Can white matter hyperintensities based Fazekas visual assessment scales inform about Alzheimer's disease pathology in the population?

Background: White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer's disease pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, Alzheimer's imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging. Methods: We identified 1144 participants from the Mayo Clinic Study of Aging consisting of older adults from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET and tau-PET standardized uptake value ratio, WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC). Results: Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.78). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97). Conclusion: Our study investigates risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research.

Item Response Analysis of the Financial Capacity Instrument-Short Form.

OBJECTIVE: The Financial Capacity Instrument-Short Form (FCI-SF) is a performance-based measure of everyday financial skills that takes 15 min to administer. Although the FCI-SF has demonstrated excellent psychometric properties, advanced psychometric methods such as item response theory (IRT) can provide important information on the performance of individual test items in measuring financial capacity and in distinguishing between healthy and cognitively impaired individuals. METHOD: Participants were 272 older adults diagnosed with mild cognitive impairment (MCI) and 1,344 cognitively healthy controls recruited from the Mayo Clinic Study of Aging at the Mayo Clinic in Rochester, Minnesota and also from the Cognitive Observations in Seniors study at the University of Alabama at Birmingham. Participants in each study were administered the FCI-SF, which evaluates coin/currency calculation, financial conceptual knowledge, use of a checkbook/register, and use of a bank statement. RESULTS: A unidimensional two-parameter logistic model best fit the 37 FCI-SF Test items, and most FCI-SF items fit the unidimensional two-parameter model well. The results indicated that all FCI-SF items robustly distinguished cognitively healthy controls from persons with MCI. CONCLUSIONS: The study results showed that the FCI-SF performed well under IRT analysis, further highlighted the psychometric properties of the FCI-SF as a valid and reliable measure of financial capacity, and demonstrated the clinical utility of the FCI-SF in distinguishing between cognitively normal and cognitively impaired individuals.

Quality assessment of functional status documentation in EHRs across different healthcare institutions.

The secondary use of electronic health records (EHRs) faces challenges in the form of varying data quality-related issues. To address that, we retrospectively assessed the quality of functional status documentation in EHRs of persons participating in Mayo Clinic Study of Aging (MCSA). We used a convergent parallel design to collect quantitative and qualitative data and independently analyzed the findings. We discovered a heterogeneous documentation process, where the care practice teams, institutions, and EHR systems all play an important role in how text data is documented and organized. Four prevalent instrument-assisted documentation (iDoc) expressions were identified based on three distinct instruments: Epic smart form, questionnaire, and occupational therapy and physical therapy templates. We found strong differences in the usage, information quality (intrinsic and contextual), and naturality of language among different type of iDoc expressions. These variations can be caused by different source instruments, information providers, practice settings, care events and institutions. In addition, iDoc expressions are context specific and thus shall not be viewed and processed uniformly. We recommend conducting data quality assessment of unstructured EHR text prior to using the information.

Development and implementation of an electronic Clinical Dementia Rating and Financial Capacity Instrument-Short Form.

Introduction: To address the need for remote assessments of cognitive decline and dementia, we developed and administered electronic versions of the Clinical Dementia Rating (CDR®) and the Financial Capacity Instrument-Short Form (FCI-SF) (F-CAP®), called the eCDR and eFCI, respectively. Methods: The CDR and FCI-SF were adapted for remote, unsupervised, online use based on item response analysis of the standard instruments. Participants completed the eCDR and eFCI first in clinic, and then at home within 2 weeks. Results: Of the 243 enrolled participants, 179 (73%) cognitively unimpaired (CU), 50 (21%) with mild cognitive impairment (MCI) or dementia, and 14 (6%) with an unknown diagnosis, 84% and 85% of them successfully completed the eCDR and eFCI, respectively, at home. Discussion: These results show initial feasibility in developing and administering online instruments to remotely assess and monitor cognitive decline along the CU to MCI/very mild dementia continuum. Validation is an important next step.

Association of Performance on the Financial Capacity Instrument-Short Form With Brain Amyloid Load and Cortical Thickness in Older Adults.

Background and Objectives: To investigate the association of the Financial Capacity Instrument-Short Form (FCI-SF) performance and timing total scores with brain ß-amyloid and cortical thickness in cognitively unimpaired (CU) (at baseline) older adults. Methods: A total of 309 participants (aged 70 years or older) of the Mayo Clinic Study of Aging underwent 11C-Pittsburgh compound B PET amyloid imaging and MRI, and completed the FCI-SF. Abnormal amyloid PET was defined as standardized uptake value ratio ≥1.48 in an Alzheimer disease (AD)-related region of interest and reduced AD signature cortical thickness as ≤2.68 mm (neurodegeneration). A cohort of 218 (of the 309) participants had follow-up visits (every 15 months) with FCI-SF data for longitudinal analysis (number of visits including baseline, median [range]: 2 [2-4]). In the analysis, we used linear regression and mixed-effects models adjusted for age, sex, education, apolipoprotein E ε4 allele status, global cognitive z score, and previous FCI-SF testing. Results: Participants' mean age (SD) was 80.2 (4.8) years (56.3% male individuals). In cross-sectional analysis, abnormal amyloid PET (vs normal) was associated with a lower FCI-SF total score and slower total composite time. In longitudinal analysis, FCI-SF total score declined faster (difference in annualized rate of change, beta coefficient [ß] [95% confidence interval (CI)] = -1.123 [-2.086 to -0.161]) and FCI-SF total composite time increased faster (difference in annualized rate of change, ß [95% CI] = 16.274 [5.951 to 26.597]) for participants with neurodegeneration at baseline (vs those without). Participants who exhibited both abnormal amyloid PET and neurodegeneration at baseline had a greater increase in total composite time when compared with the group without abnormal amyloid and without neurodegeneration (difference in annualized rate of change, ß [95% CI] = 16.750 [3.193 to 30.307]). Discussion: Performance and processing speed on the FCI-SF were associated with imaging biomarkers of AD pathophysiology in CU (at baseline) older adults. Higher burdens of imaging biomarkers were associated with longitudinal worsening on FCI-SF performance. Additional research is needed to delineate further these associations and their predictive utility at the individual person level.

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-ß burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.

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

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.

Pittsburgh Compound B and AV-1451 positron emission tomography assessment of molecular pathologies of Alzheimer's disease in progressive supranuclear palsy.

INTRODUCTION: Little is known about Alzheimer's disease molecular proteins, beta-amyloid and paired helical filament (PHF) tau, in progressive supranuclear palsy (PSP). Recent techniques have been developed to allow for investigations of these proteins in PSP. We determined the frequency of beta-amyloid deposition in PSP, and whether beta-amyloid deposition in PSP is associated with PHF-tau deposition pattern, or clinical features. METHODS: Thirty probable PSP participants underwent MRI, [18F]AV-1451 PET and Pittsburgh compound B (PiB) PET. Apolipoprotein (APOE) genotyping was also performed. A global PiB standard-uptake value ratio (SUVR) was calculated. AV-1451 SUVRs were calculated for a set of Alzheimer's disease (AD)-related regions and a set of PSP-related regions. Voxel-level analyses were conducted to assess for differences in AV-1451 uptake patterns and MRI atrophy between PiB(+) and PiB(-) cases compared to 60 normal PiB(-) controls. Statistical testing for correlations and associations between variables of interest were also performed. RESULTS: Twelve subjects (40%) showed beta-amyloid deposition. Higher PiB SUVR correlated with older age but not with AV-1451 SUVR in the AD- or PSP-related regions. Higher AV-1451 SUVR in AD-related regions was associated with higher AV-1451 SUVR in PSP-related regions. We found little evidence for beta-amyloid related differences in clinical metrics, proportion of APOE e4 carriers, pattern of AV-1451 uptake, or pattern of atrophy. CONCLUSION: Beta-amyloid deposition occurs in a relatively high proportion of PSP subjects. Unlike in Alzheimer's disease, however, there is little evidence that beta-amyloid, and PHF-tau, play a significant role in neurodegeneration in PSP.

Nursing Home Use Across The Spectrum of Cognitive Decline: Merging Mayo Clinic Study of Aging With CMS MDS Assessments.

BACKGROUND/OBJECTIVES: Objective, complete estimates of nursing home (NH) use across the spectrum of cognitive decline are needed to help predict future care needs and inform economic models constructed to assess interventions to reduce care needs. DESIGN: Retrospective longitudinal study. SETTING: Olmsted County, MN. PARTICIPANTS: Mayo Clinic Study of Aging participants assessed as cognitively normal (CN), mild cognitive impairment (MCI), previously unrecognized dementia, or prevalent dementia (age = 70-89 years; N = 3,545). MEASUREMENTS: Participants were followed in Centers for Medicare and Medicaid Services (CMS) Minimum Data Set (MDS) NH records and in Rochester Epidemiology Project provider-linked medical records for 1-year after assessment of cognition for days of observation, NH use (yes/no), NH days, NH days/days of observation, and mortality. RESULTS: In the year after cognition was assessed, for persons categorized as CN, MCI, previously unrecognized dementia, and prevalent dementia respectively, the percentages who died were 1.0%, 2.6%, 4.2%, 21%; the percentages with any NH use were 3.8%, 8.7%, 19%, 40%; for persons with any NH use, median NH days were 27, 38, 120, 305, and median percentages of NH days/days of observation were 7.8%, 12%, 33%, 100%. The year after assessment, among persons with prevalent dementia and any NH use, >50% were a NH resident all days of observation. Pairwise comparisons revealed that each increase in cognitive impairment category exhibited significantly higher proportions with any NH use. One-year mortality was especially high for persons with prevalent dementia and any NH use (30% vs 13% for those with no NH use); 58% of all deaths among persons with prevalent dementia occurred while a NH resident. CONCLUSIONS: Findings suggest reductions in NH use could result from quality alternatives to NH admission, both among persons with MCI and persons with dementia, together with suitable options for end-of-life care among persons with prevalent dementia.

Age and education corrected older adult normative data for a short form version of the Financial Capacity Instrument.

Financial capacity is an instrumental activity of daily living (IADL) that comprises multiple abilities and is critical to independence and autonomy in older adults. Because of its cognitive complexity, financial capacity is often the first IADL to show decline in prodromal and clinical Alzheimer's disease and related disorders. Despite its importance, few standardized assessment measures of financial capacity exist and there is little, if any, normative data available to evaluate financial skills in the elderly. The Financial Capacity Instrument-Short Form (FCI-SF) is a brief measure of financial skills designed to evaluate financial skills in older adults with cognitive impairment. In the current study, we present age- and education-adjusted normative data for FCI-SF variables in a sample of 1344 cognitively normal, community-dwelling older adults participating in the Mayo Clinic Study of Aging (MCSA) in Olmsted County, Minnesota. Individual FCI-SF raw scores were first converted to age-corrected scaled scores based on position within a cumulative frequency distribution and then grouped within 4 empirically supported and overlapping age ranges. These age-corrected scaled scores were then converted to age- and education-corrected scaled scores using the same methodology. This study has the potential to substantially enhance financial capacity evaluations of older adults through the introduction of age- and education-corrected normative data for the FCI-SF by allowing clinicians to: (a) compare an individual's performance to that of a sample of similar age and education peers, (b) interpret various aspects of financial capacity relative to a normative sample, and (c) make comparisons between these aspects. (PsycINFO Database Record

Direct medical costs and source of cost differences across the spectrum of cognitive decline: a population-based study.

BACKGROUND: Objective cost estimates and source of cost differences are needed across the spectrum of cognition, including cognitively normal (CN), mild cognitive impairment (MCI), newly discovered dementia, and prevalent dementia. METHODS: Subjects were a subset of the Mayo Clinic Study of Aging stratified-random sampling of Olmsted County, MN, residents aged 70 to 89 years. A neurologist reviewed provider-linked medical records to identify prevalent dementia (review date = index). Remaining subjects were invited to participate in prospective clinical/neuropsychological assessments; participants were categorized as CN, MCI, or newly discovered dementia (assessment date = index). Costs for medical services/procedures 1-year pre-index (excluding indirect and long-term care costs) were estimated using line-item provider-linked administrative data. We estimated contributions of care-delivery site and comorbid conditions (including and excluding neuropsychiatric diagnoses) to between-category cost differences. RESULTS: Annual mean medical costs for CN, MCI, newly discovered dementia, and prevalent dementia were $6042, $6784, $9431, $11,678, respectively. Hospital inpatient costs contributed 70% of total costs for prevalent dementia and accounted for differences between CN and both prevalent and newly discovered dementia. Ambulatory costs accounted for differences between CN and MCI. Age-, sex-, education-adjusted differences reached significance for CN versus newly discovered and prevalent dementia and for MCI versus prevalent dementia. After considering all comorbid diagnoses, between-category differences were reduced (e.g., prevalent dementia minus MCI (from $4842 to $3575); newly discovered dementia minus CN (from $3578 to $711)). Following the exclusion of neuropsychiatric diagnoses from comorbidity adjustment, between-category differences tended to revert to greater differences. CONCLUSIONS: Cost estimates did not differ significantly between CN and MCI. Substantial differences between MCI and prevalent dementia reflected high inpatient costs for dementia and appear partly related to co-occurring mental disorders. Such comparisons can help inform models aimed at identifying where, when, and for which individuals proposed interventions might be cost-effective.

Advancing Alzheimer's disease diagnosis, treatment, and care: recommendations from the Ware Invitational Summit.

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.

Visual assessment versus quantitative three-dimensional stereotactic surface projection fluorodeoxyglucose positron emission tomography for detection of mild cognitive impairment and Alzheimer disease.

INTRODUCTION: We examined the clinical impact of commercially available quantitation software using 3-dimensional stereotactic surface projection (3D-SSP) on the diagnostic accuracy of 18F fluorodeoxyglucose positron emission tomography (18F FDG PET) in mild cognitive impairment (MCI) and Alzheimer disease (AD). METHODS: Enrollees underwent clinical evaluation to determine cognitive status and subsequent 18F FDG PET neuroimaging. Four blinded readers (2 novices and 2 experts) rated the images for degree of abnormality and interpretive confidence without and with 3D-SSP. Diagnostic accuracy was determined with area under the curve (area under the curve) of a receiver operating characteristic (receiver operating characteristic) curve analysis and change in confidence with model-based means (LSMeans). RESULTS: Twenty-three normal controls and 31 patients with cognitive impairment (18 MCI and 13 AD) were enrolled (28 female and 26 male; mean age 74 years). During follow-up (mean 3.6 years), all normal participants remained normal, 12 of 18 participants with MCI progressed to dementia, and all participants with baseline dementia progressed. The area under the curve with 3D-SSP (0.88; 95% CI: 0.76-0.95) was significantly higher than without it (0.72; 95% CI: 0.55-0.83). The specificity increased from 26% to 63% for novices and from 56% to 87% for experts with addition of 3D-SSP, whereas the sensitivity was essentially unchanged at 86% and 86% for the beginners and 81% and 79% for the experts. The interpretive confidence increased significantly from 3.3 to 4.0 (maximum value = 5, P = 0.048). CONCLUSION: The use of commercially available 3D-SSP quantitation improved diagnostic accuracy for evaluation of MCI and AD with 18F FDG PET.

Assessment of cognition in mild cognitive impairment: a comparative study.

The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer's disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer's Disease by 2020 Web site (http://pad2020.org). A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Differential item functioning of the Boston Naming Test in cognitively normal African American and Caucasian older adults.

Scores on the Boston Naming Test (BNT) are frequently lower for African American when compared with Caucasian adults. Although demographically based norms can mitigate the impact of this discrepancy on the likelihood of erroneous diagnostic impressions, a growing consensus suggests that group norms do not sufficiently address or advance our understanding of the underlying psychometric and sociocultural factors that lead to between-group score discrepancies. Using item response theory and methods to detect differential item functioning (DIF), the current investigation moves beyond comparisons of the summed total score to examine whether the conditional probability of responding correctly to individual BNT items differs between African American and Caucasian adults. Participants included 670 adults age 52 and older who took part in Mayo's Older Americans and Older African Americans Normative Studies. Under a two-parameter logistic item response theory framework and after correction for the false discovery rate, 12 items where shown to demonstrate DIF. Of these 12 items, 6 ("dominoes," "escalator," "muzzle," "latch," "tripod," and "palette") were also identified in additional analyses using hierarchical logistic regression models and represent the strongest evidence for race/ethnicity-based DIF. These findings afford a finer characterization of the psychometric properties of the BNT and expand our understanding of between-group performance.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.