Browsing by Author "Mielke, Michelle M."
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Item Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health‐related comorbidities in a community‐dwelling cohort(Wiley, 2024) Rudolph, Marc D.; Sutphen, Courtney L.; Register, Thomas C.; Whitlow, Christopher T.; Solingapuram Sai, Kiran K.; Hughes, Timothy M.; Bateman, James R.; Dage, Jeffrey L.; Russ, Kristen A.; Mielke, Michelle M.; Craft, Suzanne; Lockhart, Samuel N.; Neurology, School of MedicineIntroduction: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. Methods: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Results: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. Discussion: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Highlights: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.Item Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline(Wiley, 2022) Mielke, Michelle M.; Aakre, Jeremiah A.; Algeciras-Schimnich, Alicia; Proctor, Nicholas K.; Machulda, Mary M.; Eichenlaub, Udo; Knopman, David S.; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jac, Clifford R., Jr.; Petersen, Ronald C.; Dage, Jeffrey L.; Neurology, School of MedicineIntroduction: The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood. Methods: Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p-tau181 were measured with Elecsys immunoassays. CSF p-tau181 and p-tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain-specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging. Results: CSF p-tau217 was superior to p-tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p-tau181 and p-tau217 were associated with risk of MCI among amyloid-positive individuals. Differences between CSF p-tau measures predicting cortical thickness were subtle. Discussion: There are subtle differences for CSF p-tau217 and p-tau181 as prognostic AD markers.Item Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes(American Medical Association, 2021) Mielke, Michelle M.; Frank, Ryan D.; Dage, Jeffrey L.; Jeromin, Andreas; Ashton, Nicholas J.; Blennow, Kaj; Karikari, Thomas K.; Vanmechelen, Eugene; Zetterberg, Henrik; Algeciras-Schimnich, Alicia; Knopman, David S.; Lowe, Val; Bu, Guojun; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Petersen, Ronald C.; Neurology, School of MedicineImportance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed. Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. Design, setting, and participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. Main outcomes and measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. Conclusions and relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.Item A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease(Elsevier, 2014-11) Jessen, Frank; Amariglio, Rebecca E.; van Boxtel, Martin; Breteler, Monique; Ceccaldi, Mathieu; Chételat, Gaël; Dubois, Bruno; Dufouil, Carole; Ellis, Kathryn A.; van der Flier, Wiesje M.; Glodzik, Lidia; van Harten, Argonde C.; de Leon, Mony J.; McHugh, Pauline; Mielke, Michelle M.; Molinuevo, Jose Luis; Mosconi, Lisa; Osorio, Ricardo S.; Perrotin, Audrey; Petersen, Ronald C.; Rabin, Laura A.; Rami, Lorena; Reisberg, Barry; Rentz, Dorene M.; Sachdev, Perminder S.; de la Sayette, Vincent; Saykin, Andrew J.; Scheltens, Philip; Shulman, Melanie B.; Slavin, Melissa J.; Sperling, Reisa A.; Stewart, Robert; Uspenskaya, Olga; Vellas, Bruno; Visser, Pieter Jelle; Wagner, Michael; Department of Radiology and Imaging Sciences, IU School of MedicineThere is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.Item Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease(Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; VandeVrede, Lawren; Willis, Deanna; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael W.; Udeh-Momoh , Chinedu T.; Medicine, School of MedicineDiagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders.Item Discovery of Genes Underlying Cognitive Resilience in Individuals Predisposed to Alzheimer's Disease Risk(Wiley, 2025-01-09) Tsai, Wei; McNiff, Caitlin E.; Reddy, Joseph S.; Wang, Xue; Quicksall, Zachary; Nho, Kwangsik; Dunn, Amy R.; Allen, Mariet; Heckman, Michael G.; Ren, Yingxue; Zhao, Na; Kantarci, Kejal; Mielke, Michelle M.; Petersen, Ronald C.; Kaczorowski, Catherine C.; Carrasquillo, Minerva M.; Saykin, Andrew J.; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of MedicineBackground: Two main risk factors of Alzheimer’s disease (AD) are aging and APOE‐ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered “cognitively resilient”. This study aimed to identify molecular factors that confer cognitive resilience in APOE‐ε4 carriers ≥ 80 years of age and may serve as biomarkers. Method: We applied weighted gene co‐expression network analysis (WGCNA) to generate consensus co‐expression networks from blood of participants in two antemortem cohorts, the Mayo Clinic Study of Aging (MCSA, n=105), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=91), using RNA‐sequencing and microarray data, respectively. We associated these networks with resilience (resilient vs non‐resilient), cognitive endophenotypes and hippocampal volume. Preservation between consensus networks from blood and those derived from postmortem brain tissues of AD and control donors from AMP‐AD (n=1174) was evaluated. We validated the human findings in four AD mouse models. Finally, machine learning models were utilized to discriminate cases (AD+mild cognitive impairment (MCI)) from controls in MCSA, ADNI and ANMerge antemortem cohorts. Result: Four consensus networks were significantly correlated with a memory phenotype (logical memory delayed recall=LMDR) and hippocampal volume in both MCSA and ADNI. Among these, blood expression module M3 was most preserved with the brain transcriptome. M3 was enriched with NDUF hub genes that are involved in the mitochondrial respiratory chain. Expression levels of M3 and many blood NDUFs had significant associations with better LMDR and hippocampal volume. In brain, NDUFs were upregulated in controls compared to AD, and their expression levels were associated with better global cognition and decreased AD neuropathology. Many NDUFs were significantly downregulated in the hippocampus or cortex of AD mice compared to wild‐types. Lastly, models that included blood NDUFs improved diagnostic accuracy of AD+MCI compared to models that only included demographic and risk variables (age, sex, APOE‐ε4) in MCSA, ADNI and ANMerge. In MCSA and ADNI, adding NDUFs’ expression to models that included established blood biomarkers (Aβ42/40, ptau181, NFL) further improved diagnostic accuracy. Conclusion: Our results suggest that mitochondrial NDUFs are centrally‐linked peripheral molecular signatures that may be resilience factors against AD and serve as both therapeutic targets and novel diagnostic biomarkers.Item Evaluation of the Effect of Systolic Blood Pressure and Pulse Pressure on Cognitive Function: The Women's Health and Aging Study II(Public Library of Science, 2011) Yasar, Sevil; Ko, Jean Y.; Nothelle, Stephanie; Mielke, Michelle M.; Carlson, Michelle C.; Medicine, School of MedicineBackground: Evidence suggests that elevated systolic blood pressure (SBP) and pulse pressure (PP) in midlife is associated with increased risk for cognitive impairment later in life. There is mixed evidence regarding the effects of late life elevated SBP or PP on cognitive function, and limited information on the role of female gender. Methods/principal findings: Effects of SBPand PPon cognitive abilities at baseline and over a 9-year period were evaluated in 337 non-demented community-dwelling female participants over age 70 in the Women's Health and Aging Study II using logistic and Cox proportional hazards regression analyses. Participants aged 76-80 years with SBP≥160 mmHg or PP≥84 mmHg showed increased incidence of impairment on Trail Making Test-Part B (TMT, Part B), a measure of executive function, over time when compared to the control group that included participants with normal and pre-hypertensive SBP (<120 and 120-139 mmHg) or participants with low PP (<68 mmHg) (HR = 5.05 [95%CI = 1.42, 18.04], [HR = 5.12 [95%CI = 1.11; 23.62], respectively). Participants aged 70-75 years with PP≥71 mmHg had at least a two-fold higher incidence of impairment on HVLT-I, a measure of verbal learning, over time when compared to participants with low PP (<68 mmHg) (HR = 2.44 [95%CI = 1.11, 5.39]). Conclusions/significance: Our data suggest that elevated SBP or PP in older non-demented women increases risk for late-life cognitive impairment and that PP could be used when assessing the risk for impairment in cognitive abilities. These results warrant further, larger studies to evaluate possible effects of elevated blood pressure in normal cognitive aging.Item Global neuropathologic severity of Alzheimer's disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels(Springer, 2022-12-27) Murray, Melissa E.; Moloney, Christina M.; Kouri, Naomi; Syrjanen, Jeremy A.; Matchett, Billie J.; Rothberg, Darren M.; Tranovich, Jessica F.; Hicks Sirmans, Tiffany N.; Wiste, Heather J.; Boon, Baayla D. C.; Nguyen, Aivi T.; Reichard, R. Ross; Dickson, Dennis W.; Lowe, Val J.; Dage, Jeffrey L.; Petersen, Ronald C.; Jack, Clifford R., Jr.; Knopman , David S.; Vemuri, Prashanthi; Graff-Radford, Jonathan; Mielke, Michelle M.; Neurology, School of MedicineBackground Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer’s disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. Methods We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated. Results The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R2 = 0.31) and 59% in plasma p-tau217 (Adj. R2 = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm2 was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R2 = 0.25–0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously. Conclusions Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration.Item Implementing a biomarker‐enabled care pathway to accelerate identification of early‐stage Alzheimer’s disease in primary care(Wiley, 2025-01-09) Borson, Soo; Au, Rhoda; Chodos, Anna H.; Gandy, Sam E.; Jain, Holly; Kerwin, Diana R.; Mintzer, Jacobo; Monroe, Stephanie; Robinson, Delecia; Wilcock, Donna M.; Mielke, Michelle M.; Neurology, School of MedicineBackground: New blood‐based and digital biomarkers for Alzheimer’s disease (AD) make early detection possible at stages when novel, disease‐specific therapies are likely to be most effective. These approaches may offer less invasive, more cost‐effective alternatives to traditional methods such as cerebrospinal fluid (CSF) collection or positron emission tomography (PET) imaging for diagnosing and staging AD. Building care pathways leveraging blood‐based and digital biomarkers starts with understanding the current biomarker landscape and considering opportunities for widespread implementation in primary care clinical practice. Methods: A multidisciplinary team representing neurology, neuropsychology, geriatrics, primary care, epidemiology, laboratory programs, and patient advocacy was convened to review a summary of current biomarker research findings and discuss barriers and opportunities to implement biomarkers as part of an AD consensus‐driven clinical care pathway. Results: The emergence of biomarkers has shifted diagnosis from primarily clinical to a biological definition of AD. However, there is currently no consensus on where biomarkers fit within an AD care pathway and when they should be utilized in primary care or dementia specialist care settings. We found a relative paucity of published data on biomarker test accuracy in diagnosis outside tightly controlled research settings, limiting guidance around how results should be interpreted and managed in real‐world care settings. Evidence gaps are especially pressing for heterogeneous, diverse populations under‐represented in AD research. New biomedical therapies specific to the pathobiology of AD are driving research on blood and digital biomarkers to inform optimal ways to accelerate identification. As most individuals with AD are not evaluated by specialists, accurate and usable information about the place of biomarkers in the diagnosis and treatment of cognitive impairment must reach primary care Conclusions: With growing interest in the promise of non‐invasive biomarkers to improve detection, differentiation, and diagnosis of AD, new research is needed to generate real‐world evidence about their performance across populations, how to interpret results, and how best to use them in patient management. Effective educational strategies are needed to disseminate high‐quality evidence that engages primary care and healthcare delivery systems in implementing optimal clinical pathways. More detailed learnings for successful care pathway implementation will be shared.Item Implementing early detection of cognitive impairment in primary care to improve care for older adults(Wiley, 2025) Fowler, Nicole R.; Partrick, Katherine A.; Taylor, James; Hornbecker, Michael; Kelleher, Kevin; Boustani, Malaz; Cummings, Jeffrey L.; MacLeod, Tim; Mielke, Michelle M.; Brosch, Jared R.; Lee, Janice; Shobin, Eli; Galvin, James E.; Fillit, Howard; Udeh-Momoh, Chinedu; Willis, Deanna R.; Medicine, School of MedicinePrimary care is the ideal setting for early detection of mild cognitive impairment (MCI) and Alzheimer's disease and related dementias (ADRD), as it serves as the primary point of care for most older adults. With the growing aging population, reliance on specialists for detection and diagnosis is unsustainable, highlighting the need for primary care-led assessment. Recent research findings on successful brain health prevention strategies, AD diagnostic tools, and anti-amyloid treatments empower primary care to play a central role in early detection and intervention. Primary care-focused resources are being developed, including tools for cognitive assessments and materials designed to educate patients about brain health and initiate discussions on lifestyle modifications, thereby making early detection more feasible and efficient. Identifying risk factors early enables providers to implement interventions that can slow cognitive decline and improve outcomes for patients and caregivers. If left undetected and unmanaged, MCI and ADRD can lead to worse outcomes, including increased falls, hospitalizations, financial vulnerability, and caregiver stress. Early detection enables the identification of reversible causes of cognitive impairment, supports the management of comorbidities worsened by cognitive decline, mitigates safety risks, and can preserve quality of life. Importantly, primary care is essential for addressing ADRD-related health disparities that disproportionately affect racial minorities, rural populations, and those of lower socioeconomic status. With a focus on the United States healthcare system, this perspective addresses how implementing early detection practices into primary care can improve outcomes for patients and caregivers, reduce societal burdens, and promote health equity in ADRD care.