Publications by authors named "Prashanthi Vemuri"

185 Publications

Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Eli Lilly and Company, Indianapolis, Indiana, USA.

Introduction: 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.
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http://dx.doi.org/10.1002/alz.12415DOI Listing
July 2021

Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes.

JAMA Neurol 2021 Jul 26. Epub 2021 Jul 26.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.

Importance: 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.
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http://dx.doi.org/10.1001/jamaneurol.2021.2293DOI Listing
July 2021

Diffusion models reveal white matter microstructural changes with ageing, pathology and cognition.

Brain Commun 2021 19;3(2):fcab106. Epub 2021 May 19.

Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.

White matter microstructure undergoes progressive changes during the lifespan, but the neurobiological underpinnings related to ageing and disease remains unclear. We used an advanced diffusion MRI, Neurite Orientation Dispersion and Density Imaging, to investigate the microstructural alterations due to demographics, common age-related pathological processes (amyloid, tau and white matter hyperintensities) and cognition. We also compared Neurite Orientation Dispersion and Density Imaging findings to the older Diffusion Tensor Imaging model-based findings. Three hundred and twenty-eight participants (264 cognitively unimpaired, 57 mild cognitive impairment and 7 dementia with a mean age of 68.3 ± 13.1 years) from the Mayo Clinic Study of Aging with multi-shell diffusion imaging, fluid attenuated inversion recovery MRI as well as amyloid and tau PET scans were included in this study. White matter tract level diffusion measures were calculated from Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging. Pearson correlation and multiple linear regression analyses were performed with diffusion measures as the outcome and age, sex, education/occupation, white matter hyperintensities, amyloid and tau as predictors. Analyses were also performed with each diffusion MRI measure as a predictor of cognitive outcomes. Age and white matter hyperintensities were the strongest predictors of all white matter diffusion measures with low associations with amyloid and tau. However, neurite density decrease from Neurite Orientation Dispersion and Density Imaging was observed with amyloidosis specifically in the temporal lobes. White matter integrity (mean diffusivity and free water) in the corpus callosum showed the greatest associations with cognitive measures. All diffusion measures provided information about white matter ageing and white matter changes due to age-related pathological processes and were associated with cognition. Neurite orientation dispersion and density imaging and diffusion tensor imaging are two different diffusion models that provide distinct information about variation in white matter microstructural integrity. Neurite Orientation Dispersion and Density Imaging provides additional information about synaptic density, organization and free water content which may aid in providing mechanistic insights into disease progression.
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http://dx.doi.org/10.1093/braincomms/fcab106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202149PMC
May 2021

Selecting software pipelines for change in flortaucipir SUVR: Balancing repeatability and group separation.

Neuroimage 2021 Sep 9;238:118259. Epub 2021 Jun 9.

Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester 55905, MN, USA.

Since tau PET tracers were introduced, investigators have quantified them using a wide variety of automated methods. As longitudinal cohort studies acquire second and third time points of serial within-person tau PET data, determining the best pipeline to measure change has become crucial. We compared a total of 415 different quantification methods (each a combination of multiple options) according to their effects on a) differences in annual SUVR change between clinical groups, and b) longitudinal measurement repeatability as measured by the error term from a linear mixed-effects model. Our comparisons used MRI and Flortaucipir scans of 97 Mayo Clinic study participants who clinically either: a) were cognitively unimpaired, or b) had cognitive impairments that were consistent with Alzheimer's disease pathology. Tested methods included cross-sectional and longitudinal variants of two overarching pipelines (FreeSurfer 6.0, and an in-house pipeline based on SPM12), three choices of target region (entorhinal, inferior temporal, and a temporal lobe meta-ROI), five types of partial volume correction (PVC) (none, two-compartment, three-compartment, geometric transfer matrix (GTM), and a tau-specific GTM variant), seven choices of reference region (cerebellar crus, cerebellar gray matter, whole cerebellum, pons, supratentorial white matter, eroded supratentorial WM, and a composite of eroded supratentorial WM, pons, and whole cerebellum), two choices of region masking (GM or GM and WM), and two choices of statistic (voxel-wise mean vs. median). Our strongest findings were: 1) larger temporal-lobe target regions greatly outperformed entorhinal cortex (median sample size estimates based on a hypothetical clinical trial were 520-526 vs. 1740); 2) longitudinal processing pipelines outperformed cross-sectional pipelines (median sample size estimates were 483 vs. 572); and 3) reference regions including supratentorial WM outperformed traditional cerebellar and pontine options (median sample size estimates were 370 vs. 559). Altogether, our results favored longitudinally SUVR methods and a temporal-lobe meta-ROI that includes adjacent (juxtacortical) WM, a composite reference region (eroded supratentorial WM + pons + whole cerebellum), 2-class voxel-based PVC, and median statistics.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118259DOI Listing
September 2021

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology.

Alzheimers Dement 2021 May 21. Epub 2021 May 21.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [ F]Florbetaben and [ F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.
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http://dx.doi.org/10.1002/alz.12350DOI Listing
May 2021

White matter abnormalities are key components of cerebrovascular disease impacting cognitive decline.

Brain Commun 2021 12;3(2):fcab076. Epub 2021 Apr 12.

Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.

While cerebrovascular disease can be observed using MRI, the multiplicity and heterogeneity in the mechanisms of cerebrovascular damage impede accounting for these measures in ageing and dementia studies. Our primary goal was to investigate the key sources of variability across MRI markers of cerebrovascular disease and evaluate their impact in comparison to amyloidosis on cognitive decline in a population-based sample. Our secondary goal was to evaluate the prognostic utility of a cerebrovascular summary measure from all markers. We included both visible lesions seen on MRI (white matter hyperintensities, cortical and subcortical infarctions, lobar and deep microbleeds) and early white matter damage due to systemic vascular health using diffusion changes in the genu of the corpus callosum. We identified 1089 individuals aged ≥60 years with concurrent amyloid-PET and MRI scans from the population-based Mayo Clinic Study of Aging. We divided these into discovery and validation datasets. Using the discovery dataset, we conducted principal component analyses and ascertained the main sources of variability in cerebrovascular disease markers. Using linear regression and mixed effect models, we evaluated the utility of these principal components and combinations of these components for the prediction of cognitive performance along with amyloidosis. Our main findings were (i) there were three primary sources of variability among the CVD measures-white matter changes are driven by white matter hyperintensities and diffusion changes; number of microbleeds (lobar and deep); and number of infarctions (cortical and subcortical); (ii) Components of white matter changes and microbleeds but not infarctions significantly predicted cognition trajectories in all domains with greater contributions from white matter; and (iii) The summary vascular score explained 3-5% of variability in baseline global cognition in comparison to 3-6% variability explained by amyloidosis. Across all cognitive domains, the vascular summary score had the least impact on memory performance (∼1%). Though there is mechanistic heterogeneity in the cerebrovascular disease markers measured on MRI, these changes can be grouped into three components and together explain variability in cognitive performance equivalent to the impact of amyloidosis on cognition. White matter changes represent dynamic ongoing damage, predicts future cognitive decline across all domains and diffusion measurements help capture white matter damage due to systemic vascular changes. Therefore, measuring and accounting for white matter changes using diffusion MRI and white matter hyperintensities along with microbleeds will allow us to capture vascular contributions to cognitive impairment and dementia.
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http://dx.doi.org/10.1093/braincomms/fcab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072521PMC
April 2021

Lipidomic Network of Mild Cognitive Impairment from the Mayo Clinic Study of Aging.

J Alzheimers Dis 2021 ;81(2):533-543

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

Background: Lipid alterations contribute to Alzheimer's disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers.

Objective: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groupsMethods:Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without.

Results: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses.

Conclusion: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.
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http://dx.doi.org/10.3233/JAD-201347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154710PMC
January 2021

NIA-AA Alzheimer's Disease Framework: Clinical Characterization of Stages.

Ann Neurol 2021 06 6;89(6):1145-1156. Epub 2021 Apr 6.

Department of Radiology, Mayo Clinic, Rochester, MN.

Background: To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid.

Methods: The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.

Results: Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).

Interpretation: The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145-1156.
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http://dx.doi.org/10.1002/ana.26071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131266PMC
June 2021

Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology.

Acta Neuropathol Commun 2021 03 23;9(1):48. Epub 2021 Mar 23.

Department of Radiology, Mayo Clinic-Minnesota, 200 First Street SW, Rochester, MN, 55905, USA.

Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.
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http://dx.doi.org/10.1186/s40478-021-01154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986461PMC
March 2021

Cerebral Amyloid Angiopathy Burden and Cerebral Microbleeds: Pathological Evidence for Distinct Phenotypes.

J Alzheimers Dis 2021 ;81(1):113-122

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia.

Objective: To determine whether CMBs on antemortem MRI correlate with CAA.

Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs.

Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs.

Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOEɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.
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http://dx.doi.org/10.3233/JAD-201536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113155PMC
January 2021

Study of Symptomatic vs. Silent Brain Infarctions on MRI in Elderly Subjects.

Front Neurol 2021 17;12:615024. Epub 2021 Feb 17.

Departments of Radiology, Mayo Clinic, Rochester, MN, United States.

Brain infarctions are closely associated with future risk of stroke and dementia. Our goal was to report (i) frequency and characteristics that differentiate symptomatic vs. silent brain infarctions (SBI) on MRI and (ii) frequency and location by vascular distribution (location of stroke by major vascular territories) in a population based sample. From Mayo Clinic Study of Aging, 347 participants (≥50 years) with infarcts detected on their first MRI were included. Infarct information was identified visually on a FLAIR MRI image and a vascular territory atlas was registered to the FLAIR image data in order to identify the arterial territory of infarction. We identified the subset with a clinical history of stroke based on medical chart review and used a logistic regression to evaluate the risk factors associated with greater probability of a symptomatic stroke vs. SBI. We found that 14% of all individuals with infarctions had a history of symptomatic stroke (Silent: = 300, symptomatic: = 47). Factors associated with a symptomatic vs. SBI were size which had an odds ratio of 3.07 ( < 0.001), greater frequency of hypertension (odds ratio of 4.12, = 0.025) and alcohol history (odds ratio of 4.58, = 0.012). The frequency of infarcts was greater in right hemisphere compared to the left for SBI. This was primarily driven by middle cerebral artery (MCA) infarcts (right = 60%, left = 40%, = 0.005). While left hemisphere strokes are more common for symptomatic carotid disease and in clinical trials, right hemispheric infarcts may be more frequent in the SBI group.
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http://dx.doi.org/10.3389/fneur.2021.615024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925615PMC
February 2021

Comparison of CSF neurofilament light chain, neurogranin, and tau to MRI markers.

Alzheimers Dement 2021 05 4;17(5):801-812. Epub 2021 Mar 4.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: We determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).

Methods: Analyses included 536 non-demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t-tau, amyloid beta (Aβ)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes.

Results: Higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aβ42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA.

Discussion: CSF NfL predicts changes in white matter integrity, t-tau reflects non-specific changes in cortical thickness, and Ng reflects AD-specific synaptic and neuronal degeneration.
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http://dx.doi.org/10.1002/alz.12239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119371PMC
May 2021

Gait Speed and Instrumental Activities of Daily Living in Older Adults After Hospitalization: A Longitudinal Population-Based Study.

J Gerontol A Biol Sci Med Sci 2021 Feb 27. Epub 2021 Feb 27.

Department of Anesthesiology and Perioperative Medicine, Rochester, Minnesota, USA.

Background: Hospitalization can impair physical and functional status of older adults, but it is unclear whether these deficits are transient or chronic. This study determined the association between hospitalization of older adults and changes in long-term longitudinal trajectories of two measures of physical and functional status: gait speed (GS) and Instrumental Activities of Daily Living measured with Functional Activities Questionnaire (FAQ).

Methods: Linear mixed effects models assessed the association between hospitalization (non-elective vs. elective, and surgical vs. medical) and outcomes of GS and FAQ score in participants (>60 years old) enrolled in the Mayo Clinic Study of Aging who had longitudinal assessments.

Results: Of 4,902 participants, 1,879 had ≥1 hospital admission. Median GS at enrollment was 1.1 m/s. The slope of the annual decline in GS before hospitalization was -0.015 m/s. The parameter estimate [95%CI] for additional annual change in GS trajectory after hospitalization was -0.009 [-0.011 to -0.006] m/s, P<0.001. The accelerated GS decline was greater for medical vs. surgical hospitalizations (-0.010 vs. -0.003 m/s, P=0.005), and non-elective vs. elective hospitalizations (-0.011 vs -0.006 m/s, P=0.067). The odds of a worsening FAQ-score increased on average by 4% per year. Following hospitalization, odds of FAQ-score worsening further increased (multiplicative annual increase in odds ratio per year [95%C] following hospitalization was 1.05 [1.03, 1.07], P<0.001).

Conclusions: Hospitalization of older adults is associated with accelerated long-term decline in GS and functional limitations, especially after non-elective admissions and those for medical indications. However, for most well-functioning participants these changes have little clinical significance.
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http://dx.doi.org/10.1093/gerona/glab064DOI Listing
February 2021

Longitudinal deterioration of white-matter integrity: heterogeneity in the ageing population.

Brain Commun 2021 22;3(1):fcaa238. Epub 2021 Jan 22.

Department of Radiology, Mayo Clinic, Rochester, MN 559 05, USA.

Deterioration in white-matter health plays a role in cognitive ageing. Our goal was to discern heterogeneity of white-matter tract vulnerability in ageing using longitudinal imaging data (two to five imaging and cognitive assessments per participant) from a population-based sample of 553 elderly participants (age ≥60 years). We found that different clusters (healthy white matter, fast white-matter decliners and intermediate white-matter group) were heterogeneous in the spatial distribution of white-matter integrity, systemic health and cognitive trajectories. White-matter health of specific tracts (genu of corpus callosum, posterior corona radiata and anterior internal capsule) informed about cluster assignments. Not surprisingly, brain amyloidosis was not significantly different between clusters. Clusters had differential white-matter tract vulnerability to ageing (commissural fibres > association/brainstem fibres). Identification of vulnerable white-matter tracts is a valuable approach to assessing risk for cognitive decline.
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http://dx.doi.org/10.1093/braincomms/fcaa238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884606PMC
January 2021

Changing the face of neuroimaging research: Comparing a new MRI de-facing technique with popular alternatives.

Neuroimage 2021 05 11;231:117845. Epub 2021 Feb 11.

Department of Radiology, Mayo Clinic, Rochester, MN, United States.

Recent advances in automated face recognition algorithms have increased the risk that de-identified research MRI scans may be re-identifiable by matching them to identified photographs using face recognition. A variety of software exist to de-face (remove faces from) MRI, but their ability to prevent face recognition has never been measured and their image modifications can alter automated brain measurements. In this study, we compared three popular de-facing techniques and introduce our mri_reface technique designed to minimize effects on brain measurements by replacing the face with a population average, rather than removing it. For each technique, we measured 1) how well it prevented automated face recognition (i.e. effects on exceptionally-motivated individuals) and 2) how it altered brain measurements from SPM12, FreeSurfer, and FSL (i.e. effects on the average user of de-identified data). Before de-facing, 97% of scans from a sample of 157 volunteers were correctly matched to photographs using automated face recognition. After de-facing with popular software, 28-38% of scans still retained enough data for successful automated face matching. Our proposed mri_reface had similar performance with the best existing method (fsl_deface) at preventing face recognition (28-30%) and it had the smallest effects on brain measurements in more pipelines than any other, but these differences were modest.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154695PMC
May 2021

Variants in and are associated with higher tau deposition.

Brain Commun 2020 26;2(2):fcaa159. Epub 2020 Sep 26.

Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA.

Tau deposition is a key biological feature of Alzheimer's disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study of tau-positron emission tomography on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test nucleotide polymorphism associations with AV-1451 (F-flortaucipir) tau-positron emission tomography burden in an Alzheimer's-signature composite region of interest, using an additive genetic model and covarying for age, sex and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (=9.91 × 10,  = 0.20) in the tau phosphorylation regulatory gene (protein phosphatase 2 regulatory subunit B) and for rs117402302 (=4.00 × 10,  = 0.19) near (insulin-like growth factor 2 mRNA-binding protein 3). The association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three single nucleotide polymorphisms within (microtubule-associated protein tau) displayed nominal associations with tau-positron emission tomography burden, and the association of the (apolipoprotein E) ɛ4 allele with tau-positron emission tomography was marginally nonsignificant (=0.06,  = 0.07). No associations with tau-positron emission tomography burden were identified for other single nucleotide polymorphisms associated with Alzheimer's disease clinical diagnosis in prior large case-control studies. Our findings nominate and as novel potential influences on tau pathology which warrant further functional characterization. Our data are also supportive of previous literature on the associations of genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer's susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.
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http://dx.doi.org/10.1093/braincomms/fcaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780444PMC
September 2020

Brain MRI after critical care admission: A longitudinal imaging study.

J Crit Care 2021 Apr 5;62:117-123. Epub 2020 Dec 5.

Department of Radiology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. Electronic address:

Purpose: To investigate the association between episodes of critical care hospitalizations and delirium with structural brain changes in older adults.

Materials And Methods: We included Mayo Clinic Study of Aging participants ≥60 years old at the time of study enrollment (October 29, 2004, through September 11, 2017) with available brain MRI and 'amyloid' positron emission tomography (PET) scans. We tested the hypothesis that a) intensive care unit (ICU) admission is associated with greater cortical thinning and atrophy in entorhinal cortex, inferior temporal cortex, middle temporal cortex, and fusiform cortex (Alzheimer''s disease-signature regions); b) atrophy in hippocampus and corpus callosum; c) delirium accelerates these changes; and d) ICU admission is not associated with increased deposition of cortical amyloid.

Results: ICU admission was associated with cortical thinning in temporal, frontal, and parietal cortices, and decreases in hippocampal/corpus callosum volumes, but not Alzheimer''s disease-signature regions. For hippocampal volume, and 10 of 14 cortical thickness measurements, the change following ICU admission was significantly more pronounced for those who experienced delirium. ICU admission was not associated with an increased amyloid burden.

Conclusions: Critical care hospitalization is associated with accelerated brain atrophy in selected brain regions, without increases in amyloid deposition, suggesting a pathogenesis based on neurodegeneration unrelated to Alzheimer''s pathway.
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http://dx.doi.org/10.1016/j.jcrc.2020.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946765PMC
April 2021

Theoretical frameworks and approaches used within the Reserve, Resilience and Protective Factors professional interest area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

Alzheimers Dement (Amst) 2020 11;12(1):e12115. Epub 2020 Nov 11.

Department of Radiology Mayo Clinic Rochester Minnesota USA.

Introduction: Reserve, resilience, maintenance, and related concepts are intensely debated in aging and Alzheimer's disease research.

Methods: Through a short survey, we gathered information about theoretical concepts and methodologies used among research groups of the Reserve, Resilience, and Protective Factors Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

Results: Overall 53 research groups responded. Reserve and resilience were the most frequently used conceptual frameworks. Education, occupation, leisure, and social activities were frequently used as measures, as were longitudinal designs. Neuropsychological assessments were almost universal, and usage of imaging biomarkers was frequent. In observational-epidemiological study designs, resilience and reserve together (vs reserve alone) were commonly used as theoretical frameworks.

Discussion: We provide a first description of concepts and methodologies used among reserve and resilience researchers. This will inform initiatives aiming to reach consensus on terminology and applications to establish common definitions.
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http://dx.doi.org/10.1002/dad2.12115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656169PMC
November 2020

Artificial Intelligence-Electrocardiography to Predict Incident Atrial Fibrillation: A Population-Based Study.

Circ Arrhythm Electrophysiol 2020 12 13;13(12):e009355. Epub 2020 Nov 13.

Department of Cardiovascular Medicine (G.C., X.Y., Z.I.A., K.C.S., P.A.F., P.A.N.), Mayo Clinic, Rochester, MN.

Background: An artificial intelligence (AI) algorithm applied to electrocardiography during sinus rhythm has recently been shown to detect concurrent episodic atrial fibrillation (AF). We sought to characterize the value of AI-enabled electrocardiography (AI-ECG) as a predictor of future AF and assess its performance compared with the CHARGE-AF score (Cohorts for Aging and Research in Genomic Epidemiology-AF) in a population-based sample.

Methods: We calculated the probability of AF using AI-ECG, among participants in the population-based Mayo Clinic Study of Aging who had no history of AF at the time of the baseline study visit. Cox proportional hazards models were fit to assess the independent prognostic value and interaction between AI-ECG AF model output and CHARGE-AF score. C statistics were calculated for AI-ECG AF model output, CHARGE-AF score, and combined AI-ECG and CHARGE-AF score.

Results: A total of 1936 participants with median age 75.8 (interquartile range, 70.4-81.8) years and median CHARGE-AF score 14.0 (IQR, 13.2-14.7) were included in the analysis. Participants with AI-ECG AF model output of >0.5 at the baseline visit had cumulative incidence of AF 21.5% at 2 years and 52.2% at 10 years. When included in the same model, both AI-ECG AF model output (hazard ratio, 1.76 per SD after logit transformation [95% CI, 1.51-2.04]) and CHARGE-AF score (hazard ratio, 1.90 per SD [95% CI, 1.58-2.28]) independently predicted future AF without significant interaction (=0.54). C statistics were 0.69 (95% CI, 0.66-0.72) for AI-ECG AF model output, 0.69 (95% CI, 0.66-0.71) for CHARGE-AF, and 0.72 (95% CI, 0.69-0.75) for combined AI-ECG and CHARGE-AF score.

Conclusions: In the present study, both the AI-ECG AF model output and CHARGE-AF score independently predicted incident AF. The AI-ECG may offer a means to assess risk with a single test and without requiring manual or automated clinical data abstraction.
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http://dx.doi.org/10.1161/CIRCEP.120.009355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127001PMC
December 2020

Association of Hospitalization with Long-Term Cognitive Trajectories in Older Adults.

J Am Geriatr Soc 2021 Mar 31;69(3):660-668. Epub 2020 Oct 31.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Importance: Hospitalizations are associated with cognitive decline in older adults.

Objective: To determine the association between hospitalization characteristics and the trajectory of cognitive function in older adults.

Design: Population-based longitudinal study of cognitive aging.

Setting: Olmsted Medical Center and Mayo Clinic, the only centers in Olmsted County, Minnesota, with hospitalization capacity.

Participants: Individuals without dementia at baseline, with consecutive cognitive assessments from 2004 through 2017, and at least one visit after the age of 60.

Measurements: The primary outcome was longitudinal changes in global cognitive z-score. Secondary outcomes were changes in four cognitive domains: memory, attention/executive function, language, and visuospatial skills. Hospitalization characteristics analyzed included elective versus nonelective, medical versus surgical, critical care versus no critical care admission, and long versus short duration admissions.

Results: Of 4,587 participants, 1,622 had 1 and more hospital admission. Before hospitalization, the average slope of the global z-score was -0.031 units/year. After hospitalization, the rate of annual global z-score accelerated by -0.051 (95% CI = -0.057, -0.045) units, P < .001, resulting in an estimated annual slope after the first hospitalization of -0.082. The accelerated decline was found in all four cognitive domains (memory, visuospatial, language, and executive, all P < .001). The acceleration of the decline in global z-score following hospitalization was greater for medical compared to surgical hospitalizations (slope change following hospitalization = -0.064 vs -0.034 for medical vs surgical, P < .001), and nonelective compared to elective admissions (slope change following hospitalization = -0.075 vs -0.037 for nonelective vs elective, P < .001). The acceleration of cognitive decline was not different for hospitalization with intensive care unit admission versus not.

Conclusions: Hospitalization of older adults is associated with accelerated decline of global and domain-specific cognitive domains, with the rate of decline dependent upon type of admission. The clinical impact of this accelerated decline will depend on the individual's baseline cognitive reserve and expected longevity.
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http://dx.doi.org/10.1111/jgs.16909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969446PMC
March 2021

Predicting future rates of tau accumulation on PET.

Brain 2020 10;143(10):3136-3150

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.
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http://dx.doi.org/10.1093/brain/awaa248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586089PMC
October 2020

Association of Cortical and Subcortical β-Amyloid With Standardized Measures of Depressive and Anxiety Symptoms in Adults Without Dementia.

J Neuropsychiatry Clin Neurosci 2021 22;33(1):64-71. Epub 2020 Oct 22.

Departments of Health Sciences Research (Krell-Roesch, Syrjanen, Rakusa, Kremers, Mielke, Vassilaki), Radiology (Vemuri, Lowe, Jack), Psychiatry and Psychology (Machulda), and Neurology (Mielke, Knopman, Petersen), Mayo Clinic, Rochester, Minn.; Institute of Sports and Sports Science, Karlsruhe Institute of Technology, Karlsruhe, Germany (Krell-Roesch); Department of Neurology, University Medical Center, Maribor, Slovenia (Rakusa); International Clinical Research Center, St. Anne Hospital, Brno, Czech Republic (Stokin); and Department of Neurology, Barrow Neurological Institute, Phoenix (Geda).

Objective: The purpose of this study was to test the hypothesis that subcortical β-amyloid (Aβ) deposition was associated with elevated scores on standardized measures of depressive and anxiety symptoms when compared with cortical (Aβ) deposition in persons without dementia.

Methods: The authors performed a cross-sectional study, derived from the population-based Mayo Clinic Study of Aging, comprising participants aged ≥70 years (N=1,022; 55% males; 28% apolipoprotein E [APOE] ε4 carriers; without cognitive impairment, N=842; mild cognitive impairment; N=180). To assess Aβ deposition in cortical and subcortical (the amygdala, striatum, and thalamus) regions, participants underwent Pittsburgh Compound B positron emission tomography (PiB-PET) and completed the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). The investigators ran linear regression models to examine the association between PiB-PET standardized uptake value ratios (SUVRs) in the neocortex and subcortical regions and depressive and anxiety symptoms (BDI-II and BAI total scores). Models were adjusted for age, sex, education level, and APOE ε4 carrier status and stratified by cognitive status (without cognitive impairment, mild cognitive impairment).

Results: Cortical PiB-PET SUVRs were associated with depressive symptoms (β=0.57 [SE=0.13], p<0.001) and anxiety symptoms (β=0.34 [SE=0.13], p=0.011). PiB-PET SUVRs in the amygdala were associated only with depressive symptoms (β=0.80 [SE=0.26], p=0.002). PiB-PET SUVRs in the striatum and thalamus were associated with depressive symptoms (striatum: β=0.69 [SE=0.18], p<0.001; thalamus: β=0.61 [SE=0.24], p=0.011) and anxiety symptoms (striatum: β=0.56 [SE=0.18], p=0.002; thalamus: β=0.65 [SE=0.24], p=0.008). In the mild cognitive impairment subsample, Aβ deposition, regardless of neuroanatomic location, was associated with depressive symptoms but not anxiety symptoms.

Conclusions: Elevated amyloid deposition in cortical and subcortical brain regions was associated with higher depressive and anxiety symptoms, although these findings did not significantly differ by cortical versus subcortical Aβ deposition. This cross-sectional observation needs to be confirmed by a longitudinal study.
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http://dx.doi.org/10.1176/appi.neuropsych.20050103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856245PMC
October 2020

Association of Initial β-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment.

JAMA Neurol 2021 Feb;78(2):217-228

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Importance: Tau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum.

Objective: To investigate the association of β-amyloid (Aβ) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between Aβ and tau accumulation and inform clinical trial design.

Design, Setting, And Participants: This cohort study included individuals aged 65 to 85 years who were CU and had participated in the Mayo Clinic Study of Aging, with serial cognitive assessments, serial magnetic resonance imaging, 11C-Pittsburgh compound B (Aβ) PET scans, and 18F-flortaucipir PET scans, collected from May 2015 to March 2020. Persons were excluded if they lacked follow-up PET scans. A similarly evaluated CU group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were also studied. These data were collected from September 2015 to March 2020.

Exposures: Participants were stratified by index Aβ levels on PET into low Aβ (≤8 centiloid [CL]), subthreshold Aβ (9-21 CL), suprathreshold Aβ (22-67 CL), and high Aβ (≥68 CL).

Main Outcomes And Measures: Changes over a mean of 2.7 (range, 1.1-4.1) years in flortaucipir PET in entorhinal, inferior temporal, and lateral parietal regions of interest and an AD meta-region of interest (ROI).

Results: A total of 167 people were included (mean age, 74 [range, 65-85] years; 75 women [44.9%]); 101 individuals were excluded lacking follow-up, and 114 individuals from the ADNI were also studied (mean [SD] age, 74.14 [5.29] years; 64 women [56.1%]). In the Mayo Clinic Study of Aging, longitudinal flortaucipir accumulation rates in the high Aβ group were greater than the suprathreshold, subthreshold, and low Aβ groups in the entorhinal ROI (suprathreshold, 0.025 [95% CI, 0.013-0.037] standardized uptake value ratio [SUVR] units; subthreshold, 0.026 [95% CI, 0.014-0.037] SUVR units; low Aβ, 0.034 [95% CI, 0.02-0.049] SUVR units), inferior temporal ROI (suprathreshold, 0.025 [95% CI, 0.014-0.035] SUVR units; subthreshold, 0.027 [95% CI, 0.017-0.037] SUVR units; low Aβ, 0.035 [95% CI, 0.022-0.047] SUVR units), and the AD meta-ROI (suprathreshold, 0.023 [95% CI, 0.013-0.032] SUVR units; subthreshold, 0.025 [95% CI, 0.016-0.034] SUVR units; low Aβ, 0.032 [95% CI, 0.021-0.043] SUVR units) (all P < .001). Flortaucipir accumulation rates in the subthreshold and suprathreshold Aβ groups in temporal regions were nonsignificantly elevated compared with the low Aβ group. In the ADNI cohort, the variance was larger than in the Mayo Clinic Study of Aging but point estimates for annualized flortaucipir accumulation in the inferior temporal ROI were very similar. An estimated 216 participants who were CU per group with PET Aβ of 68 CL or more would be needed to detect a 25% annualized reduction in flortaucipir accumulation rate in the AD meta-ROI with 80% power.

Conclusions And Relevance: Substantial flortaucipir accumulation in temporal regions is greatest in persons aged 65 to 85 years who were CU and had high initial Aβ PET levels, compared with those with lower Aβ levels. Recruiting persons who were CU and exhibiting Aβ of 68 CL or more on an index Aβ PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure.
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http://dx.doi.org/10.1001/jamaneurol.2020.3921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573795PMC
February 2021

Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers.

Neuroimage 2021 01 6;224:117433. Epub 2020 Oct 6.

Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860631PMC
January 2021

Reduced fractional anisotropy of the genu of the corpus callosum as a cerebrovascular disease marker and predictor of longitudinal cognition in MCI.

Neurobiol Aging 2020 12 8;96:176-183. Epub 2020 Sep 8.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Our goal was to evaluate the utility of diffusion tensor imaging (DTI) for predicting future cognitive decline in mild cognitive impairment (MCI) in conjunction with Alzheimer's disease (AD) biomarkers (amyloid positron emission tomography and AD signature neurodegeneration) in 132 MCI individuals ≥60 year old with structural magnetic resonance imaging, DTI, amyloid positron emission tomography, and at least one clinical follow-up. We used mixed-effect models to evaluate the prognostic ability of fractional anisotropy of the genu of the corpus callosum (FA-Genu), as a cerebrovascular disease marker, for predicting cognitive decline along with AD biomarkers. We contrasted the value of white matter hyperintensities, a traditional cerebrovascular disease marker as well as FA in the hippocampal cingulum bundle with the FA-Genu models. FA-Genu significantly predicted cognitive decline even after accounting for AD biomarkers. WMH was not associated with cognitive decline in the model with both WMH and FA-Genu. DTI specifically FA-Genu provides unique complementary information to AD biomarkers and has significant utility for prediction of cognitive decline in MCI.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722208PMC
December 2020

Associations Between Plasma Ceramides and Cerebral Microbleeds or Lacunes.

Arterioscler Thromb Vasc Biol 2020 11 3;40(11):2785-2793. Epub 2020 Sep 3.

Departments of Neurology (E.T.I., J.G.-R., R.C.P., D.S.K., M.M.M.), Mayo Clinic Rochester, MN.

Objective: High plasma ceramide levels and ratios are associated with poor outcomes in individuals with cardiovascular disease; less is known about their relation to cerebral small vessel disease. We examined whether high plasma ceramide levels or ratios were associated with cerebral microbleeds (CMBs) and lacunes and whether associations differ by sex. Approach and Results: We included 548 participants enrolled in the MCSA (Mayo Clinic Study of Aging) with concurrent plasma ceramide assays and magnetic resonance imaging. CMBs were quantified on T2* magnetic resonance imaging and lacunes on T2 fluid-attenuated inversion recovery magnetic resonance imaging. Fasting plasma ceramides were assayed using liquid chromatography-electrospray ionization tandem mass spectrometry. We used logistic regression models adjusting for age, sex, hypertension, and diabetes mellitus to examine the relationship between ceramides and presence of a lacune; hurdle models were used for presence and number of CMBs. Each SD increase in the log ceramide C16:0/24:0 ratio was associated with greater odds of a CMB (odds ratio, 1.28 [95% CI, 1.01-1.64]). There was an interaction between sex and the ceramide C16:0/24:0 ratio (=0.049). The association between this ratio and presence of a CMB was stronger for women (odds ratio, 1.87 [95% CI, 1.20-3.00]) than men (odds ratio, 1.09 [95% CI, 0.80-1.46]). Several ceramides and all ceramide ratios were associated with number of CMBs. We did not find associations between plasma ceramides and lacunes.

Conclusions: In a population-based sample, the plasma ceramide C16:0/24:0 ratio was associated with CMBs and was stronger for women. Plasma ceramides are differentially associated with cerebral small vessel pathologies.
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http://dx.doi.org/10.1161/ATVBAHA.120.314796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577943PMC
November 2020

Brain Regional Glucose Metabolism, Neuropsychiatric Symptoms, and the Risk of Incident Mild Cognitive Impairment: The Mayo Clinic Study of Aging.

Am J Geriatr Psychiatry 2021 02 17;29(2):179-191. Epub 2020 Jun 17.

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ. Electronic address:

Objective: The authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction.

Methods: About 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status.

Results: Participants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ = 11.83, degree of freedom [df] = 1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ = 29.68, df = 1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ = 34.13, df = 1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ = 21.92, df = 1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ = 15.39, df = 1).

Conclusion: Combined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS.
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http://dx.doi.org/10.1016/j.jagp.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744363PMC
February 2021

Fully bayesian longitudinal unsupervised learning for the assessment and visualization of AD heterogeneity and progression.

Aging (Albany NY) 2020 07 9;12(13):12622-12647. Epub 2020 Jul 9.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Tau pathology and brain atrophy are the closest correlate of cognitive decline in Alzheimer's disease (AD). Understanding heterogeneity and longitudinal progression of atrophy during the disease course will play a key role in understanding AD pathogenesis. We propose a framework for longitudinal clustering that simultaneously: 1) incorporates whole brain data, 2) leverages unequal visits per individual, 3) compares clusters with a control group, 4) allows for study confounding effects, 5) provides cluster visualization, 6) measures clustering uncertainty. We used amyloid-β positive AD and negative healthy subjects, three longitudinal structural magnetic resonance imaging scans (cortical thickness and subcortical volume) over two years. We found three distinct longitudinal AD brain atrophy patterns: one typical diffuse pattern (n=34, 47.2%), and two atypical patterns: minimal atrophy (n=23 31.9%) and hippocampal sparing (n=9, 12.5%). We also identified outliers (n=3, 4.2%) and observations with uncertain classification (n=3, 4.2%). The clusters differed not only in regional distributions of atrophy at baseline, but also longitudinal atrophy progression, age at AD onset, and cognitive decline. A framework for the longitudinal assessment of variability in cohorts with several neuroimaging measures was successfully developed. We believe this framework may aid in disentangling distinct subtypes of AD from disease staging.
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http://dx.doi.org/10.18632/aging.103623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377879PMC
July 2020

Prevalence and Heterogeneity of Cerebrovascular Disease Imaging Lesions.

Mayo Clin Proc 2020 06;95(6):1195-1205

Department of Radiology, Mayo Clinic, Rochester, MN.

Objective: To report population age-specific prevalence of core cerebrovascular disease lesions (infarctions, cerebral microbleeds, and white-matter hyperintensities detected with magnetic resonance imaging); estimate cut points for white-matter hyperintensity positivity; investigate sex differences in prevalence; and estimate prevalence of any core cerebrovascular disease features.

Patients And Methods: Participants in the population-based Mayo Clinic Study of Aging aged 50 to 89 years underwent fluid-attenuated inversion recovery and T2* gradient-recalled echo magnetic resonance imaging to assess cerebrovascular disease between October 10, 2011, and September 29, 2017. We characterized each participant as having infarct, normal versus abnormal white-matter hyperintensity, cerebral microbleed, or a combination of lesions. Prevalence of cerebrovascular disease biomarkers was derived through adjustment for nonparticipation and standardization to the population of Olmsted County, Minnesota.

Results: Among 1462 participants without dementia (median [range] age, 68 [50 to 89] y; men, 52.7%), core cerebrovascular disease features increased with age. Prevalence (95% CI) of cerebral microbleeds was 13.6% (11.6%-15.6%); infarcts, 11.7% (9.7%-13.8%); and abnormal white-matter hyperintensity, 10.7% (8.7%-12.6%). Infarcts and cerebral microbleeds were more common among men. In contrast, abnormal white-matter hyperintensity was more common among women ages 60 to 79 y and men, ages 80 y and older. Prevalence of any core cerebrovascular disease feature determined by presence of at least one cerebrovascular disease feature increased from 9.5% (ages 50 to 59 y) to 73.8% (ages 80 to 89 y).

Conclusion: Whereas this study focused on participants without dementia, the high prevalence of cerebrovascular disease imaging lesions in elderly persons makes assignment of clinical relevance to cognition and other downstream manifestations more probabilistic than deterministic.
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http://dx.doi.org/10.1016/j.mayocp.2020.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316133PMC
June 2020
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