Publications by authors named "Heather J Wiste"

76 Publications

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

Ann Neurol 2021 Mar 26. Epub 2021 Mar 26.

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.
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http://dx.doi.org/10.1002/ana.26071DOI Listing
March 2021

CSF dynamics as a predictor of cognitive progression.

Neuroimage 2021 May 23;232:117899. Epub 2021 Feb 23.

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

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117899DOI Listing
May 2021

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

Neuroimage 2021 Feb 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
February 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

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

CSF biomarkers in Olmsted County: Evidence of 2 subclasses and associations with demographics.

Neurology 2020 07 26;95(3):e256-e267. Epub 2020 Jun 26.

From the Departments of Neurology (A.C.V.H., M.M.M., D.S.K., R.C.P.), Health Sciences Research (H.J.W., S.D.W., M.M.M., W.K.K., R.C.P.), Laboratory Medicine and Pathology (R.B.D.), and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center Amsterdam UMC (A.C.V.H.), the Netherlands; and Roche Diagnostics (U.E., R.B.-U., A.A.-S.), Basel, Switzerland.

Objective: We studied interrelationships between CSF biomarkers and associations with ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.

Methods: We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.

Results: Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.

Conclusion: We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.
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http://dx.doi.org/10.1212/WNL.0000000000009874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455353PMC
July 2020

The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes.

Brain 2019 10;142(10):3230-3242

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

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-β and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A+T-), or high amyloid and high tau (A+T+). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A+T- (28%), and A+T+ (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A+T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A+T+ quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.
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http://dx.doi.org/10.1093/brain/awz268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763736PMC
October 2019

Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging-Alzheimer's Association Research Framework.

JAMA Neurol 2019 Jul 15. Epub 2019 Jul 15.

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

Importance: A National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms.

Objectives: To estimate the sex- and age-specific prevalence of 3 imaging biomarker-based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease.

Design, Setting, And Participants: The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019.

Main Outcomes And Measures: The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease).

Results: The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P < .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P < .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women.

Conclusions And Relevance: Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.
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http://dx.doi.org/10.1001/jamaneurol.2019.1971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632154PMC
July 2019

Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia.

JAMA 2019 06;321(23):2316-2325

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Importance: A National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers.

Objective: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information.

Design, Setting, And Participants: Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018.

Exposures: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles.

Main Outcomes And Measures: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only.

Results: Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier.

Conclusions And Relevance: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.
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http://dx.doi.org/10.1001/jama.2019.7437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582267PMC
June 2019

Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults.

Neurology 2019 07 30;93(1):e29-e39. Epub 2019 May 30.

From the Departments of Radiology (V.J.L., T.J.B., H.-K.M., P.F., M.L.S., M.K.P., K.K., D.T.J., P.V., C.G.S., C.R.J.), Health Sciences Research (H.J.W., S.D.W., T.M.T., M.M. Mielke, R.O.R.), Information Technology (M.L.S.), Neurology (B.F.B., K.A.J., D.T.J., J.G.-R., M.M. Mielke, D.S.K., R.C.P.), Neuroscience (M.E.M.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN.

Objective: To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults.

Methods: Tau- and amyloid-PET were performed in 579 CU participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49.

Results: Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+.

Conclusions: Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.
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http://dx.doi.org/10.1212/WNL.0000000000007728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659005PMC
July 2019

FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis.

Brain 2018 04;141(4):1201-1217

Department of Neurology, Mayo Clinic, Rochester, Minnesota, 55905, USA.

See Gordon (doi:10.1093/brain/awy052) for a scientific commentary on this article.Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis may account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating > 0) with amnestic presentations ≥ 75 years who had MRI and PET imaging with 18F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18F-FDG-PET were screened and those with TDP-43-negative Alzheimer's disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer's disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and may serve as a biomarker for hippocampal sclerosis.
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http://dx.doi.org/10.1093/brain/awy049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889045PMC
April 2018

Longitudinal tau PET in ageing and Alzheimer's disease.

Brain 2018 05;141(5):1517-1528

Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.
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http://dx.doi.org/10.1093/brain/awy059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917767PMC
May 2018

Tau-negative amnestic dementia masquerading as Alzheimer disease dementia.

Neurology 2018 03 7;90(11):e940-e946. Epub 2018 Feb 7.

From the Departments of Neurology (H.B., W.G.M., J.G.-R., R.C.P., B.F.B., D.S.K., D.T.J.), Psychiatry and Psychology (M.M.M.), Radiology (S.A.P., H.J.W., M.L.S., C.R.J., D.T.J.), Pathology (J.E.P.), and Nuclear Medicine (V.J.L.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (M.E.M.), Mayo Clinic, Jacksonville, FL.

Objective: To describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.

Methods: Eight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.

Results: All participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR <1.33).

Conclusions: The participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.
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http://dx.doi.org/10.1212/WNL.0000000000005124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858947PMC
March 2018

Widespread brain tau and its association with ageing, Braak stage and Alzheimer's dementia.

Brain 2018 01;141(1):271-287

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

See Herholz (doi:10.1093/brain/awx340) for a scientific commentary on this article.Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (≥50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30-49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations.
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http://dx.doi.org/10.1093/brain/awx320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837250PMC
January 2018

Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum.

Cortex 2017 12 3;97:143-159. Epub 2017 Oct 3.

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

Functionally related brain regions are selectively vulnerable to Alzheimer's disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer's disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer's disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer's disease dementia, we found several distinct spatial patterns of tau deposition, including 'Braak-like' and 'non-Braak-like', across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with 'non-Braak-like' patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer's disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.cortex.2017.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773067PMC
December 2017

Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50-95 years: a cross-sectional study.

Lancet Neurol 2017 06 26;16(6):435-444. Epub 2017 Apr 26.

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

Background: A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older.

Methods: All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50-89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A-) or abnormal (A+) amyloid using amyloid PET, normal (T-) or abnormal (T+) tau using tau PET, and normal (N-) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging.

Findings: The numbers of participants in each profile group were 165 A-T-N-, 35 A-T+N-, 63 A-T-N+, 19 A-T+N+, 44 A+T-N-, 25 A+T+N-, 35 A+T-N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55-64) in A-T-N- and 57 years (54-64) in A-T+N- to a median 80 years (75-84) in A+T-N+ and 79 years (73-87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A- group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N-, A+T-N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A-T+N-, A-T-N+, and A-T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A-T-N- prevalence declined and A+T+N+ and A-T+N+ prevalence increased. In both men and women, A-T-N- was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities.

Interpretation: Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired.

Funding: National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation.
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http://dx.doi.org/10.1016/S1474-4422(17)30077-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516534PMC
June 2017

A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer's disease severity.

Neuroimage Clin 2016 30;11:802-812. Epub 2016 May 30.

Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.

Alzheimer's disease (AD) researchers commonly use MRI as a quantitative measure of disease severity. Historically, hippocampal volume has been favored. Recently, "AD signature" measurements of gray matter (GM) volumes or cortical thicknesses have gained attention. Here, we systematically evaluate multiple thickness- and volume-based candidate-methods side-by-side, built using the popular FreeSurfer, SPM, and ANTs packages, according to the following criteria: (a) ability to separate clinically normal individuals from those with AD; (b) (extent of) correlation with head size, a nuisance covariatel (c) reliability on repeated scans; and (d) correlation with Braak neurofibrillary tangle stage in a group with autopsy. We show that volume- and thickness-based measures generally perform similarly for separating clinically normal from AD populations, and in correlation with Braak neurofibrillary tangle stage at autopsy. Volume-based measures are generally more reliable than thickness measures. As expected, volume measures are highly correlated with head size, while thickness measures are generally not. Because approaches to statistically correcting volumes for head size vary and may be inadequate to deal with this underlying confound, and because our goal is to determine a measure which can be used to examine age and sex effects in a cohort across a large age range, we thus recommend thickness-based measures. Ultimately, based on these criteria and additional practical considerations of run-time and failure rates, we recommend an AD signature measure formed from a composite of thickness measurements in the entorhinal, fusiform, parahippocampal, mid-temporal, inferior-temporal, and angular gyrus ROIs using ANTs with input segmentations from SPM12.
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http://dx.doi.org/10.1016/j.nicl.2016.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187496PMC
October 2017

Defining imaging biomarker cut points for brain aging and Alzheimer's disease.

Alzheimers Dement 2017 Mar 30;13(3):205-216. Epub 2016 Sep 30.

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

Introduction: Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness.

Methods: We examined five methods for determining cut points.

Results: The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal.

Discussion: In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method.
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http://dx.doi.org/10.1016/j.jalz.2016.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344738PMC
March 2017

[Formula: see text]Practice effects and longitudinal cognitive change in clinically normal older adults differ by Alzheimer imaging biomarker status.

Clin Neuropsychol 2017 01 11;31(1):99-117. Epub 2016 Oct 11.

d Department of Neurology , College of Medicine, Mayo Clinic , Rochester , MN , USA.

Objective: The objective of this study was to examine practice effects and longitudinal cognitive change in 190 clinically normal elderly classified according to a two-feature biomarker model for Alzheimer's disease.

Methods: All participants completed neuropsychological testing, MRI, FDG-PET, and PiB-PET at their baseline evaluation. We divided participants into four groups based on neuroimaging measures of amyloid (A+ or A-) and neurodegeneration (N+ or N-) and reexamined cognition at 15- and 30-month intervals.

Results: The A-N- group showed significant improvements in the memory and global scores. The A+N- group also showed significant improvements in the memory and global scores as well as attention. The A-N+ group showed a significant decline in attention at 30 months. The A+N+ group showed significant improvements in memory and the global score at 15 months followed by a significant decline in the global score at 30 months.

Conclusion: Amyloidosis in the absence of neurodegeneration did not have an adverse impact on practice effects or the 30-month cognitive trajectories. In contrast, participants with neurodegeneration (either A-N+ or A+N+) had worse performance at the 30-month follow-up. Our results show that neurodegeneration has a more deleterious effect on cognition than amyloidosis in clinically normal individuals.
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http://dx.doi.org/10.1080/13854046.2016.1241303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408356PMC
January 2017

Age and neurodegeneration imaging biomarkers in persons with Alzheimer disease dementia.

Neurology 2016 Aug 15;87(7):691-8. Epub 2016 Jul 15.

From the Departments of Neurology (D.S.K., P.V., M.M. Mielke, R.O.R., B.F.B., D.T.J., R.C.P.) and Radiology (C.R.J., V.J.L., K.K., J.L.G., M.L.S., D.T.J.), Mayo Clinic Alzheimer's Disease Research Center (D.S.K., C.R.J., B.F.B., D.T.J., R.C.P.), Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (H.J.W., S.D.W.), Division of Epidemiology, Department of Health Sciences Research (M.M. Mielke, R.O.R., R.C.P.), and Department of Psychiatry, Division of Psychology (M.M. Machulda), Mayo Clinic and Foundation, Rochester, MN.

Objective: To examine neurodegenerative imaging biomarkers in Alzheimer disease (AD) dementia from middle to old age.

Methods: Persons with AD dementia and elevated brain β-amyloid with Pittsburgh compound B (PiB)-PET imaging underwent [(18)F]-fluorodeoxyglucose (FDG)-PET and structural MRI. We evaluated 3 AD-related neurodegeneration biomarkers: hippocampal volume adjusted for total intracranial volume (HVa), FDG standardized uptake value ratio (SUVR) in regions of interest linked to AD, and cortical thickness in AD-related regions of interest. We examined associations of each biomarker with age and evaluated age effects on cutpoints defined by the 90th percentile in AD dementia. We assembled an age-, sex-, and intracranial volume-matched group of 194 similarly imaged clinically normal (CN) persons.

Results: The 97 participants with AD dementia (aged 49-93 years) had PiB SUVR ≥1.8. A nonlinear (inverted-U) relationship between FDG SUVR and age was seen in the AD group but an inverse linear relationship with age was seen in the CN group. Cortical thickness had an inverse linear relationship with age in AD but a nonlinear (flat, then inverse linear) relationship in the CN group. HVa showed an inverse linear relationship with age in both AD and CN groups. Age effects on 90th percentile cutpoints were small for FDG SUVR and cortical thickness, but larger for HVa.

Conclusions: In persons with AD dementia with elevated PiB SUVR, values of each neurodegeneration biomarker were associated with age. Cortical thickness had the smallest differences in 90th percentile cutpoints from middle to old age, and HVa the largest differences.
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http://dx.doi.org/10.1212/WNL.0000000000002979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999168PMC
August 2016

Transition rates between amyloid and neurodegeneration biomarker states and to dementia: a population-based, longitudinal cohort study.

Lancet Neurol 2016 Jan 18;15(1):56-64. Epub 2015 Nov 18.

Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA; Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA.

Background: In a 2014 cross-sectional analysis, we showed that amyloid and neurodegeneration biomarker states in participants with no clinical impairment varied greatly with age, suggesting dynamic within-person processes. In this longitudinal study, we aimed to estimate rates of transition from a less to a more abnormal biomarker state by age in individuals without dementia, as well as to assess rates of transition to dementia from an abnormal state.

Methods: Participants from the Mayo Clinic Study of Aging (Olmsted County, MN, USA) without dementia at baseline were included in this study, a subset of whom agreed to multimodality imaging. Amyloid PET (with (11)C-Pittsburgh compound B) was used to classify individuals as amyloid positive (A(+)) or negative (A(-)). (18)F-fluorodeoxyglucose ((18)F-FDG)-PET and MRI were used to classify individuals as neurodegeneration positive (N(+)) or negative (N(-)). We used all observations, including those from participants who did not have imaging results, to construct a multistate Markov model to estimate four different age-specific biomarker state transition rates: A(-)N(-) to A(+)N(-); A(-)N(-) to A(-)N(+) (suspected non-Alzheimer's pathology); A(+)N(-) to A(+)N(+); and A(-)N(+) to A(+)N(+). We also estimated two age-specific rates to dementia: A(+)N(+) to dementia and A(-)N(+) to dementia. Using these state-to-state transition rates, we estimated biomarker state frequencies by age.

Findings: At baseline (between Nov 29, 2004, to March 7, 2015), 4049 participants did not have dementia (3512 [87%] were clinically normal and 537 [13%] had mild cognitive impairment). 1541 individuals underwent imaging between March 28, 2006, to April 30, 2015. Transition rates were low at age 50 years and, with one exception, exponentially increased with age. At age 85 years compared with age 65 years, the rate was nearly 11-times higher (17.2 vs 1.6 per 100 person-years) for the transition from A(-)N(-) to A(-)N(+), three-times higher (20.8 vs 6.1) for A(+)N(-) to A(+)N(+), and five-times higher (13.2 vs 2.6) for A(-)N(+) to A(+)N(+). The rate of transition was also increased at age 85 years compared with age 65 years for A(+)N(+) to dementia (7.0 vs 0.8) and for A(-)N(+) to dementia (1.7 vs 0.6). The one exception to an exponential increase with age was the transition rate from A(-)N(-) to A(+)N(-), which increased from 4.0 transitions per 100 person-years at age 65 years to 6.9 transitions per 100 person-years at age 75 and then plateaued beyond that age. Estimated biomarker frequencies by age from the multistate model were similar to cross-sectional biomarker frequencies.

Interpretation: Our transition rates suggest that brain ageing is a nearly inevitable acceleration toward worse biomarker and clinical states. The one exception is the transition to amyloidosis without neurodegeneration, which is most dynamic from age 60 years to 70 years and then plateaus beyond that age. We found that simple transition rates can explain complex, highly interdependent biomarker state frequencies in our population.

Funding: National Institute on Aging, Alexander Family Professorship of Alzheimer's Disease Research, the GHR Foundation.
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http://dx.doi.org/10.1016/S1474-4422(15)00323-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784263PMC
January 2016

Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community.

JAMA Neurol 2016 Jan;73(1):85-92

Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota.

Importance: The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain.

Objective: To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers.

Design, Setting, And Participants: A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated.

Main Outcomes And Measures: Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures.

Results: At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB- noncarriers). These associations were largely independent of APOE4.

Conclusions And Relevance: In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.
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http://dx.doi.org/10.1001/jamaneurol.2015.3098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710552PMC
January 2016

Role of β-Amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment.

JAMA Neurol 2015 Dec;72(12):1475-83

Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota2Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota5Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic and F.

Importance: To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI).

Objective: To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.

Design, Setting, And Participants: Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography.

Main Outcomes And Measures: Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions.

Results: In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups.

Conclusions And Relevance: Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.
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http://dx.doi.org/10.1001/jamaneurol.2015.2323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735877PMC
December 2015

Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings.

Brain 2015 Dec 30;138(Pt 12):3747-59. Epub 2015 Sep 30.

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

We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.
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http://dx.doi.org/10.1093/brain/awv283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655341PMC
December 2015

Left ventricular hypertrophy after hypertensive pregnancy disorders.

Heart 2015 Oct 4;101(19):1584-90. Epub 2015 Aug 4.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Objective: Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesised that women with a history of hypertensive pregnancy would have altered LV geometry and function when compared with women with only normotensive pregnancies.

Methods: In this cohort study, we analysed echocardiograms of 2637 women who participated in the Family Blood Pressure Program. We compared LV mass and function in women with hypertensive pregnancies with those with normotensive pregnancies.

Results: Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared with women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42; 95% CI 1.01 to 1.99, p=0.05), after adjusting for age, race, research network of the Family Blood Pressure Program, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19; CI 0.08 to 1.78, p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups.

Conclusions: A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy.

Clinical Trial Registrations: GENOA- NCT00005269; HyperGEN- NCT00005267; Sapphire- NCT00005270; GenNet- NCT00005268.
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http://dx.doi.org/10.1136/heartjnl-2015-308098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568146PMC
October 2015

Clinical Outcomes of Cardiac Resynchronization with Epicardial Left Ventricular Lead.

Pacing Clin Electrophysiol 2015 Oct 13;38(10):1201-9. Epub 2015 Aug 13.

Division of Cardiology, Department of Medicine, University of California, San Diego, California.

Background: Left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) can be achieved via a transvenous or epicardial route. A surgically implanted epicardial LV (eLV) lead is used after a standard transvenous LV (tLV) lead implantation has failed. However, studies of clinical outcomes in patients with eLV leads and comparisons of outcome between tLV and eLV-CRT are sparse. Therefore, the purpose of this study is to compare clinical response between tLV-CRT and eLV-CRT, as well as to understand the differences within the eLV-CRT population.

Methods: Forty-four patients received eLV-CRT following unsuccessful attempts of tLV-CRT implantation between 2002 and 2013 at the University of California, San Diego (UCSD) and Mayo Clinics. These patients were matched for age, gender, and etiology of cardiomyopathy in a 1:2 ratio with a cohort of patients who received tLV-CRT during the same time period.

Results: During a mean follow-up of 57 months, similar clinical outcomes and survival rate were noted between tLV and eLV-CRT patients (all P > 0.05). Within the eLV-CRT group, dilated cardiomyopathy patients had significant improvement in New York Heart Association class and ejection fraction (both P < 0.05), while ischemic cardiomyopathy patients did not (both P > 0.05). eLV-CRT patients with nonanterior lead location had significantly improved survival (P < 0.001). There was also a trend for improved survival in those with nonapical lead location (P = 0.09).

Conclusion: In this case-matched two-centered study, comparable improvements were noted in patients with tLV-CRT and eLV-CRT. Operators should target nonanterior and nonapical locations during eLV-CRT implantation. Use of eLV-CRT should be considered a viable alternative for CRT candidates.
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http://dx.doi.org/10.1111/pace.12687DOI Listing
October 2015

Impact of surgical ventricular reconstruction on sphericity index in patients with ischaemic cardiomyopathy: follow-up from the STICH trial.

Eur J Heart Fail 2015 Apr 16;17(4):453-63. Epub 2015 Mar 16.

Echocardiography Core Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN, USA; Division of Cardiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Aims: We sought to evaluate associations between baseline sphericity index (SI) and clinical outcome, and changes in SI after coronary artery bypass graft (CABG) surgery with or without surgical ventricular reconstruction (SVR) in ischaemic cardiomyopathy patients enrolled in the SVR study (Hypothesis 2) of the Surgical Treatment for Ischemic Heart Failure (STICH) trial.

Methods And Results: Among 1000 patients in the STICH SVR study, we evaluated 546 patients (255 randomized to CABG alone and 291 to CABG + SVR) whose baseline SI values were available. SI was not significantly different between treatment groups at baseline. After 4 months, SI had increased in the CABG + SVR group, but was unchanged in the CABG alone group (0.69 ± 0.10 to 0.77 ± 0.12 vs. 0.67 ± 0.07 to 0.66 ± 0.09, respectively; P < 0.001). SI did not significantly change from 4 months to 2 years in either group. Although LV end-systolic volume and EF improved significantly more in the CABG + SVR group compared with CABG alone, the severity of mitral regurgitation significantly improved only in the CABG alone group, and the estimated LV filling pressure (E/A ratio) increased only in the CABG + SVR group. Higher baseline SI was associated with worse survival after surgery (hazard ratio 1.21, 95% confidence interval 1.02 - 1.43; P = 0.026). Survival was not significantly different by treatment strategy.

Conclusion: Although SVR was designed to improve LV geometry, SI worsened after SVR despite improved LVEF and smaller LV volume. Survival was significantly better in patients with lower SI regardless of treatment strategy.
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http://dx.doi.org/10.1002/ejhf.256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664050PMC
April 2015

Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span.

JAMA Neurol 2015 May;72(5):511-9

Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota.

Importance: Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.

Objective: To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old.

Design, Setting, And Participants: Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old.

Main Outcomes And Measures: Memory, HVa, and amyloid PET.

Results: Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward, APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers.

Conclusions And Relevance: Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.
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http://dx.doi.org/10.1001/jamaneurol.2014.4821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428984PMC
May 2015

Effects of tricuspid valve regurgitation on outcome in patients with cardiac resynchronization therapy.

Am J Cardiol 2015 Mar 6;115(6):783-9. Epub 2015 Jan 6.

Davidai Arrhythmia Center, Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel.

Cardiac resynchronization therapy (CRT) has a symptomatic and survival benefit for patients with heart failure (HF), but the percentage of nonresponders remains relatively high. The aims of this study were to assess the clinical significance of baseline tricuspid regurgitation (TR) or worsening TR after implantation of a CRT device on the response to therapy. This is a multicenter retrospective analysis of prospectively collected databases that includes 689 consecutive patients who underwent implantation of CRT. The patients were divided into groups according to baseline TR grade and according to worsening TR within 15 months after device implantation. Outcome was assessed by clinical and echocardiographic response within 15 months and by estimated survival for a median interquartile range follow-up time of 3.3 years (1.6, 4.6). TR worsening after CRT implantation was documented in 104 patients (15%). These patients had worse clinical and echocardiographic response to CRT, but worsening of TR was not a significant predictor of mortality (p = 0.17). According to baseline echocardiogram, 620 patients (90%) had some degree of TR before CRT implant. Baseline TR was an independent predictor of worse survival (p <0.001), although these patients had significantly better clinical and echocardiographic response compared with patients without TR. In conclusion, worsening of TR after CRT implantation is a predictor of worse clinical and echocardiographic response but was not significantly associated with increased mortality. Baseline TR is associated with reduced survival despite better clinical and echocardiographic response after CRT implantation.
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http://dx.doi.org/10.1016/j.amjcard.2014.12.046DOI Listing
March 2015

Independent comparison of CogState computerized testing and a standard cognitive battery with neuroimaging.

Alzheimers Dement 2014 Nov 15;10(6):779-89. Epub 2014 Nov 15.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Inexpensive, non-invasive tools for assessing Alzheimer-type pathophysiologies are needed. Computerized cognitive assessments are prime candidates.

Methods: Cognitively normal participants, aged 51-71, with magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z-scores and neuroimaging.

Results: Slower reaction times for CogState Identification and One Back, and lower memory and attention z-scores, were associated (P < .05) with FDG-PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z-scores with neuroimaging were small and of a similar magnitude.

Conclusions: CogState subtests were cross-sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers.
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http://dx.doi.org/10.1016/j.jalz.2014.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273919PMC
November 2014