{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T16:03:20Z","timestamp":1780675400950,"version":"3.54.1"},"reference-count":51,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Frontal release signs (FRS) are primitive reflexes that regress with brain maturation and reappear in the setting of brain injury or neurodegeneration. Despite their association with dementia, the prognostic utility of this finding in the setting of early cognitive decline and preclinical disease is poorly understood.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate the association of FRS with future cognitive decline in research participants.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study examined the presence of FRS (from 2005-2024) among research cohort participants with intact cognition or mild impairment at study baseline. The study used single-center data collection of longitudinal research cohort data through the Uniform Data Set at the University of Kentucky Alzheimer Disease Research Center (UK ADRC). Participants aged 70 years or older at first assessment were identified at baseline enrollment as having intact cognition or mild impairment based on consensus report and had at least 2 total annual assessments that included standard protocols involving assessment of FRS on neurological exam from the UK ADRC.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Participants were noted to be FRS positive or FRS negative.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The main outcome of interest was incident dementia based on annual consensus diagnosis. Cause-specific hazard models were used to estimate the risk of transition to dementia when at least 2 FRS were present (FRS positive) at baseline vs when 0 or 1 FRS were present (FRS negative), and linear mixed models were used to investigate the association of baseline FRS positivity with cognitive performance over time.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n A total of 873 participants (mean [SD] age, 76.9 [5.6] years; 527 female [60.4%]) were included, with a mean (SD) of 16.1 (2.8) years of education. The prevalence of FRS positivity at baseline was 59 of 672 participants (8.8%) with intact cognition and 48 of 201 participants (23.9%) with mild impairment. FRS positivity was associated with an increased risk of dementia for participants who were cognitively intact; in this group, 15 of 59 participants who were FRS positive (25.4%) progressed to dementia compared with 89 of 613 participants (14.5%) who were FRS negative (hazard ratio, 1.78; 95% CI, 1.02-3.09).<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This study\u2019s findings suggest that FRS may be a quick, noninvasive, and low-cost adjunct to neurological examination with prognostic utility in the earliest stages of cognitive decline.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.17060","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T15:30:21Z","timestamp":1780673421000},"page":"e2617060","source":"Crossref","is-referenced-by-count":0,"title":["Frontal Release Signs and Future Decline in Research Participants With Intact Cognition"],"prefix":"10.1001","volume":"9","author":[{"given":"Lauren G.","family":"Bojarski","sequence":"first","affiliation":[{"name":"University of Kentucky Sanders-Brown Center on Aging, Lexington"},{"name":"Department of Neurology, University of Kentucky Medical Center, Lexington"},{"name":"Epidemiology and Environmental Health, University of Kentucky, Lexington"},{"name":"Now with Department of Neurology, West Virginia University Rockefeller Neuroscience Institute, Morgantown"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Jicha","sequence":"additional","affiliation":[{"name":"University of Kentucky Sanders-Brown Center on Aging, Lexington"},{"name":"Department of Neurology, University of Kentucky Medical Center, Lexington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif Pinar","family":"Coskun","sequence":"additional","affiliation":[{"name":"University of Kentucky Sanders-Brown Center on Aging, Lexington"},{"name":"Department of Neurology, University of Kentucky Medical Center, Lexington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick A.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"University of Kentucky Sanders-Brown Center on Aging, Lexington"},{"name":"Department of Neurology, University of Kentucky Medical Center, Lexington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Van Eldik","sequence":"additional","affiliation":[{"name":"University of Kentucky Sanders-Brown Center on Aging, Lexington"},{"name":"Neuroscience, University of Kentucky, Lexington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L.","family":"Abner","sequence":"additional","affiliation":[{"name":"University of Kentucky Sanders-Brown Center on Aging, Lexington"},{"name":"Epidemiology and Environmental Health, University of Kentucky, Lexington"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"issue":"3A","key":"zoi260478r1","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1590\/S0004-282X2005000400004","article-title":"Primitive reflexes and cognitive function.","volume":"63","author":"Damasceno","year":"2005","journal-title":"Arq Neuropsiquiatr"},{"issue":"3","key":"zoi260478r2","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1002\/ana.410120316","article-title":"Primitive reflexes and cognitive function in the elderly.","volume":"12","author":"Koller","year":"1982","journal-title":"Ann Neurol"},{"issue":"12","key":"zoi260478r3","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1111\/j.1532-5415.1991.tb03567.x","article-title":"Clinical significance of primitive reflexes in Alzheimer\u2019s disease.","volume":"39","author":"Molloy","year":"1991","journal-title":"J Am Geriatr Soc"},{"key":"zoi260478r4","first-page":"169","article-title":"The neurological examination in dementia.","volume":"15","author":"Paulson","year":"1977","journal-title":"Contemp Neurol Ser"},{"key":"zoi260478r5","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1007\/PL00014170","article-title":"Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer\u2019s and other dementing processes.","volume":"249","author":"Reisberg","year":"1999","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"issue":"1","key":"zoi260478r6","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/j.1600-0404.1989.tb03707.x","article-title":"Relationship between primitive reflexes, extra-pyramidal signs, reflective apraxia and severity of cognitive impairment in dementia of the Alzheimer type.","volume":"79","author":"Bakchine","year":"1989","journal-title":"Acta Neurol Scand"},{"issue":"3","key":"zoi260478r7","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1161\/01.STR.9.3.256","article-title":"Relationship between primitive reflexes in stroke patients and rehabilitation outcome.","volume":"9","author":"Botvin","year":"1978","journal-title":"Stroke"},{"key":"zoi260478r8","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1017\/S1041610297005036","article-title":"Neurologic markers of the progression of Alzheimer\u2019s disease.","volume":"9","author":"Franssen","year":"1997","journal-title":"Int Psychogeriatr"},{"issue":"5","key":"zoi260478r9","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1093\/ageing\/24.5.375","article-title":"Primitive reflexes and dementia: results from the Canadian Study of Health and Aging.","volume":"24","author":"Hogan","year":"1995","journal-title":"Age Ageing"},{"issue":"4","key":"zoi260478r10","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1176\/jnp.2009.21.4.463","article-title":"Subtle neurological signs predict the severity of subacute cognitive and functional impairments after traumatic brain injury.","volume":"21","author":"Wortzel","year":"2009","journal-title":"J Neuropsychiatry Clin Neurosci"},{"issue":"2","key":"zoi260478r11","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1159\/000052103","article-title":"Usefulness of primitive reflexes in demented and non-demented cerebrovascular patients in daily clinical practice.","volume":"45","author":"Di Legge","year":"2001","journal-title":"Eur Neurol"},{"issue":"2","key":"zoi260478r12","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1177\/089198879500800207","article-title":"Primitive reflexes in Alzheimer\u2019s disease and vascular dementia.","volume":"8","author":"Vreeling","year":"1995","journal-title":"J Geriatr Psychiatry Neurol"},{"issue":"3","key":"zoi260478r13","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1111\/psyg.13098","article-title":"Primitive reflexes and dementia in older adults: a meta-analysis of observational and cohort studies.","volume":"24","author":"Altunkalem Seydi","year":"2024","journal-title":"Psychogeriatrics"},{"issue":"7","key":"zoi260478r14","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1007\/s00415-006-0138-7","article-title":"Prevalence of primitive reflexes and the relationship with cognitive change in healthy adults: a report from the Maastricht Aging Study.","volume":"253","author":"van Boxtel","year":"2006","journal-title":"J Neurol"},{"issue":"1","key":"zoi260478r15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1212\/CPJ.0000000000001135","article-title":"Primitive reflexes and dementia in adults with Down syndrome.","volume":"12","author":"Harp","year":"2022","journal-title":"Neurol Clin Pract"},{"issue":"1","key":"zoi260478r16","doi-asserted-by":"publisher","first-page":"59","DOI":"10.2967\/jnumed.111.096578","article-title":"Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature.","volume":"53","author":"Bohnen","year":"2012","journal-title":"J Nucl Med"},{"issue":"5","key":"zoi260478r17","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1212\/WNL.0b013e31829d86e8","article-title":"Imaging markers for Alzheimer disease: which vs how.","volume":"81","author":"Frisoni","year":"2013","journal-title":"Neurology"},{"issue":"2","key":"zoi260478r18","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1046\/j.1532-5415.2003.51067.x","article-title":"The value of positron emission tomography in the clinical evaluation of dementia.","volume":"51","author":"Gill","year":"2003","journal-title":"J Am Geriatr Soc"},{"issue":"6","key":"zoi260478r19","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.neuron.2013.12.003","article-title":"Biomarker modeling of Alzheimer\u2019s disease.","volume":"80","author":"Jack","year":"2013","journal-title":"Neuron"},{"issue":"6","key":"zoi260478r20","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/ana.22628","article-title":"An operational approach to National Institute on Aging-Alzheimer\u2019s Association criteria for preclinical Alzheimer disease.","volume":"71","author":"Jack","year":"2012","journal-title":"Ann Neurol"},{"issue":"12","key":"zoi260478r21","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1001\/archneurol.2011.183","article-title":"Evidence for ordering of Alzheimer disease biomarkers.","volume":"68","author":"Jack","year":"2011","journal-title":"Arch Neurol"},{"issue":"7","key":"zoi260478r22","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1001\/archneurol.2011.3405","article-title":"Shapes of the trajectories of 5 major biomarkers of Alzheimer disease.","volume":"69","author":"Jack","year":"2012","journal-title":"Arch Neurol"},{"issue":"1","key":"zoi260478r23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.3233\/JAD-2010-1237","article-title":"Conceptual evolution in Alzheimer\u2019s disease: implications for understanding the clinical phenotype of progressive neurodegenerative disease.","volume":"19","author":"Jicha","year":"2010","journal-title":"J Alzheimers Dis"},{"issue":"11","key":"zoi260478r24","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1212\/WNL.0b013e31828728ac","article-title":"Alzheimer disease biomarkers and insights into mild cognitive impairment.","volume":"80","author":"Knopman","year":"2013","journal-title":"Neurology"},{"issue":"8","key":"zoi260478r25","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1016\/j.neurobiolaging.2010.04.029","article-title":"Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort.","volume":"31","author":"Risacher","year":"2010","journal-title":"Neurobiol Aging"},{"issue":"5","key":"zoi260478r26","first-page":"401","article-title":"Advances in diagnostic testing for Alzheimer disease.","volume":"110","author":"Schindler","year":"2013","journal-title":"Mo Med"},{"issue":"3","key":"zoi260478r27","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease.","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimers Dement"},{"issue":"4","key":"zoi260478r28","doi-asserted-by":"publisher","first-page":"538","DOI":"10.2174\/1871527311312040016","article-title":"Strength and weaknesses of cerebrospinal fluid biomarkers in Alzheimer\u2019s disease and possible detection of overlaps with frailty process.","volume":"12","author":"Stefani","year":"2013","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"18","key":"zoi260478r30","doi-asserted-by":"publisher","first-page":"2781","DOI":"10.1016\/j.neuron.2023.05.017","article-title":"Blood-based biomarkers for Alzheimer\u2019s disease: current state and future use in a transformed global healthcare landscape.","volume":"111","author":"Hampel","year":"2023","journal-title":"Neuron"},{"issue":"11","key":"zoi260478r31","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/s41582-018-0079-7","article-title":"Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.","volume":"14","author":"Hampel","year":"2018","journal-title":"Nat Rev Neurol"},{"issue":"3","key":"zoi260478r32","doi-asserted-by":"publisher","first-page":"371","DOI":"10.14283\/jpad.2021.23","article-title":"Diagnosis of early Alzheimer\u2019s disease: clinical practice in 2021.","volume":"8","author":"Porsteinsson","year":"2021","journal-title":"J Prev Alzheimers Dis"},{"issue":"6","key":"zoi260478r33","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1038\/s41591-025-03605-x","article-title":"Blood-based biomarkers of Alzheimer\u2019s disease and incident dementia in the community.","volume":"31","author":"Grande","year":"2025","journal-title":"Nat Med"},{"issue":"3","key":"zoi260478r34","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1007\/s00415-025-12996-3","article-title":"Blood phosphorylated tau217 distinguishes amyloid-positive from amyloid-negative subjects in the Alzheimer\u2019s disease continuum: a systematic review and meta-analysis.","volume":"272","author":"Antonioni","year":"2025","journal-title":"J Neurol"},{"issue":"5","key":"zoi260478r35","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70181","article-title":"Celebrating 40 years of the University of Kentucky Alzheimer\u2019s Disease Research Center.","volume":"21","author":"Schmitt","year":"2025","journal-title":"Alzheimers Dement"},{"issue":"4","key":"zoi260478r36","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1097\/01.wad.0000213865.09806.92","article-title":"The Uniform Data Set (UDS): clinical and cognitive variables and descriptive data from Alzheimer Disease Centers.","volume":"20","author":"Morris","year":"2006","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"6","key":"zoi260478r37","doi-asserted-by":"publisher","first-page":"724","DOI":"10.2174\/156720512801322591","article-title":"University of Kentucky Sanders-Brown healthy brain aging volunteers: donor characteristics, procedures and neuropathology.","volume":"9","author":"Schmitt","year":"2012","journal-title":"Curr Alzheimer Res"},{"issue":"2","key":"zoi260478r38","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1097\/WAD.0000000000000111","article-title":"Results from the NACC Uniform Data Set neuropsychological battery crosswalk study.","volume":"30","author":"Monsell","year":"2016","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"2","key":"zoi260478r39","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1097\/WAD.0b013e318191c7dd","article-title":"The Alzheimer\u2019s Disease Centers\u2019 Uniform Data Set (UDS): the neuropsychologic test battery.","volume":"23","author":"Weintraub","year":"2009","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"2","key":"zoi260478r40","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1097\/WAD.0b013e3181ffa76d","article-title":"Factor structure of the National Alzheimer\u2019s Coordinating Centers uniform dataset neuropsychological battery: an evaluation of invariance between and within groups over time.","volume":"25","author":"Hayden","year":"2011","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"27","key":"zoi260478r42","doi-asserted-by":"publisher","first-page":"4391","DOI":"10.1002\/sim.7501","article-title":"Practical recommendations for reporting Fine-Gray model analyses for competing risk data.","volume":"36","author":"Austin","year":"2017","journal-title":"Stat Med"},{"issue":"12","key":"zoi260478r43","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1001\/archneur.1993.00540120024008","article-title":"End-stage Alzheimer\u2019s disease: Glasgow Coma Scale and the neurologic examination.","volume":"50","author":"Benesch","year":"1993","journal-title":"Arch Neurol"},{"issue":"6","key":"zoi260478r44","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1093\/arclin\/acu038.80","article-title":"Neuropsychological prediction of diagnostic stability of mild cognitive impairment.","volume":"29","author":"Clem","year":"2014","journal-title":"Arch Clin Neuropsychol"},{"issue":"12","key":"zoi260478r45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113535","article-title":"A clinical index to predict progression from mild cognitive impairment to dementia due to Alzheimer\u2019s disease.","volume":"9","author":"Lee","year":"2014","journal-title":"PLoS One"},{"key":"zoi260478r46","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.nicl.2013.11.010","article-title":"Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers.","volume":"4","author":"Da","year":"2013","journal-title":"Neuroimage Clin"},{"issue":"1","key":"zoi260478r47","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3233\/JAD-141053","article-title":"Multimodal prediction of dementia with up to 10 years follow up: the Gothenburg MCI study.","volume":"44","author":"Eckerstrom","year":"2015","journal-title":"J Alzheimers Dis"},{"issue":"2","key":"zoi260478r48","doi-asserted-by":"publisher","first-page":"625","DOI":"10.3233\/JAD-141716","article-title":"Varying strength of cognitive markers and biomarkers to predict conversion and cognitive decline in an early-stage-enriched mild cognitive impairment sample.","volume":"44","author":"Egli","year":"2015","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"zoi260478r49","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3233\/JAD-140942","article-title":"Generalizability of the disease state index prediction model for identifying patients progressing from mild cognitive impairment to Alzheimer\u2019s disease.","volume":"44","author":"Hall","year":"2014","journal-title":"J Alzheimers Dis"},{"key":"zoi260478r50","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.nicl.2014.08.023","article-title":"Random forest ensembles for detection and prediction of Alzheimer\u2019s disease with a good between-cohort robustness.","volume":"6","author":"Lebedev","year":"2014","journal-title":"Neuroimage Clin"},{"issue":"1","key":"zoi260478r51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082450","article-title":"Hierarchical interactions model for predicting mild cognitive impairment (MCI) to Alzheimer\u2019s disease (AD) conversion.","volume":"9","author":"Li","year":"2014","journal-title":"PLoS One"},{"key":"zoi260478r41","volume-title":"Recent Developments in Parkinson\u2019s Disease","author":"Fahn","year":"1987"},{"key":"zoi260478r29","unstructured":"US Food and Drug Administration. FDA clears first blood test used in diagnosing Alzheimer\u2019s disease. May 16, 2025. Accessed April 23, 2026. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-clears-first-blood-test-used-diagnosing-alzheimers-disease"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2849942\/bojarski_2026_oi_260478_1780001348.90476.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T15:30:24Z","timestamp":1780673424000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2849942"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":51,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2026.17060","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]}}}