Publications by authors named "Jeremiah Aakre"

48 Publications

The temporal onset of the core features in dementia with Lewy bodies.

Alzheimers Dement 2021 Nov 11. Epub 2021 Nov 11.

Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida, USA.

Introduction: We examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB).

Methods: In 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209).

Results: REM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles.

Discussion: An earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles.
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http://dx.doi.org/10.1002/alz.12411DOI Listing
November 2021

Sex Difference in the Relation Between Marital Status and Dementia Risk in Two Population-Based Cohorts.

J Alzheimers Dis 2021 ;83(3):1269-1279

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

Background: The modifying effect of sex on the relation between marital status and dementia has yet to be determined.

Objective: To examine if sex modifies the association between marital status and incident dementia.

Methods: Population-based samples from the Mayo Clinic Study of Aging (MCSA, N = 3,471) and the Gothenburg H70 Birth Cohort Study (H70-study, N = 913) were used. A multiplicative interaction term was used to analyze the modifying effect of sex on the relation between marital status (married versus not married) and incident dementia using Cox regression models. Further, risk of dementia by marital status was also evaluated in models separated by sex.

Results: In the MCSA, there was an interaction between marital status and sex in relation to dementia (p = 0.015). In contrast, in the H70-study, no significant interaction was observed (p = 0.28). Nevertheless, in both studies, not married men had increased risk of dementia compared to married men in models adjusted for age, education, and number of children (H70-study: 1.99; 1.06-3.76, MCSA: 1.43; 1.08-1.89). Associations remained similar after additional adjustment for depression, BMI, hypertension, dyslipidemia, and diabetes mellitus (H70-study: 2.00; 1.05-3.82, MCSA: 1.32; 0.99-1.76). Further, no significant association was observed between marital status and dementia in women (H70-study: 1.24; 0.82-1.89, MCSA: 0.82; 0.64-1.04).

Conclusion: Sex had a modifying effect on the association between marital status and incident dementia. In analyses separated by sex, not married men had an increased risk of dementia compared to married men, while no significant association was observed between marital status and risk of dementia in women.
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http://dx.doi.org/10.3233/JAD-210246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490335PMC
January 2021

Association of plasma ceramides with prevalent and incident type 2 diabetes mellitus in middle and older aged adults.

Diabetes Res Clin Pract 2021 Sep 29;179:108991. Epub 2021 Jul 29.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States; Department of Neurology, Mayo Clinic, Rochester, MN, United States. Electronic address:

Aims: The role of ceramides in the pathogenesis of type 2 diabetes mellitus (T2DM) is incompletely characterized. Given that ceramides represent therapeutic targets to disrupt the euglycemia-T2DM transition, we aimed to characterize their association with prevalent and incident T2DM in a novel cohort.

Methods: We examined the cross-sectional and longitudinal association of baseline ceramides with prevalent and incident T2DM among 1423 adults (47% women; median (range) baseline age 72 (51-95) years) in the Mayo Clinic Study of Aging cohort. We examined the associations of ceramides with prevalent T2DM (adjusted odds ratio [95% confidence interval]) at baseline and incident T2DM (adjusted hazard ratio [95% confidence interval]) during median follow-up of 6.2 years, after adjusting for demographic and metabolic factors.

Results: Among 1423 adults, there were 222 prevalent and 37 incident cases of T2DM. In cross-sectional analyses, higher levels of ceramide C16:0 were associated with lower odds of prevalent T2DM (aOR 0.84 [0.71-0.99];P = 0.03) whereas C18:0 (aOR 1.27 [1.06-1.42];P = 0.01), C18:0/16:0 (aOR 1.41 [1.22-1.62]; P < 0.001) and C18:0/24:0 (aOR 1.22 [1.05-1.41]; P = 0.01) were associated with higher odds. In Cox hazard regression models, C18:0/16:0 (aHR 1.63 [1.26-2.10];P < 0.001) and C18:0 (aHR 1.53 [1.12-2.08];P = 0.01) were associated with increased risk of incident T2DM.

Conclusions: In this prospective population-based cohort, ceramides were associated with prevalent T2DM (C16:0,C18:0, C18:0/C16:0 ratio, C18:0/C24:0 ratio) and incident T2DM (C18:0, C18:0/C16:0 ratio) and could suggest targets for the primary and secondary prevention of T2DM.
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http://dx.doi.org/10.1016/j.diabres.2021.108991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478833PMC
September 2021

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

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Eli Lilly and Company, Indianapolis, Indiana, USA.

Introduction: The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood.

Methods: Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p-tau181 were measured with Elecsys immunoassays. CSF p-tau181 and p-tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain-specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging.

Results: CSF p-tau217 was superior to p-tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p-tau181 and p-tau217 were associated with risk of MCI among amyloid-positive individuals. Differences between CSF p-tau measures predicting cortical thickness were subtle.

Discussion: There are subtle differences for CSF p-tau217 and p-tau181 as prognostic AD markers.
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http://dx.doi.org/10.1002/alz.12415DOI Listing
July 2021

Androgen Deprivation Therapy Use and Risk of Mild Cognitive Impairment in Prostate Cancer Patients.

Alzheimer Dis Assoc Disord 2021 Jan-Mar 01;35(1):44-47

Health Sciences Research.

Introduction: We examined the association between androgen deprivation therapy (ADT) use and the risk of mild cognitive impairment (MCI) among prostate cancer patients.

Methods: We included 241 cognitively unimpaired men, aged 70 to 90, with a history of prostate cancer before enrollment in the population-based Mayo Clinic Study of Aging. Using the Rochester Epidemiology Project medical records-linkage system, ADT use and length of exposure were abstracted. Follow-up visits occurred every 15 months and MCI diagnoses were made based on clinical consensus. Cox proportional hazards models, with age as the timescale, were used to examine the association between ADT use (yes/no) and length of exposure with the risk of MCI adjusting for education, apolipoprotein E, depression, and the Charlson Index score.

Results: There was no association between any ADT use (27.8% of participants) and the risk of MCI in the multivariable model [hazard ratio (HR), 1.25; 95% confidence interval (CI), 0.75-2.10]. Although not significant, there was an ADT dose-response relationship for risk of MCI: <5 years versus no use (HR, 1.08; 95% CI, 0.60-1.96) and ≥5 years versus not use (HR, 1.89; 95% CI, 0.83-4.27).

Conclusion: ADT use among prostate cancer patients was not associated with an increased risk of developing MCI.
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http://dx.doi.org/10.1097/WAD.0000000000000415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904573PMC
October 2021

Subtypes of dementia with Lewy bodies are associated with α-synuclein and tau distribution.

Neurology 2020 07 19;95(2):e155-e165. Epub 2020 Jun 19.

From the Departments of Psychiatry and Psychology (T.J.F., O.P.), Neurology (J.A.V.G., N.R.G.-R., R.J.U., Z.K.W.), and Neuroscience (M.E.M., O.A.R., D.W.D.) Mayo Clinic, Jacksonville, FL; Department of Psychiatry (N.A.), Yokohama University Medical Center, Japan; and Departments of Neurology (B.F.B., J.G.-R., D.S.K., R.C.P.), Health Sciences Research (J.A.A.), Radiology (K.K.), Laboratory Medicine and Pathology (J.E.P., R.R.R.), and Psychiatry and Psychology (J.A.F.), Mayo Clinic, Rochester, MN.

Objective: To determine whether Lewy body disease subgroups have different clinical profiles.

Methods: Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder.

Results: In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles.

Conclusions: The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.
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http://dx.doi.org/10.1212/WNL.0000000000009763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455327PMC
July 2020

Prevalence and Heterogeneity of Cerebrovascular Disease Imaging Lesions.

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

Department of Radiology, Mayo Clinic, Rochester, MN.

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

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

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

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

Brain amyloid, cortical thickness, and changes in activities of daily living.

Ann Clin Transl Neurol 2020 04 21;7(4):474-485. Epub 2020 Apr 21.

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

Objective: To examine the association of baseline elevated brain amyloid and neurodegeneration with changes in activities of daily living in participants without dementia (ND; i.e., cognitively unimpaired and participants with mild cognitive impairment) at baseline in the population-based Mayo Clinic Study of Aging.

Methods: We included 1747 ND participants with C-PiB PET and MR imaging in the study, with data on activities of daily living (as assessed by the Functional Activities Questionnaire (FAQ) and the Clinical Dementia Rating scale Sum of Boxes for functional domains (CDR-SOB (functional)), with a median (range) of 4.3 (0.0-12.7) years of follow-up. Abnormal (elevated; A+) C-PiB-PET retention ratio was defined as standardized uptake value ratio ≥ 1.48, and abnormal (reduced) AD signature cortical thickness as ≤ 2.68 mm (neurodegeneration; N+). Associations were examined with mixed effects models, adjusting for age, sex, education, apolipoprotein E ε4 allele carrier status, and global cognitive z-score.

Results: Mean age (SD) was 71.4 years (10.1), 46.7% were females, 195 (11.2%) had A+N-, 442 (25.3%) had A-N+, and 339 (19.4%) had A+N+ biomarkers. The A+N+ group had the largest annualized change in the FAQ score from baseline (difference in annual change A+N+ vs. A-N-; ß (SE): 0.80 (0.07)); associations were substantially attenuated when a time-varying global cognitive composite was included in the model (A+N+ vs. A-N-; ß (SE): 0.31 (0.05)). CDR-SOB (functional) findings partly agreed with FAQ score findings.

Interpretation: The longitudinal increase in functional limitations is greater for individuals with abnormal neuroimaging biomarkers, especially for those with both elevated brain amyloid and neurodegeneration.
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http://dx.doi.org/10.1002/acn3.51010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187716PMC
April 2020

Cerebral microbleed incidence, relationship to amyloid burden: The Mayo Clinic Study of Aging.

Neurology 2020 01 4;94(2):e190-e199. Epub 2019 Dec 4.

From the Departments of Neurology (J.G.-R., A.A.R., R.D.B., M.M.M., D.S.K., R.C.P.), Health Sciences Research (T.L., J.G., J.A., S.A.P., M.M.M., W.K.), and Radiology (A.J.S., J.H., V.J.L., C.R.J., P.V., K.K.), Mayo Clinic, Rochester, MN.

Objective: To determine the incidence of cerebral microbleeds (CMBs) and the association of amyloid PET burden with incident CMBs.

Methods: A total of 651 participants, age ≥50 years (55% male), underwent 3T MRI scans with ≥2 separate T2*-weighted gradient recalled echo sequences from October 2011 to August 2017. Eighty-seven percent underwent C Pittsburgh compound B (PiB) PET scans. Age-specific CMB incidence rates were calculated by using the piecewise exponential model. Using structural equation models (SEMs), we assessed the effect of amyloid load and baseline CMBs on future CMBs after considering the direct and indirect age, sex, vascular risk factors, and effects.

Results: Participants' mean age (SD) was 69.8 (10.0) years at baseline MRI, and 111 participants (17%) had ≥1 baseline CMB. The mean (SD) of the time interval between scans was 2.7 (1.0) years. The overall population incidence rate for CMBs was 3.6/100 person-years and increased with age: from 1.5/100 new CMBs at age 50 to 11.6/100 person-years at age 90. Using the piecewise exponential model regression, the incidence rates increased with age and the presence of baseline CMBs. The SEMs showed that (1) increasing age at MRI or carrying an 4 allele was associated with more amyloid at baseline, and higher amyloid, particularly occipital amyloid load, in turn increased the risk of a new lobar CMB; and (2) the presence of CMBs at baseline increased the risk of a lobar CMB and had a larger effect size than amyloid load.

Conclusions: Age and 4 carrier status act through amyloid load to increase the risk of subsequent lobar CMBs, but the presence of baseline CMBs is the most important risk factor for future CMBs.
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http://dx.doi.org/10.1212/WNL.0000000000008735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988987PMC
January 2020

Practical algorithms for amyloid β probability in subjective or mild cognitive impairment.

Alzheimers Dement (Amst) 2019 Dec 22;11:180. Epub 2019 Oct 22.

Department of Biostatistics, Biogen, Cambridge, MA, USA.

Introduction: Practical algorithms predicting the probability of amyloid pathology among patients with subjective cognitive decline or mild cognitive impairment may help clinical decisions regarding confirmatory biomarker testing for Alzheimer's disease.

Methods: Algorithm feature selection was conducted with Alzheimer's Disease Neuroimaging Initiative and Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing data. Probability algorithms were developed in Alzheimer's Disease Neuroimaging Initiative using nested cross-validation accompanied by stratified subsampling to obtain 1000 internally validated decision trees. Semi-independent validation was conducted using Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Independent external validation was conducted in the population-based Mayo Clinic Study of Aging.

Results: Two algorithms were developed using age and normalized immediate recall z-scores, with or without apolipoprotein E ε4 carrier status. Both algorithms had robust performance across data sets and when substituting different recall memory tests.

Discussion: The statistical framework resulted in robust probability estimation. Application of these algorithms may assist in clinical decision-making for further testing to diagnose amyloid pathology.
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http://dx.doi.org/10.1016/j.dadm.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827360PMC
December 2019

Incidence of Convexal Subarachnoid Hemorrhage in the Elderly: The Mayo Clinic Study of Aging.

J Stroke Cerebrovasc Dis 2019 Dec 24;28(12):104451. Epub 2019 Oct 24.

Department of Neurology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Objectives: Nontraumatic convexal subarachnoid hemorrhages in the elderly can be a manifestation of cerebral amyloid angiopathy associated with a high risk of future intracerebral hemorrhage. The incidence in the elderly population is unknown. Our objectives were to: 1) determine the incidence of convexal subarachnoid hemorrhage in a population-based study, and, 2) to compare apopolipoprotein-E genotype and amyloid positron emission tomographic (PET) imaging for those with versus without hemorrhage.

Methods: Between 11/29/2004 and 3/11/2017, 4462 individuals without hemorrhage at baseline participated in the population-based Mayo Clinic Study of Aging. We used the Rochester Epidemiology Project medical records-linkage system to identify intracerebral hemorrhages. Records and images were reviewed to identify convexal subarachnoid hemorrhage. Neuroimaging characteristics, demographics, medications, and apopolipoprotein-E genotype were recorded.

Results: Four cases were identified. The incidence of convexal subarachnoid hemorrhage was 14.1 per 100,000 person years. Three occurred in women, median age, 79 (range: 71-84). One patient had coexisting cerebral microbleeds. Two participants developed a subsequent lobar intracerebral hemorrhage at a median of 4.75 years after convexal subarachnoid hemorrhage. The apopolipoprotein-E -allele combinations of the 4 were: 3/3, 3/3, 2/2, and 2/3. On Pittsburgh Compound B-PET imaging, median standardized uptake value ratio with convexal subarachnoid hemorrhage was 1.86 (range: 1.38-2.34).

Conclusions: Convexal subarachnoid hemorrhage is rare in the older population, occurring with an incidence of about 14 per 100,000 person years. Yet, when present, it may be associated with a high risk of future intracerebral hemorrhage.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886710PMC
December 2019

Informant-based hearing difficulties and the risk for mild cognitive impairment and dementia.

Age Ageing 2019 11;48(6):888-894

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

Background: hearing loss has been associated with mild cognitive impairment (MCI) and dementia. Studies have not assessed whether hearing difficulties (HD) that interfere with daily activities as reported by partners can be a marker for increased risk for cognitive decline and impairment.

Objective: to assess the cross-sectional and longitudinal associations between informant-based HD, which interfere with daily activities and the risk for MCI and dementia.

Methods: the study included 4812 participants without dementia, enrolled in the Mayo Clinic Study of Aging (mean age (SD) 73.7 (9.6) years) with cognitive evaluation and informant-based report on participant's HD that interfere significantly with daily activities at baseline and for every 15 months. Cox proportional hazards models (utilising time-dependent HD status and age as the time scale) were used to examine HD and the risk for MCI or dementia, and mixed-effects models (allowing for random subject-specific intercepts and slopes) were used to examine the relationship between HD and cognitive decline.

Results: about, 981 participants had HD and 612 (12.7%) had prevalent MCI at baseline; 759 participants developed incident MCI and 273 developed incident dementia. In cognitively unimpaired participants at baseline, those with HD had higher risk for MCI (hazard ratio [HR] = 1.29, 95% confidence interval [CI] (1.10, 1.51), P = 0.002; adjusting for sex, years of education). In participants without dementia, those with HD had higher risk for dementia (HR: 1.39, 95% CI, (1.08-1.79), P = 0.011; adjusting sex and education). In individuals with MCI, HD was associated with modestly greater cognitive decline.

Conclusions: informant-based HD was associated with increased risk for MCI and dementia.
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http://dx.doi.org/10.1093/ageing/afz099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814092PMC
November 2019

Comparison of the Short Test of Mental Status and the Montreal Cognitive Assessment Across the Cognitive Spectrum.

Mayo Clin Proc 2019 08 4;94(8):1516-1523. Epub 2019 Jul 4.

Department of Neurology, Mayo Clinic, Rochester, MN.

Objective: To compare the Short Test of Mental Status (STMS) with the Montreal Cognitive Assessment (MoCA) for predicting and detecting mild cognitive impairment (MCI).

Participants And Methods: Participants from the community-based Mayo Clinic Study of Aging (MCSA) (November 24, 2010, through May 19, 2012) and an academic referral Alzheimer's Disease Research Center (ADRC) (March 16, 2015, through September 5, 2018) were analyzed. All participants were evaluated using a standardized neuropsychological battery, and a multidisciplinary consensus diagnosis was assigned. The MCSA and ADRC samples included 313 and 106 stable cognitively normal (CN) participants, 72 and 8 CN participants at baseline who developed incident MCI or dementia, 114 and 96 participants with prevalent MCI, and 25 and 132 participants with dementia, respectively.

Results: There were no statistically significant differences between the 2 tests in 6 of 7 diagnostic comparisons across academic referral and community populations. The STMS had a better area under the curve (0.90; 95% CI, 0.87-0.93) for differentiating prevalent MCI from CN participants in the MCSA cohort compared with the MoCA cohort (0.85; 95% CI, 0.81-0.89; P=.01). In addition, 53% of the stable CN participants (222 of 419) scored less than 26 on the MoCA, with specificity of 47% for diagnosing prevalent MCI.

Conclusion: We provide evidence that the STMS performs similarly to the MoCA in a variety of settings and neurodegenerative syndromes. These results suggest that the current recommended MoCA cutoff score may be overly sensitive, consistent with previous studies. We also provide a conversion table for comparing the 2 cognitive tests.
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http://dx.doi.org/10.1016/j.mayocp.2019.01.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937135PMC
August 2019

Excessive Daytime Sleepiness in Major Dementia Syndromes.

Am J Alzheimers Dis Other Demen 2019 06 10;34(4):261-264. Epub 2019 Feb 10.

1 Mayo Clinic, Rochester, MN, USA.

There has been no comparison of excessive daytime sleepiness (EDS) in patients with Alzheimer's disease dementia (AD), dementia with Lewy bodies (DLB), and behavioral variant frontotemporal dementia (bvFTD). We identified patients with mild dementia who met criteria for these disorders who also had the Epworth Sleepiness Scale (ESS) completed. The sample included 17 bvFTD, 111 AD, and 31 DLB. An ESS score ≥10 was considered abnormal and consistent with EDS. Analyses with age and sex as covariates revealed higher mean ESS scores for DLB compared to the other groups (DLB 13.9 [5], bvFTD 9.6 [8], AD 8.8 [5], P < .05). An ESS score ≥10 was significantly more likely to occur in DLB compared to bvFTD or AD (DLB 81% vs bvFTD 47% vs AD 45%, P < .01). In patients with mild dementia, EDS is greatest in DLB and comparably lower in bvFTD and AD.
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http://dx.doi.org/10.1177/1533317519828046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709580PMC
June 2019

Factors Associated With Meningioma Detected in a Population-Based Sample.

Mayo Clin Proc 2019 02;94(2):254-261

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

Objective: To determine the frequency of incidental meningioma and identify associated factors in a population-based sample of participants who systematically underwent brain imaging.

Patients And Methods: We searched the Mayo Clinic Study of Aging, a population-based sample of Olmsted County, Minnesota, residents who underwent longitudinal magnetic resonance imaging of the brain. Using a text search of radiologists' notes for 2402 individuals (median age, 75.0 years) who underwent imaging between August 10, 2005, and July 31, 2014, we identified 52 patients (2.2%) who had at least one meningioma. We estimated the association of selected risk factors with the presence of meningioma using odds ratios and 95% CIs from logistic regression models adjusted for age and sex. Based on these results, we moved the most significant variables forward to a multivariable model.

Results: Controlling for age and sex, significant associations with the presence of meningioma included higher body mass index (odds ratio [OR], 1.06; 95% CI, 1.01-1.12; P=.03), nonsteroidal anti-inflammatory drugs (OR, 2.11; 95% CI, 1.13-3.95; P=.02), aspirin (OR, 1.90; 95% CI, 1.05-3.46; P=.04), and blood pressure-lowering medication (OR, 2.06; 95% CI, 1.06-3.99; P=.03). Lower risk was associated with male sex (OR, 0.51; 95% CI, 0.29-0.90; P=.02), coronary artery disease (OR, 0.46; 95% CI, 0.22-0.97; P=.04), and higher self-reported anxiety (OR, 0.88; 95% CI, 0.78-0.98; P=.02). Simultaneous adjustment for all of these factors except aspirin in a multivariable model did not attenuate these associations (concordance, 0.71).

Conclusion: In a population-based sample of 2402 participants, 52 (2.2%) had an incidental meningioma. They were more likely to be female and have higher body mass index. Meningioma was also associated with certain medications (nonsteroidal anti-inflammatory drugs and blood pressure-lowering medications) and inversely with anxiety and coronary artery disease.
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http://dx.doi.org/10.1016/j.mayocp.2018.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519073PMC
February 2019

Association Between Functional Performance and Alzheimer's Disease Biomarkers in Individuals Without Dementia.

J Am Geriatr Soc 2018 12 21;66(12):2274-2281. Epub 2018 Nov 21.

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

Objectives: To examine the cross-sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI)).

Design: Cross-sectional.

Setting: Olmsted County, Minnesota.

Participants: Population-based Mayo Clinic Study of Aging (MCSA) participants (aged ≥ 50, mean age 71.3 ± 10.2; 53.4% male; 28.3% apolipoprotein (APO)E ε4 allele carriers, 1,578 CU, 204 MCI) who underwent C-Pittsburgh compound B ( C-PiB) positron emission tomography (PET) (N=1,782).

Measurements: We defined an abnormal (high) C-PiB-PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A-) and neurodegeneration (N+/N-). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ).

Results: Participants with a CDR-SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77-8.67, adjusting for age, sex, education, global cognitive z-score, and APOE ε4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04-2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A-N + in CU participants.

Conclusion: The findings of this cross-sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. J Am Geriatr Soc 66:2274-2281, 2018.
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http://dx.doi.org/10.1111/jgs.15577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391872PMC
December 2018

The Association of Multimorbidity With Preclinical AD Stages and SNAP in Cognitively Unimpaired Persons.

J Gerontol A Biol Sci Med Sci 2019 05;74(6):877-883

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

Background: Multimorbidity (defined as ≥2 chronic conditions) has been associated with increased risk of mild cognitive impairment and cross-sectionally with imaging biomarkers of neurodegeneration in cognitively unimpaired persons aged ≥70 years. Its association with preclinical Alzheimer's disease stages has not been studied in detail yet. The objective of the study was to assess the cross-sectional association of multimorbidity with preclinical Alzheimer's disease stages and suspected non-amyloid pathophysiology in cognitively unimpaired participants of the Mayo Clinic Study of Aging (≥50 years of age).

Methods: The study included 1,535 cognitively unimpaired participants with multimorbidity, 11C-PiB positron emission topography and magnetic resonance imaging data available. Abnormal (elevated) 11C-PiB-positron emission topography retention ratio (A+; standardized uptake value ratio >1.42) and abnormal (reduced) Alzheimer's disease signature cortical thickness (N+; <2.67 mm) were used to define biomarker combinations (A-N-, A+N-, A-N+, A+N+). Chronic medical conditions were ascertained by using the Rochester Epidemiology Project medical records linkage system and International Classification of Diseases criteria. Cross-sectional associations were examined using multinomial logistic regression models adjusting for age, sex, education, and apolipoprotein E ɛ4 allele status.

Results: Frequency of A+, N+, A+N+, and A-N+ biomarker groups increased significantly with increasing number of chronic conditions. Multimorbidity was significantly associated with A+N+ (vs A-N-; odds ratio, 1.76, 95% confidence interval 1.02, 2.90) and A-N+ (vs A-N-; odds ratio, 2.16, 95% confidence interval 1.47, 3.18). There was a dose-response relationship between increasing number of chronic conditions (eg, 0-1, 2-3, and 4+) and the odds of A+N+ and A-N+ (vs A-N-).

Conclusions: Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies.
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http://dx.doi.org/10.1093/gerona/gly149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521911PMC
May 2019

Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers.

J Alzheimers Dis 2018 ;64(1):281-290

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

Background: There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood.

Objectives: To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11C-PiB-PET scan measures of amyloid-β (Aβ) deposition.

Methods: The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake.

Results: Participants' median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ4 allele). Higher MeDi score (linear regression slope (beta):-0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:-0.043, p = 0.002), intake of vitamin A (beta:-0.041, p = 0.003) or β-carotene (beta: -0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: -0.074, p = 0.03) were associated with lower 11C-PiB standardized uptake value ratio.

Conclusion: Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings.
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http://dx.doi.org/10.3233/JAD-171121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031931PMC
June 2019

A Survey of Patient and Partner Outcome and Treatment Preferences in Mild Cognitive Impairment.

J Alzheimers Dis 2018 ;63(4):1459-1468

Department of Psychiatry and Psychology, Mayo Clinic, Scottsdale, AZ, USA.

Background: The patient-centered movement in health care is increasing efforts to design studies and interventions that address the outcomes that matter most to patients and their families. Research has not adequately addressed Alzheimer's disease patient and caregiver preferences.

Objective: To survey the outcome and treatment preferences of patients and caregivers who had completed a multicomponent behavioral intervention for mild cognitive impairment (MCI).

Methods: Extending prior work, we conducted an online survey regarding outcome and intervention preferences. Participants were patients with MCI and partners who completed the HABIT Healthy Action to Benefit Independence & Thinking ® program.

Results: Both patient and partner respondents ranked patient quality of life as the highest priority, followed by patient self-efficacy, functional status, patient mood, and patient memory performance. Distressing behaviors and caregiver outcomes (burden, mood, and self-efficacy) had low rankings. Regarding the importance of HABIT ® program components, memory compensation training was ranked highest and wellness education lowest by all groups.

Conclusion: Additional research should compare patient preference for patient reported outcomes, traditional neuropsychological and clinician outcomes, and modern biomarker outcomes.
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http://dx.doi.org/10.3233/JAD-171161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027859PMC
June 2019

Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting.

JAMA Neurol 2018 08;75(8):970-979

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

Importance: Brain amyloid deposition is a marker of Alzheimer disease (AD) pathology. The population-based prevalence and outcomes of amyloid positivity in a population without dementia are important for understanding the trajectory of amyloid positivity to clinically significant outcomes and for designing AD prevention trials.

Objective: To determine prevalence and outcomes of amyloid positivity in a population without dementia.

Design, Setting, And Participants: In the prospective, population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, participants without dementia were randomly selected from the county population and were clinically and cognitively evaluated at baseline and every 15 months from August 1, 2008, to September 18, 2018. They were also invited to undergo carbon11-Pittburgh compound B positron emission tomography (PET) imaging.

Exposures: Amyloid positivity (defined as a standardized uptake value ratio >1.42 on PET).

Main Outcomes And Measures: Prevalence of amyloid positivity in the Olmsted County population without dementia and risk of progression from no cognitive impairment (ie, normal cognition for age) to incident amnestic MCI (aMCI) and from MCI or aMCI to incident AD dementia.

Results: Of 3894 participants, 1671 underwent PET imaging and were included in the study; 2198 did not undergo imaging, and 25 were excluded for other reasons. The mean (SD) age of participants was 71.3 (9.8) years; 892 (53.4%) were men, and 179 (10.7%) had prevalent MCI. The prevalence of amyloid positivity without cognitive impairment in the population without dementia increased from 2.7% (95% CI, 0.5% to 4.9%) in persons aged 50 to 59 years to 41.3% (95% CI, 33.4% to 49.2%) in those aged 80 to 89 years at baseline. Prevalence of amyloid-positive MCI in the population without dementia increased from 0% in persons aged 50 to 59 years to 16.4% (95% CI, 10.3% to 22.5%) in those aged 80 to 89 years. The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio [HR], 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia.

Conclusions And Relevance: Population-based prevalence of amyloid-positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions.
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http://dx.doi.org/10.1001/jamaneurol.2018.0629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142936PMC
August 2018

Prevalence and Natural History of Superficial Siderosis: A Population-Based Study.

Stroke 2017 12 25;48(12):3210-3214. Epub 2017 Oct 25.

From the Department of Neurology (M.P., A.A.R., K.D.F., R.D.B., N.K., M.M.M., D.S.K., R.C.P., J.G.-R.), Department of Radiology (P.V., K.K., C.R.J., V.L.), and Department of Health Sciences Research (J.A., W.K., M.M.M.), Mayo Clinic, Rochester, MN.

Background And Purpose: Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study.

Methods: Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS.

Results: A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0-0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53-2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; <0.001). Compared with participants without SS, those with SS were also more likely to have a positive amyloid positron emission tomographic scan (76.9% versus 29.8%; <0.001).

Conclusions: SS may be encountered in the general elderly population. The association with increased amyloid burden and Apolipoprotein E ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow-up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS.
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http://dx.doi.org/10.1161/STROKEAHA.117.018974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705336PMC
December 2017

Weighting and standardization of frequencies to determine prevalence of AD imaging biomarkers.

Neurology 2017 Nov 13;89(20):2039-2048. Epub 2017 Oct 13.

From the Divisions of Epidemiology (R.O.R., M.V., M.M. Mielke, R.C.P.) and Biomedical Statistics and Informatics (J.A.S., J.A.A., W.K.K.), Department of Health Sciences Research, Department of Neurology (R.O.R., D.S.K., M.M. Mielke, J.G.-R., R.C.P.), Department of Psychiatry and Psychology (M.M. Machulda), and Department of Radiology (P.V., V.L., C.R.J.), Mayo Clinic, Rochester, MN; and Departments of Psychiatry and Psychology and Neurology (Y.E.G.), Mayo Clinic, Scottsdale, AZ.

Objective: To estimate the prevalence of elevated brain amyloid and reduced cortical thickness (as a marker for neurodegeneration) in a defined population.

Methods: Mayo Clinic Study of Aging participants underwent MRI to assess a composite Alzheimer disease (AD) signature cortical thickness measure and PET to assess brain amyloid accumulation. Participants were characterized as having elevated amyloid (A+/A-), reduced cortical thickness (N+/N-), and A+N+, A+N-, A-N+, or A-N-. The prevalence of AD biomarkers was derived by adjusting for nonparticipation and standardizing to the Olmsted County, Minnesota, population.

Results: Among 1,646 participants without dementia (mean age 70.8 years; 53.2% men), the prevalence (95% confidence interval) of amyloidosis was 21.1% (19.1%-23.2%): women, 24.3%; men, 17.5%. The prevalence of reduced cortical thickness was 28.9% (26.4%-31.5%): women, 27.9%; men, 30.2%. The prevalence estimates of biomarker categories were as follows: A-N-: 61.4%; A+N-: 9.7%; A-N+: 17.4%; and A+N+: 11.5%, and varied by sex and by ε4 carrier status. In men, prevalence estimates were as follows: A-N-: 62.6%; A+N-: 7.3%; A-N+: 19.9%; and A+N+: 10.2%. In women, prevalence estimates were as follows: A-N-: 60.4%; A+N-: 11.7%; A-N+: 15.3%; and A+N+: 12.6%. In ε4 carriers, prevalence estimates were as follows: A-N-: 54.6%; A+N-: 16.6%; A-N+: 12.4%; and A+N+: 16.4%. In non-ε4 carriers, prevalence estimates were as follows: A-N-: 63.3%; A+N-: 6.9%; A-N+: 19.9%; and A+N+: 10.0%.

Conclusions: These prevalence estimates are important for understanding age-related trends in amyloid positivity and AD signature cortical thickness in the population, and for potentially projecting the future burden of biomarkers in elderly persons.
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http://dx.doi.org/10.1212/WNL.0000000000004652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711507PMC
November 2017

Population-Based Prevalence of Cerebral Cavernous Malformations in Older Adults: Mayo Clinic Study of Aging.

JAMA Neurol 2017 07;74(7):801-805

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Importance: The prevalence of cerebral cavernous malformation (CCM) is unknown. Case ascertainment in most previous studies was based on autopsy data or clinical convenience samples, often without detailed clinical or radiologic information.

Objective: To determine the prevalence of CCM in a population-based sample of older adults.

Design, Setting, And Participants: This prospective imaging study included 4721 participants aged 50 to 89 years who were enrolled between January 1, 2004, and December 15, 2015, in the Mayo Clinic Study of Aging, a longitudinal, population-based study of residents of Olmsted County, Minnesota. An age- and sex-stratified sampling strategy was used to randomly select participants from Olmsted County using the medical records linkage system of the Rochester Epidemiology Project. Participants were invited to undergo brain magnetic resonance imaging (MRI). Of the 4721 participants, 2715 had an evaluable MRI. All images were reviewed by a board-certified neuroradiologist, and MRI reports were searched for the terms cavernous malformation, cavernous angioma, and cavernoma. Two vascular neurologists reviewed MRIs, and potential CCMs were classified using Zabramski classification. Medical records of the identified individuals with CCM were reviewed along with their demographic information, medical history, and any symptoms referable to the identified CCM lesion.

Main Outcomes And Measures: Prevalence of CCM and clinical and radiologic characteristics of study participants with CCM.

Results: Of the 2715 participants who underwent MRI scans, 12 (0.44%) had CCM. With the use of inverse probability weights to adjust for participation bias, the overall prevalence was 0.46% (95% CI, 0.05-0.86). The age-adjusted prevalence was found to be 0.61% (95% CI, 0-1.47) for the 50- to 59-year age group, 0.17% (95% CI, 0-0.50) for the 60- to 69-year age group, 0.45% (95% CI, 0.09-0.81) for the 70- to 79-year age group, and 0.58% (95% CI, 0-1.29) for the 80- to 89-year age group. The sex-adjusted prevalence was 0.41% (95% CI, 0-1.00) for women and 0.51% (95% CI, 0-1.07) for men. Observed frequencies were similar in men and women, with a slight male predominance. Of the 12 participants with CCM, 9 (75%) had a single Zabramski type 2 lesion in a supratentorial location. Only 1 participant (0.037%) was symptomatic from the CCM during the study period.

Conclusions And Relevance: The findings and data from this study are important for determining the potential number of patients available for cohort studies and anticipated clinical trials in older patients with CCM.
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http://dx.doi.org/10.1001/jamaneurol.2017.0439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647645PMC
July 2017

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated with Dementia with Lewy Bodies: A Pilot Study.

Dement Geriatr Cogn Disord 2017 28;43(5-6):269-280. Epub 2017 Apr 28.

Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.

Background/aims: Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB.

Methods: We performed a 12-week pilot trial of armodafinil therapy (125-250 mg orally daily) in DLB outpatients with hypersomnia. The patients underwent neurologic examinations, a neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method.

Results: Of 20 participants, 17 completed the protocol. The median age was 72 years, most of the participants were men (80%), and most had spouses as caregivers. The Epworth Sleepiness Scale (p < 0.001), Maintenance of Wakefulness Test (p = 0.003), and Clinical Global Impression of Change (p < 0.001) scores improved at week 12. The Neuropsychiatric Inventory total score (p = 0.003), visual hallucinations (p = 0.003), and agitation (p = 0.02) improved at week 4. Caregiver overall quality of life improved at week 12 (p = 0.004). No adverse events occurred.

Conclusion: These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies for managing hypersomnolence in these patients.
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http://dx.doi.org/10.1159/000471507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503747PMC
June 2018

Duration and Pathologic Correlates of Lewy Body Disease.

JAMA Neurol 2017 Mar;74(3):310-315

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Importance: Although patients with dementia with Lewy bodies (DLB) have shorter disease duration than patients with Alzheimer disease dementia, little is known about which factors influence disease duration among patients with DLB.

Objective: To identify pathologic correlates of disease duration in participants with Lewy body disease (LBD).

Design, Setting, And Participants: This observational study, performed from September 1, 2005, to June 1, 2015, using the National Alzheimer's Coordinating Center database included 807 participants with transitional or diffuse LBD.

Main Outcomes And Measures: The study used Braak neurofibrillary tangle (NFT) stage, frequency of neuritic plaques, and LBD stage to determine whether pathologic variables are associated with disease duration.

Results: This study included 807 participants with transitional or diffuse LBD (mean [SD] age, 70.0 [9.9] at the onset of cognitive decline and 79.2 [9.8] years at death; 509 male [63.1%]). Shorter disease duration from cognitive symptom onset to death was observed in men (β, -0.73; 95% CI, -1.33 to -0.14; P = .02) and in those with a later age at onset (β, -0.11; 95% CI, -0.14 to -0.08; P < .001). Diffuse (neocortical) LBD was associated with shorter disease duration compared with transitional LBD (β, -1.52; 95% CI, -2.11 to -0.93; P < .001). Braak NFT stage and the presence of neuritic plaques were not significantly associated with differences in disease duration.

Conclusions And Relevance: Diffuse LBD was associated with shorter disease duration compared with transitional LBD, and this effect is independent of Braak NFT stage or extent of neuritic plaque disease. Identifying antemortem biomarkers of LBD stage may provide important prognostic information to patients with DLB.
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http://dx.doi.org/10.1001/jamaneurol.2016.4926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527552PMC
March 2017

Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness.

Alzheimers Dement 2017 02 25;13(2):168-177. Epub 2016 Jul 25.

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

Introduction: The Mediterranean diet (MeDi) is associated with reduced risk of cognitive impairment, but it is unclear whether it is associated with better brain imaging biomarkers.

Methods: Among 672 cognitively normal participants (mean age, 79.8 years, 52.5% men), we investigated associations of MeDi score and MeDi components with magnetic resonance imaging measures of cortical thickness for the four lobes separately and averaged (average lobar).

Results: Higher MeDi score was associated with larger frontal, parietal, occipital, and average lobar cortical thickness. Higher legume and fish intakes were associated with larger cortical thickness: legumes with larger superior parietal, inferior parietal, precuneus, parietal, occipital, lingual, and fish with larger precuneus, superior parietal, posterior cingulate, parietal, and inferior parietal. Higher carbohydrate and sugar intakes were associated with lower entorhinal cortical thickness.

Discussion: In this sample of elderly persons, higher adherence to MeDi was associated with larger cortical thickness. These cross-sectional findings require validation in prospective studies.
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http://dx.doi.org/10.1016/j.jalz.2016.06.2359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259552PMC
February 2017

Multimorbidity and neuroimaging biomarkers among cognitively normal persons.

Neurology 2016 05 13;86(22):2077-84. Epub 2016 Apr 13.

From the Departments of Health Sciences Research (M.V., J.A.A., M.M. Mielke, Y.E.G., W.K.K., R.C.P., R.O.R.) and Neurology (M.M. Mielke, Y.E.G., R.E.A., D.S.K., R.C.P., R.O.R.), Mayo Clinic, Rochester, MN; Departments of Psychiatry and Psychology and Neurology (Y.E.G.), Mayo Clinic, Scottsdale, AZ; Mayo Clinic Graduate School of Medicine (R.E.A.), Rochester, MN; and Departments of Psychiatry and Psychology (M.M. Machulda) and Radiology (V.J.L., C.R.J.), Mayo Clinic, Rochester, MN.

Objective: To assess the cross-sectional association between multimorbidity and imaging biomarkers of brain pathology in the population-based Mayo Clinic Study of Aging (MCSA).

Methods: The study consisted of 1,449 MCSA participants who were cognitively normal at the time of MRI. A subset of the participants also had (11)C-Pittsburgh compound B (n = 689) and (18)fluorodeoxyglucose (n = 688) PET scans available. Information on multimorbidity (defined as ≥2 chronic conditions) in the 5 years prior to the first imaging study was captured from the medical record using ICD-9 codes for chronic conditions and the Rochester Epidemiology Project medical records linkage system. The cross-sectional association of multimorbidity and imaging biomarkers was examined using logistic and linear regression models.

Results: Among 1,449 cognitively normal participants (mean age 79 years; 50.9% men), 85.4% had multimorbidity (≥2 chronic conditions). Multimorbidity and severe multimorbidity (≥4 chronic conditions) were associated with abnormal Alzheimer disease (AD) signature meta-region of interest (meta-ROI) (18)F-FDG hypometabolism (odds ratio [OR] 2.03; 95% confidence interval [CI] 1.10-3.77 and OR 2.22; 95% CI 1.18-4.16, respectively), and with abnormal AD signature MRI cortical thickness (OR 1.53; 95% CI 1.09-2.16 and OR 1.76; 95% CI 1.24-2.51, respectively), but was not associated with amyloid accumulation.

Conclusions: Multimorbidity was associated with brain pathology through mechanisms independent of amyloid deposition and such neuronal injury and pathology was present before any symptomatic evidence of cognitive impairment. Longitudinal follow-up will provide insights into potential causal associations of multimorbidity with changes in brain pathology.
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http://dx.doi.org/10.1212/WNL.0000000000002624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891208PMC
May 2016

Decline in Weight and Incident Mild Cognitive Impairment: Mayo Clinic Study of Aging.

JAMA Neurol 2016 04;73(4):439-46

Department of Neurology, Mayo Clinic, Rochester, Minnesota3Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

Importance: Unintentional weight loss has been associated with risk of dementia. Because mild cognitive impairment (MCI) is a prodromal stage for dementia, we sought to evaluate whether changes in weight and body mass index (BMI) may predict incident MCI.

Objective: To investigate the association of change in weight and BMI with risk of MCI.

Design, Setting, And Participants: A population-based, prospective study of participants 70 years of age or older from the Mayo Clinic Study of Aging, which was initiated on October 1, 2004. Maximum weight and height in midlife (40-65 years of age) were retrospectively ascertained from the medical records of participants using a medical records-linkage system. The statistical analyses were performed between January and November 2015.

Main Outcomes And Measures: Participants were evaluated for cognitive outcomes of normal cognition, MCI, or dementia at baseline and prospectively assessed for incident events at each 15-month evaluation. The association of rate of change in weight and BMI with risk of MCI was investigated using proportional hazards models.

Results: Over a mean follow-up of 4.4 years, 524 of 1895 cognitively normal participants developed incident MCI (50.3% were men; mean age, 78.5 years). The mean (SD) rate of weight change per decade from midlife to study entry was greater for participants who developed incident MCI vs those who remained cognitively normal (-2.0 [5.1] vs -1.2 [4.9] kg; P = .006). A greater decline in weight per decade was associated with an increased risk of incident MCI (hazard ratio [HR], 1.04 [95% CI, 1.02-1.06]; P < .001) after adjusting for sex, education, and apolipoprotein E (APOE) ε4 allele. A weight loss of 5 kg per decade corresponds to a 24% increase in risk of MCI (HR, 1.24). A higher decrease in BMI per decade was also associated with incident MCI (HR, 1.08 [95% CI, 1.03-1.13]; P = .003).

Conclusions And Relevance: These findings suggest that increasing weight loss per decade from midlife to late life is a marker for MCI and may help identify persons at increased risk for MCI.
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http://dx.doi.org/10.1001/jamaneurol.2015.4756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828256PMC
April 2016

Spectrum of cognition short of dementia: Framingham Heart Study and Mayo Clinic Study of Aging.

Neurology 2015 Nov 9;85(19):1712-21. Epub 2015 Oct 9.

From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.

Objective: To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment.

Methods: We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ≤-0.5, -1, -1.5, and -2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately.

Results: The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles.

Conclusions: Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint.
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http://dx.doi.org/10.1212/WNL.0000000000002100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653114PMC
November 2015

Association of Pancreatic Polypeptide with Mild Cognitive Impairment Varies by APOE ε4 Allele.

Front Aging Neurosci 2015 8;7:172. Epub 2015 Sep 8.

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

We conducted a preliminary case-control investigation of the association of pancreatic polypeptide (PP) with mild cognitive impairment (MCI) in 202 MCI cases (mean age, 81.6 years) and 202 age- and sex-matched cognitively normal controls in the Mayo Clinic Study of Aging. Plasma PP was measured and examined as the natural logarithm (continuous) and dichotomized at the median. The OR (95% CI) of MCI increased with increasing PP [1.46 (1.04-2.05)]. There was a negative interaction of PP with apolipoprotein E (APOE) ε4 allele; compared to the reference group (no APOE ε4 allele and low PP), the OR (95% CI) for combinations of ε4 and PP were: 2.64 (1.39-5.04) for APOE ε4 plus low PP; 2.09 (1.27-3.45) for no APOE ε4 plus high PP; and 1.91 (1.04-3.53) for no APOE ε4 plus high PP (P for interaction = 0.017). There was also a trend toward a negative interaction with type 2 diabetes (P for interaction = 0.058). Compared to no diabetes and low PP, the OR (95% CI) was 3.02 (1.22-7.46) for low PP plus diabetes but 1.80 (1.01-3.22) for high PP plus diabetes. Participants with high PP had a greater mean (SD) weight loss (kilograms per decade) than persons with low PP [-2.27 (4.07) vs. -1.61 (5.24); P = 0.016]. MCI cases had a non-significantly greater weight loss per decade compared to controls. These findings suggest that high PP alone or jointly with APOE ε4 allele or type 2 diabetes is associated with MCI, and that high PP may mitigate some effects of APOE ε4 allele and type 2 diabetes on cognition. Potential mechanisms may involve PP-related weight loss and centrally mediated effects of PP on cognition. These findings remain to be validated in other studies.
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http://dx.doi.org/10.3389/fnagi.2015.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561818PMC
October 2015
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