF) Destination: subsubsection.2.3.1 Item: Title: Day 2. Recognition Tests (OF2 and OR) Destination: subsubsection.2.3.2 Item: Title: Day 3. Spontaneous Alternation in the T-Maze (TM-SA) Destination: subsubsection.2.3.3 Item: Title: Day 4 to 9. Morris Water Maze Test (MWM) Destination: subsubsection.2.3.4 Item: Title: Statistics Destination: subsection.2.4 Item: Title: Results Destination: section.3 Children: Item: Title: Genotype and Sex-Dependent Increased Mortality Rates Destination: subsection.3.1 Item: Title: Strong Contribution of Age and Specificity of Genotype Factor on Key Variables for AD-Related Phenotype Destination: subsection.3.2 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions and Future Directions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Survival Bias and Crosstalk between Chronological and Behavioral Age: Age- and Genotype-Sensitivity Tests Define Behavioral Signatures in Middle-Aged, Old, and Long-Lived Mice with Normal and AD-Associated Aging Author: Lydia Giménez-Llort, Daniela Marin-Pardo, Paula Marazuela and Mar Hernández-Guillamón Subject: New evidence refers to a high degree of heterogeneity in normal but also Alzheimer’s disease (AD) clinical and temporal patterns, increased mortality, and the need to find specific end-of-life prognosticators. This heterogeneity is scarcely explored in very old male AD mice models due to their reduced survival. In the present work, using 915 (432 APP23 and 483 C57BL/6 littermates) mice, we confirmed the better survival curves in male than female APP23 mice and respective wildtypes, providing the chance to characterize behavioral signatures in middle-aged, old, and long-lived male animals. The sensitivity of a battery of seven paradigms for comprehensive screening of motor (activity and gait analysis), neuropsychiatric and cognitive symptoms was analyzed using a cohort of 56 animals, composed of 12-, 18- and 24-month-old male APP23 mice and wildtype littermates. Most variables analyzed detected age-related differences. However, variables related to coping with stress, thigmotaxis, frailty, gait, and poor cognition better discriminated the behavioral phenotype of male APP23 mice through the three old ages compared with controls. Most importantly, non-linear age- and genotype-dependent behavioral signatures were found in long-lived animals, suggesting crosstalk between chronological and biological/behavioral ages useful to study underlying mechanisms and distinct compensations through physiological and AD-associated aging. 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Subtype: Link Rect: 247, 111, 283, 122 Annotation: Subtype: Link Rect: 278, 88, 316, 99 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 131, 710, 169, 720 Annotation: Subtype: Link Rect: 109, 687, 146, 697 Annotation: Subtype: Link Rect: 459, 663, 497, 674 Annotation: Subtype: Link Rect: 503, 663, 539, 674 Annotation: Subtype: Link Rect: 417, 653, 454, 663 Annotation: Subtype: Link Rect: 461, 653, 497, 663 Annotation: Subtype: Link Rect: 239, 618, 276, 628 Annotation: Subtype: Link Rect: 462, 594, 499, 605 Annotation: Subtype: Link Rect: 412, 571, 449, 582 Annotation: Subtype: Link Rect: 95, 538, 133, 548 Annotation: Subtype: Link Rect: 139, 538, 175, 548 Annotation: Subtype: Link Rect: 401, 502, 439, 513 Annotation: Subtype: Link Rect: 445, 502, 481, 513 Annotation: Subtype: Link Rect: 394, 479, 431, 490 Annotation: Subtype: Link Rect: 445, 456, 483, 467 Annotation: Subtype: Link Rect: 489, 456, 525, 467 Annotation: Subtype: Link Rect: 362, 433, 400, 444 Annotation: Subtype: Link Rect: 406, 433, 442, 444 Annotation: Subtype: Link Rect: 136, 400, 173, 410 Annotation: Subtype: Link Rect: 86, 377, 124, 387 Annotation: Subtype: Link Rect: 519, 353, 557, 364 Annotation: Subtype: Link Rect: 341, 330, 379, 341 Annotation: Subtype: Link Rect: 385, 330, 421, 341 Annotation: Subtype: Link Rect: 294, 307, 331, 318 Checksum: f3c08166 Type: CRC32 Checksum: 5150690ba7bbf61a8e22e995d5459f59 Type: MD5 Checksum: 4c101b4260d6ff06f50cdf0bd7a9f5b78c438c0e Type: SHA-1 Checksum: dbd53bc9589f9bd4d94f5152da2e9ca5c9ea2fa47d6499079fb705fd25988270 Type: SHA-256