Publications by authors named "Michelle M Mielke"

319 Publications

Trends in incidence of dementia among patients with rheumatoid arthritis: A population-based cohort study.

Semin Arthritis Rheum 2021 Jun 15;51(4):853-857. Epub 2021 Jun 15.

Division of Rheumatology, Mayo Clinic, Rochester, MN, USA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. Electronic address:

Objective: We aimed to assess the incidence of dementia over time in patients with incident rheumatoid arthritis (RA) as compared to non-RA referents.

Methods: This population-based, retrospective cohort study included Olmsted County, Minnesota residents with incident RA by ACR 1987 criteria, diagnosed between 1980 and 2009. We matched non-RA referents 1:1 on age, sex, and calendar year and followed all individuals until 12/31/2019. Incident dementia was defined as two codes for Alzheimer's disease and related dementias (ADRD) at least 30 days apart. Cumulative incidence of ADRD was assessed, adjusting for the competing risk of death. Cox proportional hazards models calculated hazard ratios (HR) with 95% confidence intervals (CI) for incident ADRD by decade.

Results: After excluding individuals with prior dementia, we included 897 persons with incident RA (mean age 56 years; 69% female) and 885 referents. The 10-year cumulative incidence of ADRD in individuals diagnosed with RA during the 1980s was 12.7% (95%CI:7.9-15.7%), 1990s was 7.2% (95%CI:3.7-9.4%), and 2000s was 6.2% (95%CI:3.6-7.8%). Individuals with RA diagnosed in 2000s had insignificantly lower cumulative incidence of ADRD than those in the 1980s (HR 0.66; 95%CI:0.38-1.16). The overall HR of ADRD in individuals with RA was 1.37 (vs. referents; 95%CI:1.04-1.81). When subdivided by decade, however, the risk of ADRD in individuals diagnosed with RA was higher than referents in the 1990s (HR 1.72, 95%CI:1.09-2.70) but not 2000s (HR 0.86, 95%CI:0.51-1.45).

Conclusions: The risk of dementia in individuals with RA appears to be declining over time, including when compared to general population referents.
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http://dx.doi.org/10.1016/j.semarthrit.2021.06.003DOI Listing
June 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

A blood screening tool for detecting mild cognitive impairment and Alzheimer's disease among community-dwelling Mexican Americans and non-Hispanic Whites: A method for increasing representation of diverse populations in clinical research.

Alzheimers Dement 2021 May 31. Epub 2021 May 31.

Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, Texas, USA.

Introduction: Representation of Mexican Americans in Alzheimer's disease (AD) clinical research has been extremely poor.

Methods: Data were examined from the ongoing community-based, multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models.

Results: Data were examined from n = 1649 participants (Mexican American n = 866; non-Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups.

Discussion: A blood-based screening tool can serve as a method for increasing access to state-of-the-art AD clinical research by bridging between community-based and clinic-based settings.
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http://dx.doi.org/10.1002/alz.12382DOI Listing
May 2021

P-tau/Aβ42 and Aβ42/40 ratios in CSF are equally predictive of amyloid PET status.

Alzheimers Dement (Amst) 2021 18;13(1):e12190. Epub 2021 May 18.

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA.

Introduction: Measurement of amyloid beta (Aβ40 and Aβ42) and tau (phosphorylated tau [p-tau] and total tau [t-tau]) in cerebrospinal fluid (CSF) can be utilized to differentiate clinical and preclinical Alzheimer's disease dementia (AD) from other neurodegenerative processes.

Methods: CSF biomarkers were measured in 150 participants from the Mayo Clinic Study of Aging and the Alzheimer's Disease Research Center. P-tau/Aβ42 (Roche Elecsys, Fujirebio LUMIPULSE) and Aβ42/40 (Fujirebio LUMIPULSE) ratios were compared to one another and to amyloid positron emission tomography (PET) classification.

Results: Strong correlation was observed between LUMIPULSE p-tau/Aβ42 and Aβ42/40, as well as Elecsys and LUMIPULSE p-tau/Aβ42 and Aβ42/40 (Spearman's ρ = -0.827, -0.858, and 0.960, respectively). Concordance between LUMIPULSE p-tau/Aβ42 and Aβ42/40 was 96% and between Elecsys p-tau/Aβ42 and both LUMIPULSE ratios was 97%. All ratios had > 94% overall, positive, and negative percent agreement with amyloid PET classification.

Discussion: These data suggest that p-tau/Aβ42 and Aβ42/40 ratios provide similar clinical information in the assessment of amyloid pathology.
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http://dx.doi.org/10.1002/dad2.12190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129859PMC
May 2021

Building a framework for inclusion in health services research: Development of and pre-implementation faculty and staff attitudes toward the Diversity, Equity, and Inclusion (DEI) plan at Mayo Clinic.

J Clin Transl Sci 2021 Jan 5;5(1):e88. Epub 2021 Jan 5.

Department of Neurology, Washington University, St. Louis, MO, USA.

Objective: To mitigate the impact of racism, sexism, and other systemic biases, it is essential for organizations to develop strategies to address their diversity, equity and inclusion (DEI) climates. The objective of this formative evaluation was to assess Mayo Clinic Department of Health Sciences Research (HSR) faculty and staff perceptions toward a proposed departmental DEI plan and to explore findings by diversity and professional subgroups.

Materials And Methods: Key plan components include recruitment and support for diverse individuals; training for all HSR employees and leaders; and a review system to capture diversity and inclusion feedback for leaders. Additional activities include building inclusion "nudges" into existing performance reviews. To assess pre-implementation beliefs about specific plan components, we polled attendees at a departmental staff meeting in July 2020.

Results: Overall, respondents ( = 162) commonly endorsed a blinded promotion review process and DEI training for all staff and leaders as most important. In contrast, respondents expressed less support for plan activities related to "nudges." However, attitudes among certain diversity or professional groups toward specific plan activities diverged from their non-diversity group counterparts. Qualitative feedback indicated awareness of the need to address DEI issues.

Discussion: Overall, HSR faculty and staff respondents conveyed support for the plan. However, some specific plan activities were perceived differently by members of certain diversity or professional subgroups.

Conclusion: These findings present a DEI framework on which other institutions can build and point to future directions for how DEI activities may be differentially perceived by impacted faculty and staff.
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http://dx.doi.org/10.1017/cts.2020.575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111694PMC
January 2021

Knowledge gaps in Alzheimer's disease immune biomarker research.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

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

Considerable evidence has accumulated implicating a role for immune mechanisms in moderating the pathology in Alzheimer's disease dementia. However, the appropriate therapeutic target, the appropriate direction of manipulation, and the stage of disease at which to begin treatment remain unanswered questions. Part of the challenge derives from the absence of any selective pressure to develop a coordinated beneficial immune response to severe neural injury in adults. Thus, immune responses to the prevailing stimuli are likely to contain both beneficial and detrimental components. Knowledge gaps include: (1) how a biomarker change relates to the underlying biology, (2) the degree to which pathological stage group differences reflect a response to pathology versus trait differences among individuals regulating risk of developing pathology, (3) the degree to which biomarker levels are predictive of subsequent changes in pathology and/or cognition, and (4) experimental manipulations in model systems to determine whether differences in immune biomarkers are causally related to pathology.
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http://dx.doi.org/10.1002/alz.12342DOI 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

Epidemiology and Natural History of Inclusion Body Myositis: A 40-Year Population-Based Study.

Neurology 2021 05 20;96(21):e2653-e2661. Epub 2021 Apr 20.

From the Department of Neurology (S.S., M.M.M., J.M., M.M., E.N., T.L.), Department of Health Sciences Research (M.M.M., J.M.), and Division of Rheumatology (F.C.E.), Department of Medicine, Mayo Clinic, Rochester, MN.

Objectives: To determine the prevalence and natural history of sporadic inclusion body myositis (sIBM) and to test the hypothesis that patients with sIBM have higher cancer or mortality rates than the general population.

Methods: We sought patients with sIBM defined by the 2011 European Neuromuscular Centre (ENMC) diagnostic criteria among Olmsted County, Minnesota, residents in 40-year time period.

Results: We identified 20 patients (10 clinicopathologically defined, 9 clinically defined, and 1 probable) according to the ENMC criteria and 1 patient with all features of clinicopathologically defined sIBM except for symptom onset at <45 years of age. The prevalence of sIBM in 2010 was 18.20 per 100,000 people ≥50 years old. Ten patients developed cancers. The incidence of cancers in sIBM did not differ from that observed in the general population (odds ratio 1.89, 95% confidence interval [CI] 0.639-5.613, = 0.24). Two-thirds of patients developed dysphagia, and half required a feeding tube. Nine patients required a wheelchair. The median time from symptom onset to wheelchair dependence was 10.5 (range 1-29) years. Overall life expectancy was shorter in the sIBM group compared to the general population (84.1 [95% CI 78-88.4] vs 87.5 [95% CI 85.2-89.5] years, = 0.03). Thirteen patients died; 9 deaths were sIBM related (7 respiratory and 2 unspecified sIBM complications). Female sex ( = 0.03) and dysphagia ( = 0.05) were independent predictors of death.

Conclusion: Olmsted County has the highest prevalence of sIBM reported to date. Patients with sIBM have similar risk of cancer, but slightly shorter life expectancy compared to matched patients without sIBM.

Classification Of Evidence: This study provides Class II evidence that patients with sIBM have similar risks of cancers and slightly shorter life expectancy compared to controls.
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http://dx.doi.org/10.1212/WNL.0000000000012004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205447PMC
May 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 Jun 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

Sex differences in CSF biomarkers for neurodegeneration and blood-brain barrier integrity.

Alzheimers Dement (Amst) 2021 17;13(1):e12141. Epub 2021 Mar 17.

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology the Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden.

Introduction: As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (Q) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand.

Methods: Participants were derived from two Swedish samples: the population-based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, Q, n = 39252, age 0 to 95). In the population-based study, Q and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, Q and NfL sex differences were tested in relation to age.

Results: Men had higher Q and NfL concentrations and had higher Q and NfL concentrations from adolescence throughout life. NfL was not related to WML, but Q correlated positively with WMLs.

Discussion: The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.
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http://dx.doi.org/10.1002/dad2.12141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968119PMC
March 2021

Neuropsychiatric symptoms and the outcome of cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging.

Int J Geriatr Psychiatry 2021 Mar 16. Epub 2021 Mar 16.

Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.

Objective: Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. We examined associations between NPS and the outcomes of global and domain-specific cognitive trajectories.

Methods: In this longitudinal study conducted in the setting of the population-based Mayo Clinic Study of Aging, 5081 community-dwelling, nondemented individuals aged ≥50 years (51% males) underwent NPS assessment using Neuropsychiatric Inventory Questionnaire (NPI-Q), and Beck Depression and Anxiety Inventories (BDI-II, BAI). Global and domain-specific (memory, language, attention, and visuospatial skills) cognitive performance was assessed through neuropsychological testing every 15 months. Associations between baseline NPS and trajectories for individual yearly change in cognitive z-scores were calculated using linear mixed-effect models.

Results: Cognition declined regardless of NPS status over the median follow-up of 4.5 years. Presence of NPS was associated with increased cognitive decline. Differences in annualized change in global cognition z-scores for participants with NPS compared to without NPS ranged from -0.018 (95% CI -0.032, -0.004; p = 0.011) for irritability to -0.159 (-0.254, -0.065; p = 0.001) for hallucinations. Associations between NPS and annual decline in global cognition were significant for most NPI-Q-assessed NPS and clinical depression (BDI-II≥13). Participants with NPI-Q-assessed depression, apathy, nighttime behavior, and clinical depression had greater decline in all domain-specific z-scores; presence of delusions and anxiety was associated with more pronounced decline in language, attention and visuospatial skills.

Conclusion: NPS were associated with a more accelerated cognitive decline. Clinical assessment and potential treatment of NPS is warranted even in a community setting as NPS may impact cognitive decline in nondemented individuals.
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http://dx.doi.org/10.1002/gps.5528DOI Listing
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

Early-Onset Parkinsonism and Early-Onset Parkinson's Disease: A Population-Based Study (2010-2015).

J Parkinsons Dis 2021 Mar 10. Epub 2021 Mar 10.

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

Background: Early-onset Parkinson's disease (EOPD), occurring between ages 40 and 55, carries social, societal, and personal consequences and may progress, with fewer comorbidities than typical, later-onset disease.

Objective: To examine the incidence and survival of EOPD and other Parkinsonism occurring before age 55 in the population-based cohort of residents in seven Minnesota counties.

Methods: A movement-disorder specialist reviewed all the medical records in a 2010-2015 Parkinsonism-incident cohort to confirm diagnosis and subtypes.

Results: We identified 27 patients diagnosed at <  50 years with incident Parkinsonism 2010-15:11 (41%) cases of EOPD, 13 (48%) drug-induced Parkinsonism, and 3 (11%) other Parkinsonism and 69 incident cases of Parkinsonism <  55 years of age. Overall incidence for Parkinsonism <  50 years was 1.98/100,000 person-years, and for EOPD was 0.81/100,000 person-years. In patients <  55 years, Parkinsonism incidence was 5.05/100,000 person-years: in EOPD, 2.05/100,000 person-years. Levodopa-induced dyskinesia was present in 45%of EOPD (both <  50 years and <  55 years). Onset of cardinal motor symptoms was proximate to the diagnosis of EOPD, except for impaired postural reflexes, which occurred later in the course of EOPD. Among the 69 Parkinsonism cases <  55 years, 9 (13%; all male) were deceased (only 1 case of EOPD). Men had a higher mortality risk compared to women (p = 0.049).

Conclusion: The incidence of EOPD <  50 years was 0.81/100,000 person-years (1.98 in Parkinsonism all type); prior to 55 years was 2.05/100,000 person-years (5.05 in Parkinsonism all type) with higher incidence in men than women. Men with Parkinsonism, all type, had higher mortality compared to women.
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http://dx.doi.org/10.3233/JPD-202464DOI Listing
March 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

Diagnostic accuracy of the Cogstate Brief Battery for prevalent MCI and prodromal AD (MCI A T ) in a population-based sample.

Alzheimers Dement 2021 04 1;17(4):584-594. Epub 2021 Mar 1.

Division of Neurocognitive Disorders, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: This study evaluated the diagnostic accuracy of the Cogstate Brief Battery (CBB) for mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) in a population-based sample.

Methods: Participants included adults ages 50+ classified as cognitively unimpaired (CU, n = 2866) or MCI (n = 226), and a subset with amyloid (A) and tau (T) positron emission tomography who were AD biomarker negative (A-T-) or had prodromal AD (A+T+).

Results: Diagnostic accuracy of the Learning/Working Memory Composite (Lrn/WM) for discriminating all CU and MCI was moderate (area under the curve [AUC] = 0.75), but improved when discriminating CU A-T- and MCI A+T+ (AUC = 0.93) and when differentiating MCI participants without AD biomarkers from those with prodromal AD (AUC = 0.86). Conventional cut-offs yielded lower than expected sensitivity for both MCI (38%) and prodromal AD (73%).

Discussion: Clinical utility of the CBB for detecting MCI in a population-based sample is lower than expected. Caution is needed when using currently available CBB normative data for clinical interpretation.
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http://dx.doi.org/10.1002/alz.12219DOI Listing
April 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

CERT reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):45. Epub 2021 Feb 17.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands.

Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.

Methods: A plasmid expressing CERT, the long isoform of CERTs, was used to study the interaction of CERT with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERT protein was employed to study interaction of CERT with amyloid-β (Aβ), Aβ aggregation process in presence of CERT, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERT was overexpressed in neurons by adeno-associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety, and locomotion. At week 12, brains were investigated for sphingolipid levels by mass spectrometry, plaques, and neuroinflammation by immunohistochemistry, gene expression, and/or immunoassay.

Results: Here, we report that CERT binds to APP, modifies Aβ aggregation, and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERT, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERT in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation, and modulates microglia by decreasing their pro-inflammatory phenotype.

Conclusion: Our results demonstrate a crucial role of CERT in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.
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http://dx.doi.org/10.1186/s13195-021-00780-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890977PMC
February 2021

Peripheral Markers of Neurovascular Unit Integrity and Amyloid-β in the Brains of Menopausal Women.

J Alzheimers Dis 2021 ;80(1):397-405

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

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer's disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers.

Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women.

Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1-42 (Aβ1-42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs.

Results: Only the number of microvesicles positive for Aβ1-42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045).

Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.
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http://dx.doi.org/10.3233/JAD-201410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075395PMC
January 2021

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD.

Mov Disord 2021 05 6;36(5):1216-1228. Epub 2021 Feb 6.

Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement.

Objective: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).

Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD patients compared to PD patients.

Results: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD compared to PD . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD compared to PD . (3) CSF levels of total α-synuclein were lower in PD compared to PD . All of these findings were most pronounced in PD with severe mutations (PD ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PD .

Interpretation: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD with severe variants. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28472DOI Listing
May 2021

Association of Premenopausal Bilateral Oophorectomy With Restless Legs Syndrome.

JAMA Netw Open 2021 02 1;4(2):e2036058. Epub 2021 Feb 1.

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

Importance: Restless legs syndrome is a common neurologic disorder that is more prevalent in women than in men, and it has been suggested that female hormones may be involved in the disorder's pathophysiology.

Objective: To determine whether women who underwent premenopausal bilateral oophorectomy were at increased risk of restless legs syndrome.

Design, Setting, And Participants: This cohort study was performed using data from the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 for a population in Olmsted County, Minnesota. There were 1653 women who underwent premenopausal bilateral oophorectomy before the age of 50 years for a benign indication between 1988 and 2007 and 1653 age-matched women (of same age plus or minus 1 year) in a reference group. Follow-up was conducted until the end of the study period (ie, December 31, 2014). Data were analyzed from January to July 2020.

Exposures: Undergoing bilateral oophorectomy, as shown in medical record documentation.

Main Outcomes And Measures: Diagnosis of restless legs syndrome, as defined using Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, was recorded.

Results: Among 3306 women, the median (interquartile range) age at baseline was 44.0 (40.0-47.0) years. Women who underwent bilateral oophorectomy, compared with women who did not undergo this procedure, had a greater number of chronic conditions at the index date (eg, 300 women [18.1%] vs 171 women [10.3%] with ≥3 chronic conditions; overall P < .001), were more likely to have obesity (576 women [34.8%] vs 442 women [27.1%]; overall P < .001), and were more likely to have a history of anemia of any type (573 women [34.7%] vs 225 women [13.6%]; P < .001), iron deficiency anemia (347 women [21.0%] vs 135 women [8.2%]; P < .001), and restless legs syndrome before the index date (32 women [1.9%] vs 14 women [0.8%]; P = .008). Women who underwent bilateral oophorectomy prior to natural menopause had a higher risk of restless legs syndrome after the index date compared with women in the reference group (120 diagnoses vs 74 diagnoses), with an adjusted hazard ratio (HR) of 1.44 (95% CI, 1.08-1.92; P = .01). After stratification by indication for the bilateral oophorectomy, there was an increased risk of restless legs syndrome among women without a benign ovarian condition (HR, 1.52; 95% CI, 1.03-2.25; P = .04) but not among women with a benign condition (HR, 1.25; 95% CI, 0.80-1.96; P = .34). Treatment with estrogen therapy through the age of 46 years in women who underwent bilateral oophorectomy at younger ages was not associated with a difference in risk.

Conclusions And Relevance: This cohort study found that risk of restless legs syndrome was increased among women who underwent bilateral oophorectomy prior to menopause, especially those without a benign ovarian indication.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.36058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851733PMC
February 2021

A Workshop on Cognitive Aging and Impairment in the 9/11-Exposed Population.

Int J Environ Res Public Health 2021 01 14;18(2). Epub 2021 Jan 14.

World Trade Center Health Program, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Washington, DC 20201, USA.

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting's agenda and provide an overview of the presentation materials and group discussion.
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http://dx.doi.org/10.3390/ijerph18020681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830144PMC
January 2021

Risk Factors and Wellness Measures Associated with Prediabetes and Newly Diagnosed Type 2 Diabetes Mellitus in Hispanic Adults.

Metab Syndr Relat Disord 2021 04 15;19(3):180-189. Epub 2021 Jan 15.

Division of Endocrinology, Mayo Clinic, Rochester, Minnesota, USA.

To characterize the associations of clinical risk factors, lifestyle factors, and wellness measures with prediabetes and new type 2 diabetes mellitus (T2DM) diagnosis in Hispanic adults and guide primary prevention. Biobank enrolled 3733 Hispanic adults from Phoenix, AZ, United States, from 2013 to 2018. This analysis included participants with euglycemia, prediabetes, or new T2DM diagnosis (, no prior T2DM diagnosis) at enrollment. Participants completed a baseline questionnaire on cardiometabolic risk factors and wellness measures and provided biometric measurements. The associations of factors and measures with odds (95% confidence interval) of prediabetes and new T2DM diagnosis were analyzed in logistic regression models. Among 3299 participants with euglycemia ( = 1301), prediabetes ( = 1718), and new T2DM diagnosis ( = 280) at enrollment, 72% were women ( = 2376/3299). In adjusted models, most cardiometabolic risk factors were positively associated with prediabetes and new T2DM diagnosis, with stronger associations for new T2DM diagnosis. Obesity (body mass index ≥30 kg/m vs. lower) was associated with higher odds of new T2DM diagnosis (3.14 [2.30-4.28];  < 0.01) than prediabetes versus euglycemia (1.96 [1.66-2.32];  < 0.01) and Interaction ( = 0.01). Similarly, waist circumference, family history of diabetes, and average systolic and diastolic blood pressure were associated with higher odds of new T2DM diagnosis versus euglycemia than prediabetes versus euglycemia. Using stepwise logistic regression modeling, a parsimonious model of age, family history of diabetes, waist circumference, diastolic blood pressure, passive tobacco exposure, and self-rated general health were associated with new T2DM diagnosis versus euglycemia. In Hispanic adults, modifiable cardiometabolic and lifestyle factors were associated with prediabetes and new T2DM diagnosis. Personalized interventions targeting these factors and measures could guide T2DM primary prevention efforts among Hispanic adults.
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http://dx.doi.org/10.1089/met.2020.0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997711PMC
April 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

Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging.

J Alzheimers Dis 2021 ;79(1):377-388

Biodesign Institute, Arizona State University, Tempe, AZ, USA.

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults.

Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status.

Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores.

Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition.

Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.
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http://dx.doi.org/10.3233/JAD-200959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839815PMC
January 2021