Visual Memory and Spatial Navigation as Preclinical Indicators of Alzheimer's Disease

Visual Memory and Spatial Navigation as Preclinical Indicators of Alzheimer's Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Visual Memory and Spatial Navigation as Preclinical Indicators of Alzheimer's Disease Jennifer Nevers This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3253822/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract INTRODUCTION: There is an absence of standardized measures for spatial navigation (SN) deficits related to possible visual memory (VM) decline in preclinical Alzheimer’s disease (AD). This work sought to identify VM changes over time in the cognitively normal (CN) years of those later diagnosed with AD (pre-AD) compared to those who remained CN (non-AD). METHODS: Mixed-effects analysis was performed on the Benson Complex Figure Test (BCTF) delayed recall scores for VM on longitudinal (1-6 years) of pre-AD and non-AD samples from the National Alzheimer’s Coordinating Center. Analysis for sex differences was included. RESULTS: All pre-AD groups demonstrated a significant ( P < .001) decrease in VM over time compared to non-AD groups with a Cohen’s d range of .853 to 1.076 across time points. DISCUSSION: The BCTF may serve as an AD screening instrument in CN persons and support inquiry to identify potential SN deficits secondary to VM decline. Neurology Alzheimer’s Disease Benson Complex Figure Test cognitively normal delayed recall preclinical sex differences spatial navigation visual memory Figures Figure 1 Figure 2 Figure 3 1. Background Alzheimer’s disease (AD) progresses along a continuum spanning decades before clinical diagnosis. Across the globe, an estimated 416 million persons are within the AD continuum, but less than 8% are diagnosed despite the death rate rising 145% from 2000 to 2019. 1,2 As the pathology in the remaining undiagnosed persons advances towards dementia, the death rate can be expected to increase. Given the failure of pharmaceuticals prescribed for AD dementia, earlier-stage treatment strategies are needed to slow or interrupt the disease progression. 2,3 Yet the absence of early indicators of AD confounds our ability to screen for AD in persons with normal cognition. However, evidence suggests it may be possible to design clinical criteria and screening tools to gauge preclinical cognitive changes via objective neuropsychiatric evidence in verbal episodic memory and spatial navigation (SN) (Nevers, unpublished data). The screening for cognitive changes as an indicator of AD and SN-related deficits may be furthered with measurements of change in visual memory. In general, SN involves visually recalling cognitive maps of locations and physically moving oneself along a route from one place to another. Multiple brain areas inform visual memory and SN processes 4–9 , and specific neuronal network connectivity is associated with both functions. 9–12 Early tau-related neuronal dysfunction and toxicity 13 occur within the transentorhinal cortex, the entorhinal cortex, and the hippocampus 14–16 ; these structures are associated with visual memory and SN processes. 4–6,8 As more tau-related damage accumulates, it interferes with neural connectivity throughout the brain. 10 By the time AD pathology has advanced to dementia, the impact of deterioration on visual memory hinders object recognition and cues, such as familiar street signs, address numbers, and landmarks, necessary to inform SN. 16–18 However, there may be longitudinal changes in visual memory that a neuropsychiatric test could measure to screen for cognitively normal persons with AD. If so, there may be an impact on SN performance secondary to the visual memory changes. The Benson Complex Figure Test (BCFT) delayed recall is a gold standard neuropsychiatric test for visual memory. 10 A decline in visual memory performance, as measured by the BCTF, is associated with interference with neural connectivity due to damage from phosphorylated tau, an AD biomarker. A retrospective analysis of longitudinal visual memory performance during the cognitively normal years in persons later diagnosed with AD (pre-AD) may indicate visual memory differences from those who do not develop the disease (non-AD). If there is evidence of difference, there is a potential to screen for previously unrecognized signs of change in navigational ability secondary to subclinical decline in visual memory. Therefore, it may be possible to design effective treatments to reduce the progression of visual memory loss and navigational degeneration early in the disease continuum. This retrospective longitudinal secondary analysis aimed to (a) determine the feasibility of SN as a preclinical indicator of AD and (b) determine the feasibility of the BCFT delayed recall as a proxy for preclinical SN changes. Specifically, this study (a) compared longitudinal BCFT delayed recall scores of pre-AD and non-AD persons and (b) compared the performance trajectories separately for females and males. 2. Methods 2.1 Data Source This study used the participant data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) Version 3. The Institutional Review Board authorizes the NACC at the University of Washington to release the deidentified data for research. 19 Every Alzheimer’s Disease Research Center (ADRC) complies with individual Institutional Review Boards to ensure research compliance, informed consent, and ethics. The deidentified participant data is free and available to the public for research. As such, secondary analysis of the available data does not require additional IRB approval and is considered exempt by Washington State University. 2.2 Sample The participant data for this study is from the September 2022 NACC data freeze and the years available for the BCFT span 2015 to 2022. The available annual cognitive assessment data during the preclinical years ranged from 1 to 6 years (Table 1 ). The pre-AD sample (n = 194) was comprised of 66 males and 128 females. The male age range was 47–96; the female age range was 65–96. The non-AD group (n = 5,154) with 1,941 males and 3,213 females. The available pre-AD sample data were from 20 ADRCs, and the non-AD sample data were from all the ADRCs. Table 1 Data Years Pre-AD Group Non-AD Pre-AD Females Non-AD Females Pre-AD Males Non-AD Males 6 years 8 927 8 919 n/a n/a 5 years 36 2318 25 1425 11 857 4 years 47 3345 32 2087 15 1211 3 years 88 4211 62 2581 26 1542 2 years 118 3824 80 2302 38 1404 1 years 192 5579 127 3365 65 2022 Note: The National Alzheimer’s Coordinating Center participants who begin participation as cognitively normal (CN) and are later diagnosed as AD (pre-AD) begin at various years before eventual disease progression into dementia. Retrospectively their CN years are preclinical and are analyzed with participants who remained cognitively intact (non-AD). 2.3 Cognitive Assessment The ADRC clinicians determined the participants’ cognitive status based on the neuropsychiatric test battery performance and pertinent physical assessment data. The cognitive status is based upon the clinical assessment of participant and co-participant answers to cognitive domain questions designed for the Clinical Dementia Rating (CDR) Dementia Staging Instrument. A cognitively normal participant is given a CDR global score of 0. Any score above 0 indicates they are no longer cognitively normal. A maximum score of 3 is given for severe impairment. This study's pre-AD and non-AD participant assessments were during the normal cognitive status years. The BCTF requires the participant to view and memorize an abstract figure for 1 minute and then immediately draw that figure (immediate recall). After 10 to 15 minutes, the clinician prompts the participant to redraw that image (delayed recall). Clinicians use a ruler and protractor to help judge the abstract drawing elements for accuracy. A maximum score of 17 points may be received on the test. This is a different type of dementia than Alzheimer’s type (NACC). Data on neural connectivity associated with BCTF scores 10 was unavailable for this study. 2.4 Statistical Analysis A linear mixed model analysis was performed for the retrospective longitudinal study. Random effects included time and individual differences. Fixed effects were applied for group change over time. The effect size for individual time points is reported as Cohen’s d based on the equivalent Glass’s delta for different sample sizes. All confidence intervals (CI) were set at 95%. 3. Results The pre-AD group average score decreased annually by − .219, P < .001 with CI (-.251, − .187) whereas the non-AD group decreased annually by − .039, P = .001with CI (-062, − .015). The effect size when the confidence intervals for the individual time points no longer overlapped was Cohen’s d = .948, and by the last visit, Cohen’s d = 1.003 (Fig. 1). Female participants in the pre-AD group average score per annual assessment decreased by − .235, P < .001 with CI (-.275, − .195), whereas the non-AD group decreased annually by − .045, P = .003 with CI (-.074, − .016). The effect size when the group CIs no longer overlapped was Cohen’s d = .929, and by the last visit, Cohen’s d = 1.076 (Fig. 2). Males in the pre-AD group average score per annual assessment decreased by − .189, P < .001 with CI (.241, − .138), but the non-AD group decreased by − .033, and this was not significant P = .081 with CI (-.071, .004). There was no CI overlap at any time point between the male groups; the first effect size was Cohen’s d = .948, and by the last visit, Cohen’s d = .853 (Fig. 3). 4. Discussion This study compared longitudinal change over time in visual memory as measured with the Benson Complex Figure Test delayed recall in the pre-AD group and a non-AD group of NACC participants. All the pre-AD groups had significant decreases and large effect sizes compared to the non-AD groups in scores over time. Across 5 years of analysis for the males, there was no CI overlap for any time point and the effect size between the groups was large at the reported time points. The females had a CI overlap at 6 years remaining as cognitively normal. The pre-AD female average decrease across all time points was greater than the males, and by the last year, as cognitively normal, their effect size was greater than the males. In studies comparing differences between healthy males and females, the males have better visual memory than females. This male advantage is linked with greater general visuospatial ability. 20,21 There is little difference in visual memory in cross-sectional studies comparing cognitively normal persons with AD biomarkers to those without biomarkers. 22, 23 Longitudinal studies show that cognitively normal persons with AD biomarkers demonstrate a steeper decline in visual memory performance than those without the biomarkers. 24–26 A decreased performance on the BCFT delayed recall is associated with the increased impairment with a visual memory of scenes in the later stages of AD. 27 In this study, all pre-AD groups, male and female, demonstrated decreased visual memory performance compared to the non-AD groups. Beginning at 5 years remaining as cognitively normal, the pre-AD females did demonstrate a greater decline than the pre-AD males, as noted by the lower mean BCTF scores. The visuospatial advantage observed to be a factor in male visual memory 21 may provide more resilience for pre-AD males than the females, There are known limitations with the BCFT in terms of inter-rater reliability. Although measurement tools are utilized in the scoring process, clinicians must still use their judgment on the elements of the drawing. Additional limitations include differences in pre-AD sample sizes, with the pre-AD male group sample size smaller than the female sample. There is also a difference in sample size between the pre-AD and the non-AD groups. Although a decline in test performance is associated with decreased connectivity 10 , it is unknown if the pre-AD samples’ longitudinal performance correlates with a connectivity decline. However, the evidence from this retrospective secondary analysis demonstrates the feasibility of the test as a screening indicator for AD, without requiring evidence of AD biomarkers, in participants known to become later diagnosed within the NACC UDS. The youngest age for the pre-AD participants, 47 years for males and 65 years for females, suggests the onset of VM decline in this population may begin earlier for this population. The findings from this study suggest that BCTF delayed recall may be a useful cognitive screening instrument indicating visual memory decline in cognitively normal persons with early pathology. Such a measure can be utilized to assess for any correlated change in navigational behaviors. Further, diagnostic imaging for structural connectivity paired with standardized preclinical BCTF scores may increase sensitivity and specificity in research and clinical practice. Any standardization of BCTF scores for early disease should be inclusive of potential differences between males and females. Data from future studies may inform targeted interventions for VM, and SN changes secondary to any pathology process. Declarations Conflict of Interest Statement: The Author has nothing to declare. DATE: 08/31/22 TO: Lonnie Nelson and Jennifer Nevers, FROM: Julie Scheid, Office of Research Assurances (3143) The project "The Spatial Navigation and Diaschisis Hypothesis: A Deconstruction of Preclinical Alzheimer’s Disease", IRB #19658-001, has been certified by the WSU Human Research Protection Program (HRPP) as Not Human Subject Research (NHSR). The project does not meet the definition(s) of Human Subject as defined in 45 CFR 46, and does not require IRB review. PROJECT SUMMARY: "This will be a secondary analysis of deidentified data in the National Alzheimer’s Coordinating Center Uniform Database. The statistical analysis will be mixed effects regression. To address the critical need to diagnose AD in the earliest stage, we aim to 1: Identify SN SCI in multiple cognitive domains in the preclinical stage of AD. 2: Examine the relationship between preclinical AD cognitive signs and symptoms among persons with AD in comparison to those with amnestic mild cognitive impairment (aMCI), and 3:Identify AD onset with evidence of SCI in NACC participants not diagnosed with AD according to NIA’s diagnostic criteria." NHSR JUSTIFICATION: There is no “interaction or intervention” with living individuals therefore 45CFR46.102 (e)(1)(i) does not apply. The researcher is not utilizing identifiable data or biospecimens from a living individual, therefore 45CFR46.102 (e)(1)(ii) does not apply. References Gustavsson A, Norton N, Fast T, Frölich L, Georges J, Holzapfel D, et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimer’s & Dementia. 2023;19(2):658–670. doi: 10.1002/alz.12694 Gaugler J, James B, Johnson T, Reimer J, Solis M, Weuve J, et al. 2022 Alzheimer’s disease facts and figures. Alzheimer Dement 2022;18(4):700–789. doi: 10.1002/alz.12638 Passeri E, Elkhoury K, Morsink M, Broersen, K, Linder, M, Malaplateet C, et al. Alzheimer’s disease: treatment strategies and their limitations. International Journal of Molecular Sciences. 2022;23(22):13954. doi: 10.3390/ijms232213954 Eichenbaum H. The role of the hippocampus in navigation is memory. J Neurophysiol. 2017;117(4):1785–1796. doi: 10.1152/jn.00005.2017 Hasselmo ME. A model of episodic memory: mental time travel along encoded trajectories using grid cells. Neurobiol Learn Mem. 2009;92(4):559–573. doi: 10.1016/j.nlm.2009.07.005 Bicanski A, Burgess N. A Computational Model of Visual Recognition Memory via Grid Cells. Current Biology. 2019;29(6):979–990.e4. doi: 10.1016/j.cub.2019.01.077 Mitchell AS, Czajkowski R, Zhang N, Jeffery K, Nelson AJD. Retrosplenial cortex and its role in spatial cognition. Brain Neurosci Adv. 2018;2:2398212818757098. doi: 10.1177/2398212818757098 Chersi F, Burgess N. The Cognitive Architecture of Spatial Navigation: Hippocampal and Striatal Contributions. Neuron. 2015;88(1):64–77. doi: 10.1016/j.neuron.2015.09 Ekstrom AD, Arnold AEGF, Iaria G. A critical review of the allocentric spatial representation and its neural underpinnings: toward a network-based perspective. Frontiers in Human Neuroscience. 2014;8. Hall Z, Chien B, Zhao Y, Risacher SL, Saykin AJ, Wu YC, et al. Tau deposition and structural connectivity demonstrate differential association patterns with neurocognitive tests. Brain Imaging and Behavior. 2022;16(2):702–714. doi: 10.1007/s11682-021-00531 McIntosh AR, Sekuler AB, Penpeci C, et al. Recruitment of unique neural systems to support visual memory in normal aging. Current Biology. 1999;9(21):1275-S2. doi: 10.1016/S0960-9822(99)80512-0 Nau M, Julian JB, Doeller CF. How the Brain’s Navigation System Shapes Our Visual Experience. Trends Cogn Sci. 2018;22(9):810–825. doi: 10.1016/j.tics.2018.06.008 Liang SY, Wang ZT, Tan L, Yu JT. Tau Toxicity in Neurodegeneration. Mol Neurobiol. 2022;59(6):3617–3634. doi: 10.1007/s12035-022-02809-3 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259. doi: 10.1007/BF00308809 Banks PJ, Warburton EC, Brown MW, Bashir ZI. Chapter Seven - Mechanisms of Synaptic Plasticity and Recognition Memory in the Perirhinal Cortex. In: Khan ZU, Muly EC, eds. Progress in Molecular Biology and Translational Science . Vol 122. Molecular Basis of Memory. Waltham, MA: Academic Press; 2014:193–209. doi: 10.1016/B978-0-12-420170-5.00007-6 Maass A, Lockhart SN, Harrison TM, Bell RK, Mellinger T, Swinnerton, K, et al. Entorhinal tau pathology, episodic memory decline, and neurodegeneration in aging. J Neurosci. 2018;38(3):530–543. doi: 10.1523/JNEUROSCI.2028-17.2017 Zanco M, Plácido J, Marinho V, Ferreira J, de Oliveira F, Monteiro-Junior R, et al. Spatial navigation in the elderly with Alzheimer’s disease: A cross-sectional study. J Alzheimers Dis. 2018;66(4):1683–1694. doi: 10.3233/JAD-180819 Davis R, Sikorskii A. Eye tracking analysis of visual cues during wayfinding in early stage Alzheimer’s disease. Dement Geriatr Cogn Disord. 2020;49(1):91–97. doi: 10.1159/000506859 Weintraub S, Besser L, Dodge HH, Teylan M, Ferris S, Goldstein F, et al. Version 3 of the Alzheimer disease centers’ neuropsychological test battery in the uniform data Set (UDS). Alzheimer Dis Assoc Disord. 2018;32(1):10–17. doi: 10.1097/WAD.0000000000000223 Pauls F, Petermann F, Lepach AC. Gender differences in episodic memory and visual working memory including the effects of age. Memory. 2013;21(7):857–874. doi: 10.1080/09658211.2013.765892 Siedlecki KL. Spatial visualization ability mediates the male advantage in spatial and visual episodic memory. Journal of Individual Differences. 2016;37(3):194–200. doi: https://doi.org/10.1027/1614-0001/a000207 Hollands S, Lim YY, Buckley R, et al. Amyloid-β related memory decline is not associated with subjective or informant rated cognitive impairment in healthy adults. J Alzheimers Dis. 2015;43(2):677–686. doi: 10.3233/JAD-140678 Johnson SC, Christian BT, Okonkwo OC, et al. Amyloid burden and neural function in people at risk for Alzheimer’s Disease. Neurobiol Aging. 2014;35(3):576–584. doi: 10.1016/j.neurobiolaging.2013.09.028 Petersen RC, Wiste HJ, Weigand SD, et al. Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol. 2016;73(1):85–92. doi: 10.1001/jamaneurol.2015.309 Zhao Y, Tudorascu DL, Lopez OL, et al. Amyloid β deposition and suspected non-Alzheimer pathophysiology and cognitive decline patterns for 12 Years in oldest old participants without dementia. JAMA Neurol. 2018;75(1):88–96. doi: 10.1001/jamaneurol.2017.30 Lim YY, Maruff P, Pietrzak RH, et al. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer’s disease. Brain: a journal of neurology. 2014;137(1):221–231. doi: 10.1093/brain/awt286 Reeves S, Williams V, Costela FM, Palumbo R, Umoren, Christopher MM, et al. Narrative video scene description task discriminates between levels of cognitive impairment in Alzheimer’s disease. Neuropsychology. 2020;34(4):437–446. doi: 10.1037/neu0000621 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3253822","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":225634030,"identity":"c30b4755-b4e4-40c1-86c4-653cbae2e929","order_by":0,"name":"Jennifer Nevers","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYBACxgYgkWCDEJCDUGyEtKQhBIwJaoEAJC2JDYS0MLf3HnvwIMEmn0G6+ZjExz116RvOnzFg+FB2GLfDes6lGyQkpFk2yBxLk5zx7HDuhhs5BowzzuHRMiPHTCLxx2EDBokcY2OeAwdyt93gMWDmbcOjZf4bM4mEhP9ALfmfjf8cqEs3AzqM+S8+LTN4QFoOgGxhfMxwgDnB7ECOATMjPi09OSAtyQZsEmmGD3sOHDbcfyOt4CDQhzi1GLafMZP8kWBnwC+R/ODAjwN18pL9hzc++FFmjVtLA5SBEhEHcKoHAnl8kqNgFIyCUTAKwAAA65lVXO0VgyYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0007-8226-3742","institution":"Washington State University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Nevers","suffix":""}],"badges":[],"createdAt":"2023-08-11 01:55:55","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-3253822/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3253822/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":41535396,"identity":"42ed086a-79e5-4a9f-8b86-e65d8c7c998c","added_by":"auto","created_at":"2023-08-14 13:35:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":66427,"visible":true,"origin":"","legend":"\u003cp\u003eBenson Complex Figure Copy (BCTF) Delayed Recall Scores. The groups include both male and female participants. The group that was later diagnosed with Alzheimer’s disease (pre-AD) demonstrated lower mean scores than the group that remained cognitively normal (non-AD) at every time point.\u003c/p\u003e","description":"","filename":"Figure1BCTFGroupsMaleFemale20230810.png","url":"https://assets-eu.researchsquare.com/files/rs-3253822/v1/4fb965cdfa0ff335c73a559c.png"},{"id":41533388,"identity":"47a84255-2d87-40e7-a981-ed5fac85d891","added_by":"auto","created_at":"2023-08-14 13:27:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54396,"visible":true,"origin":"","legend":"\u003cp\u003eFemale Group Performances on the Benson Complex Figure Copy (BCTF) Delayed Recall. The females later diagnosed with Alzheimer's disease (pre-AD) decreased in the mean score over time compared to females who remained. cognitively normal (non-AD).\u003c/p\u003e","description":"","filename":"Figure2BCTFFemales.png","url":"https://assets-eu.researchsquare.com/files/rs-3253822/v1/08838653d7d30bffd0ffeeae.png"},{"id":41533389,"identity":"1bf6ae06-7879-40a9-8918-e8c49e291d9b","added_by":"auto","created_at":"2023-08-14 13:27:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":62378,"visible":true,"origin":"","legend":"\u003cp\u003eMale Group Performances on the Benson Complex Figure Copy (BCTF). The males who progressed to Alzheimer’s dementia (pre-AD) have consistently lower mean scores than those who remained cognitively normal (non-AD).\u003c/p\u003e","description":"","filename":"Figure3BCFTMales20230810at7.29.46PM.png","url":"https://assets-eu.researchsquare.com/files/rs-3253822/v1/6ebcfd84a0be1c7b6da61cdf.png"},{"id":41535406,"identity":"62f37503-e7bb-4d17-8e51-e0e9553f3c7f","added_by":"auto","created_at":"2023-08-14 13:35:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":302423,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3253822/v1/4a5e2c78-e334-40fa-8e67-0ea0fc367c75.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eVisual Memory and Spatial Navigation as Preclinical Indicators of Alzheimer's Disease\u003c/p\u003e","fulltext":[{"header":"1. Background","content":"\u003cp\u003eAlzheimer\u0026rsquo;s disease (AD) progresses along a continuum spanning decades before clinical diagnosis. Across the globe, an estimated 416\u0026nbsp;million persons are within the AD continuum, but less than 8% are diagnosed despite the death rate rising 145% from 2000 to 2019.\u003csup\u003e1,2\u003c/sup\u003e As the pathology in the remaining undiagnosed persons advances towards dementia, the death rate can be expected to increase. Given the failure of pharmaceuticals prescribed for AD dementia, earlier-stage treatment strategies are needed to slow or interrupt the disease progression.\u003csup\u003e2,3\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eYet the absence of early indicators of AD confounds our ability to screen for AD in persons with normal cognition. However, evidence suggests it may be possible to design clinical criteria and screening tools to gauge preclinical cognitive changes via objective neuropsychiatric evidence in verbal episodic memory and spatial navigation (SN) (Nevers, unpublished data). The screening for cognitive changes as an indicator of AD and SN-related deficits may be furthered with measurements of change in visual memory.\u003c/p\u003e \u003cp\u003eIn general, SN involves visually recalling cognitive maps of locations and physically moving oneself along a route from one place to another. Multiple brain areas inform visual memory and SN processes \u003csup\u003e4\u0026ndash;9\u003c/sup\u003e, and specific neuronal network connectivity is associated with both functions.\u003csup\u003e9\u0026ndash;12\u003c/sup\u003e Early tau-related neuronal dysfunction and toxicity \u003csup\u003e13\u003c/sup\u003e occur within the transentorhinal cortex, the entorhinal cortex, and the hippocampus \u003csup\u003e14\u0026ndash;16\u003c/sup\u003e; these structures are associated with visual memory and SN processes.\u003csup\u003e4\u0026ndash;6,8\u003c/sup\u003e As more tau-related damage accumulates, it interferes with neural connectivity throughout the brain.\u003csup\u003e10\u003c/sup\u003e By the time AD pathology has advanced to dementia, the impact of deterioration on visual memory hinders object recognition and cues, such as familiar street signs, address numbers, and landmarks, necessary to inform SN.\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e However, there may be longitudinal changes in visual memory that a neuropsychiatric test could measure to screen for cognitively normal persons with AD. If so, there may be an impact on SN performance secondary to the visual memory changes.\u003c/p\u003e \u003cp\u003eThe Benson Complex Figure Test (BCFT) delayed recall is a gold standard neuropsychiatric test for visual memory.\u003csup\u003e10\u003c/sup\u003e A decline in visual memory performance, as measured by the BCTF, is associated with interference with neural connectivity due to damage from phosphorylated tau, an AD biomarker. A retrospective analysis of longitudinal visual memory performance during the cognitively normal years in persons later diagnosed with AD (pre-AD) may indicate visual memory differences from those who do not develop the disease (non-AD). If there is evidence of difference, there is a potential to screen for previously unrecognized signs of change in navigational ability secondary to subclinical decline in visual memory. Therefore, it may be possible to design effective treatments to reduce the progression of visual memory loss and navigational degeneration early in the disease continuum.\u003c/p\u003e \u003cp\u003eThis retrospective longitudinal secondary analysis aimed to (a) determine the feasibility of SN as a preclinical indicator of AD and (b) determine the feasibility of the BCFT delayed recall as a proxy for preclinical SN changes. Specifically, this study (a) compared longitudinal BCFT delayed recall scores of pre-AD and non-AD persons and (b) compared the performance trajectories separately for females and males.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data Source\u003c/h2\u003e \u003cp\u003eThis study used the participant data from the National Alzheimer\u0026rsquo;s Coordinating Center (NACC) Uniform Data Set (UDS) Version 3. The Institutional Review Board authorizes the NACC at the University of Washington to release the deidentified data for research.\u003csup\u003e19\u003c/sup\u003e Every Alzheimer\u0026rsquo;s Disease Research Center (ADRC) complies with individual Institutional Review Boards to ensure research compliance, informed consent, and ethics. The deidentified participant data is free and available to the public for research. As such, secondary analysis of the available data does not require additional IRB approval and is considered exempt by Washington State University.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Sample\u003c/h2\u003e \u003cp\u003eThe participant data for this study is from the September 2022 NACC data freeze and the years available for the BCFT span 2015 to 2022. The available annual cognitive assessment data during the preclinical years ranged from 1 to 6 years (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The pre-AD sample \u003cem\u003e(n\u003c/em\u003e\u0026thinsp;=\u0026thinsp;194) was comprised of 66 males and 128 females. The male age range was 47\u0026ndash;96; the female age range was 65\u0026ndash;96. The non-AD group (n\u0026thinsp;=\u0026thinsp;5,154) with 1,941 males and 3,213 females. The available pre-AD sample data were from 20 ADRCs, and the non-AD sample data were from all the ADRCs.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e\u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eData Years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-AD\u003c/p\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-AD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePre-AD Females\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon-AD Females\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePre-AD Males\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNon-AD Males\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e927\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e919\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1425\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e857\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1211\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2581\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1542\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1404\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote: The National Alzheimer\u0026rsquo;s Coordinating Center participants who begin participation as cognitively normal (CN) and are later diagnosed as AD (pre-AD) begin at various years before eventual disease progression into dementia. Retrospectively their CN years are preclinical and are analyzed with participants who remained cognitively intact (non-AD).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Cognitive Assessment\u003c/h2\u003e \u003cp\u003eThe ADRC clinicians determined the participants\u0026rsquo; cognitive status based on the neuropsychiatric test battery performance and pertinent physical assessment data. The cognitive status is based upon the clinical assessment of participant and co-participant answers to cognitive domain questions designed for the Clinical Dementia Rating (CDR) Dementia Staging Instrument. A cognitively normal participant is given a CDR global score of 0. Any score above 0 indicates they are no longer cognitively normal. A maximum score of 3 is given for severe impairment. This study's pre-AD and non-AD participant assessments were during the normal cognitive status years.\u003c/p\u003e \u003cp\u003eThe BCTF requires the participant to view and memorize an abstract figure for 1 minute and then immediately draw that figure (immediate recall). After 10 to 15 minutes, the clinician prompts the participant to redraw that image (delayed recall). Clinicians use a ruler and protractor to help judge the abstract drawing elements for accuracy. A maximum score of 17 points may be received on the test. This is a different type of dementia than Alzheimer\u0026rsquo;s type (NACC). Data on neural connectivity associated with BCTF scores\u003csup\u003e10\u003c/sup\u003e was unavailable for this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eA linear mixed model analysis was performed for the retrospective longitudinal study. Random effects included time and individual differences. Fixed effects were applied for group change over time. The effect size for individual time points is reported as Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e based on the equivalent Glass\u0026rsquo;s delta for different sample sizes. All confidence intervals (CI) were set at 95%.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe pre-AD group average score decreased annually by \u0026minus;\u0026thinsp;.219, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001 with CI (-.251, \u0026minus;\u0026thinsp;.187) whereas the non-AD group decreased annually by \u0026minus;\u0026thinsp;.039, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001with CI (-062, \u0026minus;\u0026thinsp;.015). The effect size when the confidence intervals for the individual time points no longer overlapped was Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.948, and by the last visit, Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.003 (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eFemale participants in the pre-AD group average score per annual assessment decreased by \u0026minus;\u0026thinsp;.235, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001 with CI (-.275, \u0026minus;\u0026thinsp;.195), whereas the non-AD group decreased annually by \u0026minus;\u0026thinsp;.045, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;.003 with CI (-.074, \u0026minus;\u0026thinsp;.016). The effect size when the group CIs no longer overlapped was Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.929, and by the last visit, Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.076 (Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eMales in the pre-AD group average score per annual assessment decreased by \u0026minus;\u0026thinsp;.189, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001 with CI (.241, \u0026minus;\u0026thinsp;.138), but the non-AD group decreased by \u0026minus;\u0026thinsp;.033, and this was not significant \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;.081 with CI (-.071, .004). There was no CI overlap at any time point between the male groups; the first effect size was Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.948, and by the last visit, Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.853 (Fig.\u0026nbsp;3).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study compared longitudinal change over time in visual memory as measured with the Benson Complex Figure Test delayed recall in the pre-AD group and a non-AD group of NACC participants. All the pre-AD groups had significant decreases and large effect sizes compared to the non-AD groups in scores over time. Across 5 years of analysis for the males, there was no CI overlap for any time point and the effect size between the groups was large at the reported time points. The females had a CI overlap at 6 years remaining as cognitively normal. The pre-AD female average decrease across all time points was greater than the males, and by the last year, as cognitively normal, their effect size was greater than the males.\u003c/p\u003e \u003cp\u003eIn studies comparing differences between healthy males and females, the males have better visual memory than females. This male advantage is linked with greater general visuospatial ability.\u003csup\u003e20,21\u003c/sup\u003e There is little difference in visual memory in cross-sectional studies comparing cognitively normal persons with AD biomarkers to those without biomarkers.\u003csup\u003e22, 23\u003c/sup\u003e Longitudinal studies show that cognitively normal persons with AD biomarkers demonstrate a steeper decline in visual memory performance than those without the biomarkers.\u003csup\u003e24\u0026ndash;26\u003c/sup\u003e A decreased performance on the BCFT delayed recall is associated with the increased impairment with a visual memory of scenes in the later stages of AD.\u003csup\u003e27\u003c/sup\u003e In this study, all pre-AD groups, male and female, demonstrated decreased visual memory performance compared to the non-AD groups. Beginning at 5 years remaining as cognitively normal, the pre-AD females did demonstrate a greater decline than the pre-AD males, as noted by the lower mean BCTF scores. The visuospatial advantage observed to be a factor in male visual memory \u003csup\u003e21\u003c/sup\u003e may provide more resilience for pre-AD males than the females,\u003c/p\u003e \u003cp\u003eThere are known limitations with the BCFT in terms of inter-rater reliability. Although measurement tools are utilized in the scoring process, clinicians must still use their judgment on the elements of the drawing. Additional limitations include differences in pre-AD sample sizes, with the pre-AD male group sample size smaller than the female sample. There is also a difference in sample size between the pre-AD and the non-AD groups. Although a decline in test performance is associated with decreased connectivity \u003csup\u003e10\u003c/sup\u003e, it is unknown if the pre-AD samples\u0026rsquo; longitudinal performance correlates with a connectivity decline. However, the evidence from this retrospective secondary analysis demonstrates the feasibility of the test as a screening indicator for AD, without requiring evidence of AD biomarkers, in participants known to become later diagnosed within the NACC UDS. The youngest age for the pre-AD participants, 47 years for males and 65 years for females, suggests the onset of VM decline in this population may begin earlier for this population.\u003c/p\u003e \u003cp\u003eThe findings from this study suggest that BCTF delayed recall may be a useful cognitive screening instrument indicating visual memory decline in cognitively normal persons with early pathology. Such a measure can be utilized to assess for any correlated change in navigational behaviors. Further, diagnostic imaging for structural connectivity paired with standardized preclinical BCTF scores may increase sensitivity and specificity in research and clinical practice. Any standardization of BCTF scores for early disease should be inclusive of potential differences between males and females. Data from future studies may inform targeted interventions for VM, and SN changes secondary to any pathology process.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflict of Interest Statement: \u0026nbsp;The Author has nothing to declare.\u003c/p\u003e\n\u003cp\u003eDATE: 08/31/22\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTO: Lonnie Nelson and Jennifer Nevers,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFROM: Julie Scheid, Office of Research Assurances (3143)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe project \"The Spatial Navigation and Diaschisis Hypothesis: A Deconstruction of Preclinical Alzheimer’s Disease\", IRB #19658-001, has been certified by the WSU Human Research Protection Program (HRPP) as Not Human Subject Research (NHSR). The project does not meet the definition(s) of Human Subject as defined in 45 CFR 46, and does not require IRB review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePROJECT SUMMARY:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\"This will be a secondary analysis of deidentified data in the National Alzheimer’s Coordinating Center Uniform\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDatabase. The statistical analysis will be mixed effects regression. To address the critical need to diagnose AD in the earliest stage, we aim to 1: Identify SN SCI in multiple cognitive domains in the preclinical stage of AD. 2: Examine the relationship between preclinical AD cognitive signs and symptoms among persons with\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAD in comparison to those with amnestic mild cognitive impairment (aMCI), and 3:Identify AD onset with evidence of SCI in NACC participants not diagnosed with AD according to NIA’s diagnostic criteria.\"\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNHSR JUSTIFICATION:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere is no “interaction or intervention” with living individuals therefore 45CFR46.102 (e)(1)(i) does not apply. The researcher is not utilizing identifiable data or biospecimens from a living individual, therefore 45CFR46.102 (e)(1)(ii) does not apply.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eGustavsson A, Norton N, Fast T, Fr\u0026ouml;lich L, Georges J, Holzapfel D, et al. Global estimates on the number of persons across the Alzheimer\u0026rsquo;s disease continuum. Alzheimer\u0026rsquo;s \u0026amp; Dementia. 2023;19(2):658\u0026ndash;670. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/alz.12694\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGaugler J, James B, Johnson T, Reimer J, Solis M, Weuve J, et al. 2022 Alzheimer\u0026rsquo;s disease facts and figures. 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Neuropsychology. 2020;34(4):437\u0026ndash;446. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1037/neu0000621\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Washington State University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s Disease, Benson Complex Figure Test, cognitively normal, delayed recall, preclinical, sex differences, spatial navigation, visual memory ","lastPublishedDoi":"10.21203/rs.3.rs-3253822/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3253822/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eINTRODUCTION:\u003c/strong\u003e There is an absence of standardized measures for spatial navigation (SN) deficits related to possible visual memory (VM) decline in preclinical Alzheimer’s disease (AD). This work sought to identify VM changes over time in the cognitively normal (CN) years of those later diagnosed with AD (pre-AD) compared to those who remained CN (non-AD).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMETHODS:\u003c/strong\u003e Mixed-effects analysis was performed on the Benson Complex Figure Test (BCTF) delayed recall scores for VM on longitudinal (1-6 years) of pre-AD and non-AD samples from the National Alzheimer’s Coordinating Center. Analysis for sex differences was included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS:\u003c/strong\u003e All pre-AD groups demonstrated a significant (\u003cem\u003eP \u003c/em\u003e\u0026lt; .001) decrease in VM over time compared to non-AD groups with a Cohen’s \u003cem\u003ed\u003c/em\u003e range of .853 to 1.076 across time points.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCUSSION:\u003c/strong\u003e The BCTF may serve as an AD screening instrument in CN persons and support inquiry to identify potential SN deficits secondary to VM decline.\u003c/p\u003e","manuscriptTitle":"Visual Memory and Spatial Navigation as Preclinical Indicators of Alzheimer's Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-14 13:27:23","doi":"10.21203/rs.3.rs-3253822/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9abb7a1f-0599-4ed8-b270-24b9f40dc2cd","owner":[],"postedDate":"August 14th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":23967210,"name":"Neurology"}],"tags":[],"updatedAt":"2023-08-14T13:27:23+00:00","versionOfRecord":[],"versionCreatedAt":"2023-08-14 13:27:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3253822","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3253822","identity":"rs-3253822","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}