A Pilot Longitudinal Study of Changes in Clinical Outcome Measures in Posterior Cortical Atrophy Syndrome

A Pilot Longitudinal Study of Changes in Clinical Outcome Measures in Posterior Cortical Atrophy Syndrome | 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 A Pilot Longitudinal Study of Changes in Clinical Outcome Measures in Posterior Cortical Atrophy Syndrome Victoria S Pelak, Asher Mahmood, Lily Noteboom, Bernard Croisile, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7066240/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Posterior Cortical Atrophy (PCA) is a rare and atypical presentation of neurodegenerative diseases, most commonly Alzheimer’s disease (AD). It is characterized by early impairment in visual and other posterior cortical functions. The rarity, the visual phenotype, and lack of longitudinal data hinder inclusion of PCA in AD clinical trials. To inform the design of a 12-month clinical trial readiness study for PCA, we conducted a 6-month study evaluating preliminary responsiveness of standard AD clinical trial outcome measures alongside PCA-targeted assessments. Methods Twelve participants with PCA completed the study. Baseline and 6-month follow-up assessments included the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Addenbrooke’s Cognitive Examination (ACE-III), Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (ADCS-ADL), and the Colorado Posterior Cortical Questionnaire (CPC-Q). Piloted PCA-targeted assessments included a rapid screening battery for PCA (VisCorD); three psychophysical tasks assessing center-surround contrast discrimination, global dot motion detection, and luminance increment detection in noise; and an English translation of the French-language Self-Assessment Questionnaire of Perceptual Abilities (Q-ACP). Results Significant declines in ACE-III (p = 0.02) and CDR-SB (p = 0.02), independent of age and symptom duration, were observed. All participants had abnormal CPC-Q scores. Two of three psychophysical tasks showed deficits too severe to be useful for tracking PCA. The Q-ACP demonstrated a high internal consistency. Conclusions This 6-month observational study offers preliminary insights into the performance of standard and PCA-specific outcome measures, suggesting that several may be sufficiently responsive and acceptable for a 12-month longitudinal validation study to confirm their utility as endpoints. Posterior Cortical Atrophy Syndrome Atypical Alzheimer’s disease Outcome Measures Natural History Clinical Trial Readiness Figures Figure 1 Background Posterior Cortical Atrophy (PCA) is a rare and atypical presentation of Alzheimer’s disease (AD), characterized by early posterior cortical visual dysfunction(1). The true prevalence of PCA is unknown(2), but PCA has been extensively acknowledged as a rare, atypical variant of AD since its initial descriptions(1, 3, 4) and is classified as rare by Orphanet (PCA nomenclature: ORPHA:54247)(5). In dementia clinic studies, PCA represented up to 13% of early-onset AD (EOAD) and 1% of late-onset AD (LOAD, >65 years)(4, 6). Thus, the estimated U.S. PCA prevalence is 100,000, calculated from the prevalence of EOAD (200,000) and LOAD (6.5 million). The rarity of PCA, the predominance of visual impairment, and the limited availability of longitudinal data challenge the phenotype’s inclusion in AD clinical trials(7, 8). Prospective data on cognitive and functional clinical outcomes in PCA are scarce(7). In this study, we examined AD and PCA-targeted clinical cognitive and functional outcomes prospectively over six months in a small PCA cohort, to inform the design of a 12-month longitudinal study that will focus on the responsiveness of clinical outcome measures, the development of a PCA cognitive staging measure, and the exploration of plasma biomarker changes. In addition, we piloted potential PCA-targeted assessments that included a rapid screening battery for PCA(8) (which includes the previously validated Colorado Posterior Cortical Questionnaire [CPC-Q])(9), three psychophysical visual perception tasks, and an English translation of the Q-ACP (Self-Assessment Questionnaire of Perceptual Abilities)(10). Methods Ethics Approval: This work was carried out in accordance with the Declaration of Helsinki and approved by Colorado Multiple Institutional Review Board (COMIRB # 23-1125). All participants gave informed consent for participation. Participants: We recruited people between 45 and 85 years who met 2017 diagnostic criteria for PCA-Pure(1) from a single academic institution. We accepted a broad range of screening cognitive scores given the lack of staging or outcome data for PCA on which to rely upon for exclusion criteria. Participants were excluded if they had had eight or less on the Montreal Cognitive Assessment (MoCA) or nine or less on the MMSE and if they scored less than 3 points on the 10-point Cognitive Screener (10-CS)(11) at the screening visit. Procedures: Baseline and six-month follow-up visits were performed. Clinical data were collected using National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) Version 3.0 forms for Health History (Form A5), Clinician-Assessed Medical Conditions (Form D2), Family History (Form A3), Medications (Form A4), Physical Exam (Form B1), and Neurological Examination Findings (Form B8). Standard AD outcome measures included the MMSE(12), ACE-III American Version A(13), the CDR scale(14), Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (ADCS-ADL)(15). PCA-targeted measures included the a recently validated questionnaire of posterior cortical symptoms – the CPC-Q(9), pilot assessments of an English translation of the French-language Q-ACP (Self-Assessment Questionnaire of Perceptual Abilities)\(10), the Eye Clinic Rapid Screening Battery for Visual Cortical Dysfunction without threshold visual field testing (referred to as the VisCorD, as described in Supplemental Material)(8), and three visual-perceptual psychophysical tasks: center-surround (CS) contrast discrimination, global dot motion (GM) detection, and luminance increment detection in noise (LIDN), as reviewed in Supplemental Material and as previously described(16, 17). Psychophysical tasks were performed on a seventh-generation iPad using PsyPad version 2.4(18) presented at 40 cm with a luminance of 516 cd/m 2 and visual angles for each task as previously noted(16, 17) and within the public gallery of PsyPad. Statistical analysis: Descriptive statistics, a linear mixed model, Pearson correlation, and Cronbach’s alpha were used to analyze outcomes. Results Thirteen participants were enrolled and twelve completed the study, with one withdrawn after failing the 10-CS during screening. Mean age was 69.1±7.8 years and 75% were female. Demographic and outcome data are shown in Table 1. Average baseline MMSE was in the mild impairment range at 21.3±4.6 and average symptom duration at entry was 6.1±3.1 years. Declines in all outcome measures were noted, with significant changes noted for the ACE-III (p = 0.02) and the CDR-Sum of Boxes (p = 0.02) (see Table 1 and Figure 1). Significant results were not mediated by age or symptom duration. Correlations of baseline variables, adjusted using Bonferroni correction, revealed significant associations (p < 0.001) between the ACE-III and the following: MMSE, the CDR-SB, and the CDR, as well as between the CDR and CDR-SB. Correlations between the change scores for these variables were not statistically significant. Table 1. Participant characteristics and clinical outcome measures at baseline and follow up. Baseline (T0) Follow up (T1) (6 months) p-value, T1 versus T0* Age, years, mean (sd) 69.1 (7.8) Age at symptom onset, years, mean (sd) 63.5 (8.6) Education, years, mean (sd) 15.7 (2.4) Sex, female (%) 75 Symptom duration, years, median (sd) 6.1(3.1) LogMAR visual acuity, mean (sd) 0.24 (0.18) 0.39 (0.29) 0.06 MMSE, mean (sd) (maximum score = 30) 21.3 (4.6) 19.8 (5.5) 0.09 ACE-III, mean, (sd) (maximum score =100) 65.9 (19.9) 62.0 (22.0) 0.02 ADCS-ADL, mean (sd) (maximum score = 78) 58.6 (14.8) 55.1 (17.2) 0.16 ^CDR, mean (sd) (maximum score = 3) 0.9 (0.4) 1.0 (0.5) 0.34 ^CDR-SB, mean (sd) (maximum score = 18) 4.4 (2.9) 5.6 (3.2) 0.02 ^CPC-Q, mean (sd) (maximum score = 60) 26.8 (10.4) 29.4 (11.7) 0.18 ^Q-ACP, mean (sd) (maximum score = 32) 15.1 (6.6) 16.5 (7.0) 0.11 VisCorD (maximum score = 6) 2.0 (1.6) 1.8 (1.5) 0.43 ^higher scores indicate poorer performance or function; *linear mixed model; sd, standard deviation; MMSE, min-mental state examination; ACE-III, Addenbrooke’s Cognitive Examination; CDR, clinical dementia rating; CDR-SB, CDR sum of boxes; CPC-Q, Colorado Posterior Cortical Questionnaire; Q-ACP, Posterior Cortical Atrophy questionnaire. The CPC-Q, which is part of the VisCorD battery, was abnormal (score 7 or more) for 12/12 participants at baseline and six months. Individual performance on other tasks within VisCorD varied, with abnormal performance by 33% to 75% participants on tasks within the battery (see Supplemental Material). The average time to complete the VisCorD was 12.05 minutes, and the CPC-Q took an average of 6.55 minutes to complete. Psychophysical testing revealed severely abnormal perception of CS and GM stimuli (floor/near floor thresholds or inadequate perception of stimuli during training) for 9 of 12 and 6 of 12 participants, respectively. The LIDN stimuli were adequately perceived during training for 12/12 participants, and thresholds were at or near floor for only 3 of 12 participants. The English-translated version of the French-language Q-ACP had an internal consistency of items, measured by Cronbach’s alpha, of 0.86 at baseline and 0.89 at six month follow up. Conclusions Statistically significant declines in ACE-III and CDR-SB scores unrelated to age or symptom duration suggests the potential for measurable disease progression with larger cohorts and longer intervals for these outcomes. Furthermore, significant correlations between baseline measures of ACE-III and the MMSE, as well as between the ACE-III and CDR-SB, reinforce the potential utility of ACE-III in assessing and monitoring cognition in PCA, as prior studies have indicated( 13 , 19 ). The ACE-III assesses five key domains that include attention, memory, verbal fluency, language, visuospatial/visuoperceptual skills that offers potential greater sensitivity for non-amnestic presentations of mild cognitive impairment or mild dementia. The lack of correlations between change scores for ACE-III and CDR-SB suggests that short-term progression in PCA might be variable across different cognitive and functional measures and the potential need for functional outcomes that specifically target the PCA syndrome. Although, the short time frame and small sample size limit our ability to draw definitive conclusions, the findings align with our clinical observations—and those of study partners—that functional scales developed for typical or amnestic Alzheimer’s disease may not be adequate for non-amnestic phenotypes. The performance of CPC-Q at baseline for our cohort corroborates its previously established validity and relevance as a PCA screening questionnaire( 9 ). Its utility for tracking progression needs further investigation over longer time periods and with larger sample sizes. The CPC-Q is part of the Eye Clinic Rapid Screening Battery for Visual Cortical Dysfunction, which was recommended by expert consensus for PCA screening by the PCA Working Party of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Atypical Alzheimer's Disease Professional Interest Area( 8 ). Data from this six-month study represents the first report of results from this battery in PCA. The differences in performances between participants observed on other VisCorD tasks likely reflect the heterogeneous nature of visual cortical dysfunction in PCA. Future studies are necessary to determine the VisCorD validity as a screening tool or as a tracking measure for posterior cortical dysfunction. Psychophysical visual perception testing revealed severe deficits in center-surround contrast discrimination and global motion perception by PCA participants, aligning with known visual processing impairments in PCA while indicating that these tools are ineffective for tracking PCA for cohorts like ours. Given the relatively early stage based on standard measures (mean CDR 0.9 and mean MMSE 21.3), center-surround contrast discrimination and global motion are unlikely to be useful for tracking PCA progression. However, the luminance increment detection task showed fewer instances of floor/near-floor effects, and adjusting the initial luminance difference at the start could improve the task’s utility. The English translation version of the Q-ACP had good internal consistency in this small sample size, and additional cross-sectional and longitudinal studies are needed to validate the English version. Assuming a linear trend, the estimated required sample sizes for a within-subject (paired) design to detect changes over a 12-month period with 80% power and a 0.05 significance level are an n = 6 for MMSE, n = 5 for CDR-SB, n = 5 for ACE-III, n = 17 for ADCS-ADL, n = 96 for CPC-Q, and n = 64 for Q-ACP. Overall, these preliminary findings inform the design of a future 12-month longitudinal study using standard AD outcome measures with at least 17 participants to gather data for the choice of screening and longitudinal outcome measures. Larger sample sizes are necessary to further assess and validate the English translation of Q-ACP and use of the CPC-Q. Finally, with minor adjustments, luminance increment detection task warrants further investigation as an outcome measure in PCA. Declarations Ethics approval and consent to participate: This work was carried out in accordance with the Declaration of Helsinki and approved by Colorado Multiple Institutional Review Board (COMIRB # 23-1125). All participants gave informed consent for participation. Consent for publication: Not applicable Availability of data and materials: Deidentified data will be shared to all those who request the relevant raw data for non-commercial processes and in a manner that does not breach participant confidentiality given the small number of participants in the study. Related documents, including study protocol and the statistical analysis plan, if necessary, can also be shared. Competing interests: The authors declare that they have no competing interests. Funding: This work was supported by the John and Joanne Hare Fund to Accelerate PCA Research. Authors' contributions: VSP conceived and led the study, including study design, methodology, data curation, data analysis, and drafted the original manuscript. BB contributed to methodology design, data interpretation, and reviewed and edited the manuscript. AMcK contributed to methodology design, data curation, data interpretation, and reviewed and edited the manuscript. BC contributed to methodology design, data interpretation, and reviewed and edited the manuscript. AM and LN contributed to study design, data curation, and review and editing of the manuscript. All authors read and approved the final manuscript. Acknowledgements: The authors acknowledge the research participants and their family and friends who made this study possible. This work was presented at a 2025 conference: Pelak VS, Mahmood A, Noteboom L, Croisile B, McKendrick A, Bettcher B. “Changes in outcome measures in posterior cortical atrophy: A pilot study for TRAC-PCA”. Poster Presentation at the 51st Annual Meeting of the North American Neuro-Ophthalmology Society, Tucson, AZ. March 15-20, 2025. References Crutch SJ, Schott JM, Rabinovici GD, Murray M, Snowden JS, van der Flier WM, et al. Consensus classification of posterior cortical atrophy. Alzheimers Dement. 2017;13(8):870-84. Schott JM, Crutch SJ. Posterior Cortical Atrophy. Continuum (Minneap Minn). 2019;25(1):52-75. Schott JM, Crutch SJ, Carrasquillo MM, Uphill J, Shakespeare TJ, Ryan NS, et al. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. Alzheimers Dement. 2016;12(8):862-71. Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, et al. New insights into atypical Alzheimer's disease in the era of biomarkers. Lancet Neurol. 2021;20(3):222-34. S. Crutch. Posterior Cortical Atrophy. Orphanet. 2020. Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer's disease: more than age alone. J Alzheimers Dis. 2010;19(4):1401-8. Pelak VS, Mahmood A, Abe-Ridgway K. Perspectives and a Systematic Scoping Review on Longitudinal Profiles of Posterior Cortical Atrophy Syndrome. Curr Neurol Neurosci Rep. 2022;22(11):803-12. Pelak VS, Tang-Wai DF, Boeve BF, Bouwman FH, Graff-Radford J, Rabinovici G, et al. Consensus recommendations for clinical assessment tools for the diagnosis of posterior cortical atrophy syndrome from the Atypical AD PIA of ISTAART. Alzheimers Dement (Amst). 2023;15(3):e12474. Holden SK, Pelak VS, Sooy T, Heffernan KS, McConnell BV, Pressman PS, et al. Development of the Colorado posterior cortical questionnaire within an Alzheimer's disease study cohort. J Clin Exp Neuropsychol. 2022;44(3):226-36. Croisile B, Mollion H. [Q-ACP: a questionnaire for evaluating visual and gestural complaints in patients with posterior cortical atrophy]. Rev Neurol (Paris). 2011;167(6-7):485-94. 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Supplementary Files AdditionalFile1.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 30 Mar, 2026 Reviewers invited by journal 10 Sep, 2025 Editor invited by journal 16 Jul, 2025 Editor assigned by journal 15 Jul, 2025 First submitted to journal 11 Jul, 2025 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-7066240","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":513303647,"identity":"d9a475f2-b8b8-4b01-b988-7e5d8883451c","order_by":0,"name":"Victoria S 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09:18:49","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72923,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7066240/v1/627e228d00445ce4a72ba835.html"},{"id":91832234,"identity":"c361140c-8707-4ed3-8cf6-e40bb1104950","added_by":"auto","created_at":"2025-09-22 09:18:49","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":333327,"visible":true,"origin":"","legend":"\u003cp\u003eOutcome measure changes for each participant over six months.\u003c/p\u003e\n\u003cp\u003e⇑ or ⇓ indicates direction of worse performance for the measure; MMSE, mini-mental state exam; ACE-III, Addenbrooke’s Cognitive Examination; ADCS-ADL, Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory; CDR-SB, Clinical Dementia Rating Scale-Sum of Boxes; CPC-Q, Colorado Posterior Cortical Questionnaire; Q-ACP, Self-Assessment Questionnaire of Perceptual Abilities – English Translation\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7066240/v1/eec2e0162df6e8d677cfa4d0.jpg"},{"id":91834680,"identity":"e3d74118-5f2a-4dfd-a4d4-44efe4385970","added_by":"auto","created_at":"2025-09-22 09:26:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":770651,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7066240/v1/ddae73b0-c619-49a9-b391-6ae735fcf154.pdf"},{"id":91832231,"identity":"a7f7da4f-291f-48ff-9102-d670e72ca907","added_by":"auto","created_at":"2025-09-22 09:18:49","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":32730,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7066240/v1/f0622354e8de6f149835b85d.docx"}],"financialInterests":"","formattedTitle":"A Pilot Longitudinal Study of Changes in Clinical Outcome Measures in Posterior Cortical Atrophy Syndrome","fulltext":[{"header":"Background","content":"\u003cp\u003ePosterior Cortical Atrophy (PCA) is a rare and atypical presentation of Alzheimer\u0026rsquo;s disease (AD), characterized by early posterior cortical visual dysfunction(1). The true prevalence of PCA is unknown(2), but PCA has been extensively acknowledged as a rare, atypical variant of AD since its initial descriptions(1, 3, 4) and is classified as rare by Orphanet (PCA nomenclature: ORPHA:54247)(5). In dementia clinic studies, PCA represented up to 13% of early-onset AD (EOAD) and 1% of late-onset AD (LOAD, \u0026gt;65 years)(4, 6). Thus, the estimated U.S. PCA prevalence is 100,000, calculated from the prevalence of EOAD (200,000) and LOAD (6.5 million). The rarity of PCA, the predominance of visual impairment, and the limited availability of longitudinal data challenge the phenotype\u0026rsquo;s inclusion in AD clinical trials(7, 8). Prospective data on cognitive and functional clinical outcomes in PCA are scarce(7). In this study, we examined AD and PCA-targeted clinical cognitive and functional outcomes prospectively over six months in a small PCA cohort, to inform the design of a 12-month longitudinal study that will focus on the responsiveness of clinical outcome measures, the development of a PCA cognitive staging measure, and the exploration of plasma biomarker changes. In addition, we piloted potential PCA-targeted assessments that included a rapid screening battery for PCA(8) (which includes the previously validated Colorado Posterior Cortical Questionnaire [CPC-Q])(9), three psychophysical visual perception tasks, and an English translation of the Q-ACP (Self-Assessment Questionnaire of Perceptual Abilities)(10).\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was carried out in accordance with the Declaration of Helsinki and approved by Colorado Multiple Institutional Review Board (COMIRB # 23-1125). All participants gave informed consent for participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe recruited people between 45 and 85 years who met 2017 diagnostic criteria for PCA-Pure(1) from a single academic institution. We accepted a broad range of screening cognitive scores given the lack of staging or outcome data for PCA on which to rely upon for exclusion criteria. Participants were excluded if they had had eight or less on the Montreal Cognitive Assessment (MoCA) or nine or less on the MMSE and if they scored less than 3 points on the 10-point Cognitive Screener (10-CS)(11) at the screening visit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline and six-month follow-up visits were performed. Clinical data were collected using National Alzheimer\u0026rsquo;s Coordinating Center (NACC) Uniform Data Set (UDS) Version 3.0 forms for Health History (Form A5), Clinician-Assessed Medical Conditions (Form D2), Family History (Form A3), Medications (Form A4), Physical Exam (Form B1), and Neurological Examination Findings (Form B8). Standard AD outcome measures included the MMSE(12), ACE-III American Version A(13), the CDR scale(14), Alzheimer\u0026rsquo;s Disease Cooperative Study \u0026ndash; Activities of Daily Living Inventory (ADCS-ADL)(15). PCA-targeted measures included the a recently validated questionnaire of posterior cortical symptoms \u0026ndash; the CPC-Q(9), pilot assessments of an English translation of the French-language Q-ACP (Self-Assessment Questionnaire of Perceptual Abilities)\\(10), the Eye Clinic Rapid Screening Battery for Visual Cortical Dysfunction without threshold visual field testing (referred to as the VisCorD, as described in Supplemental Material)(8), and three visual-perceptual psychophysical tasks: center-surround (CS) contrast discrimination, global dot motion (GM) detection, and luminance increment detection in noise (LIDN), as reviewed in Supplemental Material and as previously described(16, 17). Psychophysical tasks were performed on a seventh-generation iPad using PsyPad version 2.4(18)\u0026nbsp;presented at 40 cm with a luminance of 516 cd/m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eand visual angles for each task as previously noted(16, 17) and within the public gallery of PsyPad.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive statistics, a linear mixed model, Pearson correlation, and Cronbach\u0026rsquo;s alpha were used to analyze outcomes.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThirteen participants were enrolled and twelve completed the study, with one withdrawn after failing the 10-CS during screening. Mean age was 69.1\u0026plusmn;7.8 years and 75% were female. Demographic and outcome data are shown in Table 1. Average baseline MMSE was in the mild impairment range at 21.3\u0026plusmn;4.6 and average symptom duration at entry was 6.1\u0026plusmn;3.1 years. Declines in all outcome measures were noted, with significant changes noted for the ACE-III (p = 0.02) and the CDR-Sum of Boxes (p = 0.02) (see Table 1 and Figure 1). Significant results were not mediated by age or symptom duration. Correlations of baseline variables, adjusted using Bonferroni correction, revealed significant associations (p \u0026lt; 0.001) between the ACE-III and the following: MMSE, the CDR-SB, and the CDR, as well as between the CDR and CDR-SB. Correlations between the \u003cem\u003echange scores\u003c/em\u003e for these variables were not statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. Participant characteristics and clinical outcome measures at baseline and follow up. \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003eBaseline (T0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003eFollow up (T1)\u003c/p\u003e\n \u003cp\u003e(6 months)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003ep-value, T1 versus T0*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eAge, years, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e69.1 (7.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eAge at symptom onset, years, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e63.5 (8.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eEducation, years, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e15.7 (2.4)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eSex, female (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e75\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eSymptom duration, years, median (sd)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e6.1(3.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eLogMAR visual acuity, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e0.24 (0.18)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.39 (0.29)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.06\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eMMSE, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e21.3 (4.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e19.8 (5.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.09\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eACE-III, mean, (sd)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score =100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e65.9 (19.9)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e62.0 (22.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eADCS-ADL, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e58.6 (14.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e55.1 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.16\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e^CDR, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e0.9 (0.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1.0 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.34\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e^CDR-SB, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e4.4 (2.9)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e5.6 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e^CPC-Q, mean (sd) \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e26.8 (10.4)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e29.4 (11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.18\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003e^Q-ACP, mean (sd)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e15.1 (6.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e16.5 (7.0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.11\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 176px;\"\u003e\n \u003cp\u003eVisCorD\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(maximum score = 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 158px;\"\u003e\n \u003cp\u003e2.0 (1.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1.8 (1.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e0.43\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e^higher scores indicate poorer performance or function; *linear mixed model; sd, standard deviation; MMSE, min-mental state examination; ACE-III, Addenbrooke\u0026rsquo;s Cognitive Examination; CDR, clinical dementia rating; CDR-SB, CDR sum of boxes; CPC-Q, Colorado Posterior Cortical Questionnaire; Q-ACP, Posterior Cortical Atrophy questionnaire.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe CPC-Q, which is part of the VisCorD battery, was abnormal (score 7 or more) for 12/12 participants at baseline and six months. Individual performance on other tasks within VisCorD varied, with abnormal performance by 33% to 75% participants on tasks within the battery (see Supplemental Material). The average time to complete the VisCorD was 12.05 minutes, and the CPC-Q took an average of 6.55 minutes to complete. Psychophysical testing revealed severely abnormal perception of CS and GM stimuli (floor/near floor thresholds or inadequate perception of stimuli during training) for 9 of 12 and 6 of 12 participants, respectively. The LIDN stimuli were adequately perceived during training for 12/12 participants, and thresholds were at or near floor for only 3 of 12 participants. The English-translated version of the French-language Q-ACP had an internal consistency of items, measured by Cronbach\u0026rsquo;s alpha, of 0.86 at baseline and 0.89 at six month follow up.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eStatistically significant declines in ACE-III and CDR-SB scores unrelated to age or symptom duration suggests the potential for measurable disease progression with larger cohorts and longer intervals for these outcomes. Furthermore, significant correlations between baseline measures of ACE-III and the MMSE, as well as between the ACE-III and CDR-SB, reinforce the potential utility of ACE-III in assessing and monitoring cognition in PCA, as prior studies have indicated(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). The ACE-III assesses five key domains that include attention, memory, verbal fluency, language, visuospatial/visuoperceptual skills that offers potential greater sensitivity for non-amnestic presentations of mild cognitive impairment or mild dementia. The lack of correlations between change scores for ACE-III and CDR-SB suggests that short-term progression in PCA might be variable across different cognitive and functional measures and the potential need for functional outcomes that specifically target the PCA syndrome. Although, the short time frame and small sample size limit our ability to draw definitive conclusions, the findings align with our clinical observations\u0026mdash;and those of study partners\u0026mdash;that functional scales developed for typical or amnestic Alzheimer\u0026rsquo;s disease may not be adequate for non-amnestic phenotypes.\u003c/p\u003e\u003cp\u003eThe performance of CPC-Q at baseline for our cohort corroborates its previously established validity and relevance as a PCA screening questionnaire(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Its utility for tracking progression needs further investigation over longer time periods and with larger sample sizes. The CPC-Q is part of the Eye Clinic Rapid Screening Battery for Visual Cortical Dysfunction, which was recommended by expert consensus for PCA screening by the PCA Working Party of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Atypical Alzheimer's Disease Professional Interest Area(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Data from this six-month study represents the first report of results from this battery in PCA. The differences in performances between participants observed on other VisCorD tasks likely reflect the heterogeneous nature of visual cortical dysfunction in PCA. Future studies are necessary to determine the VisCorD validity as a screening tool or as a tracking measure for posterior cortical dysfunction.\u003c/p\u003e\u003cp\u003ePsychophysical visual perception testing revealed severe deficits in center-surround contrast discrimination and global motion perception by PCA participants, aligning with known visual processing impairments in PCA while indicating that these tools are ineffective for tracking PCA for cohorts like ours. Given the relatively early stage based on standard measures (mean CDR 0.9 and mean MMSE 21.3), center-surround contrast discrimination and global motion are unlikely to be useful for tracking PCA progression. However, the luminance increment detection task showed fewer instances of floor/near-floor effects, and adjusting the initial luminance difference at the start could improve the task\u0026rsquo;s utility. The English translation version of the Q-ACP had good internal consistency in this small sample size, and additional cross-sectional and longitudinal studies are needed to validate the English version.\u003c/p\u003e\u003cp\u003eAssuming a linear trend, the estimated required sample sizes for a within-subject (paired) design to detect changes over a 12-month period with 80% power and a 0.05 significance level are an n\u0026thinsp;=\u0026thinsp;6 for MMSE, n\u0026thinsp;=\u0026thinsp;5 for CDR-SB, n\u0026thinsp;=\u0026thinsp;5 for ACE-III, n\u0026thinsp;=\u0026thinsp;17 for ADCS-ADL, n\u0026thinsp;=\u0026thinsp;96 for CPC-Q, and n\u0026thinsp;=\u0026thinsp;64 for Q-ACP.\u003c/p\u003e\u003cp\u003eOverall, these preliminary findings inform the design of a future 12-month longitudinal study using standard AD outcome measures with at least 17 participants to gather data for the choice of screening and longitudinal outcome measures. Larger sample sizes are necessary to further assess and validate the English translation of Q-ACP and use of the CPC-Q. Finally, with minor adjustments, luminance increment detection task warrants further investigation as an outcome measure in PCA.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis work was carried out in accordance with the Declaration of Helsinki and approved by Colorado Multiple Institutional Review Board (COMIRB # 23-1125). All participants gave informed consent for participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eDeidentified data will be shared to all those who request the relevant raw data for non-commercial processes and in a manner that does not breach participant confidentiality given the small number of participants in the study. Related documents, including study protocol and the statistical analysis plan, if necessary, can also be shared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the John and Joanne Hare Fund to Accelerate PCA Research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eVSP conceived and led the study, including study design, methodology, data curation, data analysis, and drafted the original manuscript. BB contributed to methodology design, data interpretation, and reviewed and edited the manuscript. AMcK contributed to methodology design, data curation, data interpretation, and reviewed and edited the manuscript. BC contributed to methodology design, data interpretation, and reviewed and edited the manuscript. AM and LN contributed to study design, data curation, and review and editing of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors acknowledge the research participants and their family and friends who made this study possible. This work was presented at a 2025 conference: Pelak VS, Mahmood A, Noteboom L, Croisile B, McKendrick A, Bettcher B. \u0026ldquo;Changes in outcome measures in posterior cortical atrophy: A pilot study for TRAC-PCA\u0026rdquo;. Poster Presentation at the 51st Annual Meeting of the North American Neuro-Ophthalmology Society, Tucson, AZ. March 15-20, 2025.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCrutch SJ, Schott JM, Rabinovici GD, Murray M, Snowden JS, van der Flier WM, et al. Consensus classification of posterior cortical atrophy. Alzheimers Dement. 2017;13(8):870-84.\u003c/li\u003e\n\u003cli\u003eSchott JM, Crutch SJ. Posterior Cortical Atrophy. Continuum (Minneap Minn). 2019;25(1):52-75.\u003c/li\u003e\n\u003cli\u003eSchott JM, Crutch SJ, Carrasquillo MM, Uphill J, Shakespeare TJ, Ryan NS, et al. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer\u0026apos;s disease. Alzheimers Dement. 2016;12(8):862-71.\u003c/li\u003e\n\u003cli\u003eGraff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, et al. New insights into atypical Alzheimer\u0026apos;s disease in the era of biomarkers. Lancet Neurol. 2021;20(3):222-34.\u003c/li\u003e\n\u003cli\u003eS. Crutch. Posterior Cortical Atrophy. Orphanet. 2020.\u003c/li\u003e\n\u003cli\u003eKoedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer\u0026apos;s disease: more than age alone. J Alzheimers Dis. 2010;19(4):1401-8.\u003c/li\u003e\n\u003cli\u003ePelak VS, Mahmood A, Abe-Ridgway K. Perspectives and a Systematic Scoping Review on Longitudinal Profiles of Posterior Cortical Atrophy Syndrome. Curr Neurol Neurosci Rep. 2022;22(11):803-12.\u003c/li\u003e\n\u003cli\u003ePelak VS, Tang-Wai DF, Boeve BF, Bouwman FH, Graff-Radford J, Rabinovici G, et al. Consensus recommendations for clinical assessment tools for the diagnosis of posterior cortical atrophy syndrome from the Atypical AD PIA of ISTAART. Alzheimers Dement (Amst). 2023;15(3):e12474.\u003c/li\u003e\n\u003cli\u003eHolden SK, Pelak VS, Sooy T, Heffernan KS, McConnell BV, Pressman PS, et al. Development of the Colorado posterior cortical questionnaire within an Alzheimer\u0026apos;s disease study cohort. J Clin Exp Neuropsychol. 2022;44(3):226-36.\u003c/li\u003e\n\u003cli\u003eCroisile B, Mollion H. [Q-ACP: a questionnaire for evaluating visual and gestural complaints in patients with posterior cortical atrophy]. Rev Neurol (Paris). 2011;167(6-7):485-94.\u003c/li\u003e\n\u003cli\u003eApolinario D, Lichtenthaler DG, Magaldi RM, Soares AT, Busse AL, Amaral JR, et al. Using temporal orientation, category fluency, and word recall for detecting cognitive impairment: the 10-point cognitive screener (10-CS). Int J Geriatr Psychiatry. 2016;31(1):4-12.\u003c/li\u003e\n\u003cli\u003eFolstein MF, Folstein SE, McHugh PR. \u0026quot;Mini-mental state\u0026quot;. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-98.\u003c/li\u003e\n\u003cli\u003eHsieh S, Schubert S, Hoon C, Mioshi E, Hodges JR. Validation of the Addenbrooke\u0026apos;s Cognitive Examination III in frontotemporal dementia and Alzheimer\u0026apos;s disease. Dement Geriatr Cogn Disord. 2013;36(3-4):242-50.\u003c/li\u003e\n\u003cli\u003eMorris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-4.\u003c/li\u003e\n\u003cli\u003eGalasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer\u0026apos;s disease. The Alzheimer\u0026apos;s Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9.\u003c/li\u003e\n\u003cli\u003eMcKendrick AM, Chan YM, Tien M, Millist L, Clough M, Mack H, et al. Behavioral measures of cortical hyperexcitability assessed in people who experience visual snow. Neurology. 2017;88(13):1243-9.\u003c/li\u003e\n\u003cli\u003eMcKendrick AM, Chan YM, Vingrys AJ, Turpin A, Badcock DR. Daily vision testing can expose the prodromal phase of migraine. Cephalalgia. 2018;38(9):1575-84.\u003c/li\u003e\n\u003cli\u003eTurpin A, Lawson DJ, McKendrick AM. PsyPad: a platform for visual psychophysics on the iPad. J Vis. 2014;14(3):16.\u003c/li\u003e\n\u003cli\u003eOverman MJ, Drummond N, Butler CR, Ahmed S. Tracking the clinical progression of posterior cortical atrophy: implications for post-diagnostic and therapeutic interventions. J Neurol Neurosurg Psychiatry. 2022;93(6):683-4.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Posterior Cortical Atrophy Syndrome, Atypical Alzheimer’s disease, Outcome Measures, Natural History, Clinical Trial Readiness","lastPublishedDoi":"10.21203/rs.3.rs-7066240/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7066240/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePosterior Cortical Atrophy (PCA) is a rare and atypical presentation of neurodegenerative diseases, most commonly Alzheimer\u0026rsquo;s disease (AD). It is characterized by early impairment in visual and other posterior cortical functions. The rarity, the visual phenotype, and lack of longitudinal data hinder inclusion of PCA in AD clinical trials. To inform the design of a 12-month clinical trial readiness study for PCA, we conducted a 6-month study evaluating preliminary responsiveness of standard AD clinical trial outcome measures alongside PCA-targeted assessments.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eTwelve participants with PCA completed the study. Baseline and 6-month follow-up assessments included the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Addenbrooke\u0026rsquo;s Cognitive Examination (ACE-III), Alzheimer\u0026rsquo;s Disease Cooperative Study \u0026ndash; Activities of Daily Living Inventory (ADCS-ADL), and the Colorado Posterior Cortical Questionnaire (CPC-Q). Piloted PCA-targeted assessments included a rapid screening battery for PCA (VisCorD); three psychophysical tasks assessing center-surround contrast discrimination, global dot motion detection, and luminance increment detection in noise; and an English translation of the French-language Self-Assessment Questionnaire of Perceptual Abilities (Q-ACP).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSignificant declines in ACE-III (p\u0026thinsp;=\u0026thinsp;0.02) and CDR-SB (p\u0026thinsp;=\u0026thinsp;0.02), independent of age and symptom duration, were observed. All participants had abnormal CPC-Q scores. Two of three psychophysical tasks showed deficits too severe to be useful for tracking PCA. The Q-ACP demonstrated a high internal consistency.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis 6-month observational study offers preliminary insights into the performance of standard and PCA-specific outcome measures, suggesting that several may be sufficiently responsive and acceptable for a 12-month longitudinal validation study to confirm their utility as endpoints.\u003c/p\u003e","manuscriptTitle":"A Pilot Longitudinal Study of Changes in Clinical Outcome Measures in Posterior Cortical Atrophy Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 09:18:44","doi":"10.21203/rs.3.rs-7066240/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-03-30T16:05:19+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T21:20:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2025-07-16T14:13:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-16T03:14:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-07-11T09:19:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"71f992ca-aeba-4592-82aa-ebf70a857fde","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T09:18:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 09:18:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7066240","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-7066240","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}