BackgroundCognitive processing speed is integral to everyday activities and can be improved with training in persons with mild cognitive impairment (MCI). However, whether this training maintains everyday abilities is not known.ObjectiveWe aimed to determine whether everyday functions key to independence could be preserved with two years of processing speed training.MethodsIn a randomized controlled trial, we objectively evaluated a processing speed training protocol compared to a control training protocol, in 103 persons with MCI (n = 90) or very mild dementia (n = 13) due to Alzheimer's disease (AD). Each protocol involved serial assessments, laboratory training, and home training over a two-year period. We accounted for APOE ε4 carrier status and MRI-based neurodegeneration conducted at baseline. Outcomes were longitudinal changes in performance-based Instrumental Activities of Daily Living (IADLs), community mobility, and on-road driving. We used linear mixed models to evaluate changes in these outcomes over time.ResultsChanges in IADL function, driving, and community mobility did not differ by training assignment. Greater baseline neurodegeneration predicted larger declines in all functional outcomes (p values < 0.001).ConclusionsIn persons with MCI or very mild dementia, processing speed training was no more effective for maintaining everyday functions than training involving common computer activities and games that do not target processing speed. Greater baseline neurodegeneration predicted worse performance over time on all measures of function.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7

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.

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ABSTRACTLimited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer’s Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/nearCR1,BIN1,TREM2,CD2AP,PTK2B,CLU,SHARPIN,MS4A6A,PICALM,ABCA7,APOEand two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed theSHARPINlocus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK(P=2.4×10-8) andGRB14(P=1.7×10-8) in HIS), andKIAA0825(P=2.9×10-8in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest withPadjusted=1.6×10-4) and the classical complement pathway (Padjusted=1.3×10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, andPTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

OBJECTIVE Testamentary capacity (TC) is a legal construct, which concerns a person's mental capacity to make or amend a will. Although expert clinicians are frequently asked to assess TC in forensic settings, there are few instruments and little empirical research to inform and guide their assessments. The present study describes the development and psychometric properties of a standardized assessment measure of TC (Testamentary Capacity Instrument-TCI), and investigates its reliability and validity. METHODS The TCI is an interview-based, psychometric measure, which assesses a testator's knowledge of four conceptual elements, which together comprise the legal basis for TC in the Anglo-American legal system: (1) what a will is, (2) nature and extent of assets/property, (3) possible heirs/claimants to property, and (4) plan to distribute assets to heirs after death. Cronbach's alpha and percentage exact agreement were used to examine TCI element reliabilities. Using independent samples t-tests, MANOVA and MANCOVA, we investigated validity by comparing TCI element performance of cognitively intact older adults (n = 22) and older adults with ad dementia (n = 20). RESULTS The TCI elements showed good internal consistency and good inter-rater reliability. The ad group performed significantly below the control group on all four TCI elements, with effect sizes exceeding 1.2, suggesting that the TCI has content and construct validity. CONCLUSIONS Relative to cognitively intact older adults, older adults with ad dementia showed significant impairment on all four TCI conceptual elements. The TCI has promise as a standardized quantitative measure of TC to support clinical assessment of TC in forensic settings.

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 (R)) and the Financial Capacity Instrument-Short Form (FCI-SF) (F-CAP (R)), 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.

Background and Objectives To investigate the association of the Financial Capacity Instrument–Short Form (FCI-SF) performance and timing total scores with brain β-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 [β] [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, β [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, β [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.

Contemporaneous assessment of testamentary capacity (TC) is a well-established professional activity for forensic clinicians. However, important assessment issues exist in this area that remain unsettled or controversial. Three topical TC assessment issues were identified from a review of forensic literature and the author’s personal experience as an expert witness: (1) whether neuropsychological testing is a necessary component in contemporaneous forensic assessments of TC, (2) whether clinicians are able to conduct contemporaneous assessments of TC in patients with aphasia, and (3) whether clinicians should video record their TC assessments. The paper presents each issue and related literature, provides views of the field (where available), offers the author’s viewpoint and conclusions, and makes recommendations for future research. The paper concludes that (1) neuropsychological assessment currently is a very helpful addition but not a required component of the contemporaneous assessment of TC, but may become essential with the advent of TC-specific neuropsychological measures; (2) contemporaneous assessment of TC is feasible in patients with mild aphasia, but becomes increasingly challenging and problematic in patients with more severe aphasia; and (3) whether to video record a TC assessment is an attorney and not a clinician decision.

BACKGROUND:Testamentary capacity (TC) is a legal construct about the ability to make or change a will. Although studies of financial and medical capacities have noted a strong association between capacity and cognition, no study has examined the cognitive correlates of TC in Alzheimer's disease (ad).METHODS:Study participants were 22 cognitively healthy controls and 20 persons with mild to moderate ad who were administered a neuropsychological battery and the Testamentary Capacity Instrument (TCI), a new performance-based measure of TC. Both TCI Element and TCI Total scores were calculated. TCI Total scores were calculated for the purposes of expanding correlational analyses (i.e., Pearson's product-moment) and are not intended for forensic TC evaluations. Final predictors were identified using linear and logistic regression modeling.RESULTS:All ad participants but one obtained TCI Totals that fell >2.5 standard deviations below the control group mean. Initial cognitive correlates of TCI performance were measures of general cognition, language, verbal memory, executive function, and processing speed. The four cognitive variables showing the highest t values and correlating with TCI Total score > 0.7 were entered into logistic and linear regression models. Final predictor models consisted of measures of verbal memory, executive function, and semantic knowledge and demonstrated shared variance of 0.71 (linear) and 0.82 (logistic).CONCLUSIONS:A diagnosis of ad dementia is associated with clinical impairment in TC and associated cognitive abilities and indicates that a legal assessment of TC is warranted. Second, the results offer insight into the cognitive basis of TC in persons with Alzheimer's dementia.

Background Cognitive processing speed is important for performing everyday activities in persons with mild cognitive impairment (MCI). However, its role in daily function has not been examined while simultaneously accounting for contributions of Alzheimer’s disease (AD) risk biomarkers. We examine the relationships of processing speed and genetic and neuroimaging biomarkers to composites of daily function, mobility, and driving. Method We used baseline data from 103 participants on the MCI/mild dementia spectrum from the Applying Programs to Preserve Skills trial. Linear regression models examined relationships of processing speed, structural magnetic resonance imaging (MRI), and genetic risk alleles for AD to composites of performance-based instrumental activities of daily living (IADLs), community mobility, and on-road driving evaluations. Results In multivariable models, processing speed and the brain MRI neurodegeneration biomarker Spatial Pattern of Abnormality for Recognition of Early Alzheimer’s disease (SPARE-AD) were significantly associated with functional and mobility composite performance. Better processing speed and younger age were associated with on-road driving ratings. Genetic risk markers, left hippocampal atrophy, and white matter lesion volumes were not significant correlates of these abilities. Processing speed had a strong positive association with IADL function (p < .001), mobility (p < .001), and driving (p = .002). Conclusions Cognitive processing speed is strongly and consistently associated with critical daily functions in persons with MCI in models including genetic and neuroimaging biomarkers of AD risk. SPARE-AD scores also significantly correlate with IADL performance and mobility. Results highlight the central role of processing speed in everyday task performance among persons with MCI/mild dementia.

AbstractIntroductionFederally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1.MethodsFirst, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver‐operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests.ResultsSome V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants.DiscussionFurther efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required.

AbstractBackgroundNational Institute on Aging (NIA)‐funded Alzheimer’s Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS was implemented in 2015 and included several changes to its neuropsychological battery, replacing the previous version [Version 2 (V2)]. The current study compares the V3 and V2 neuropsychological batteries with respect to their ability to distinguish among categories of cognitive impairment captured by the Clinical Dementia Rating (CDR) global scores representing either no cognitive impairment (CDR=0), questionable or mild cognitive impairment (CDR=0.5) or mild stage of dementia (CDR=1.0).MethodData from the NACC UDS V2 and V3 neuropsychological batteries were examined. There were 16,935 unique subjects from V2 and 5022 unique subjects from V3 aged 60 years and older with CDR global score ≤ 1. To reduce the influence of practice effects, only data from their first assessment was used. To control for inequalities in sample sizes between V2 and V3, we identified an approximately equal number of subjects from V2 within each CDR group. Receiver Operating Characteristics Area under Curve (ROC‐AUC) in differentiating stages of cognitive impairment were compared and optimal cut‐points based on Youden’s J scores were calculated.ResultROC‐AUCs from all of the V3 neuropsychological tests were comparable in their ability to differentiate CDR global scores with the corresponding tests in V2, despite the fact that V3 participants included more subjects at earlier stage of CDR 0.5. UDS V3 composite scores yielded similar ROC‐AUCs to the best performing individual test within each domain, while the Montreal Cognitive Assessment (MoCA) total score yielded higher ROC‐AUCs than any individual MoCA index scores. Racial differences in differentiating between CDR=0 and CDR=0.5 were also found.ConclusionA nonproprietary suite of neuropsychological tests in UDS V3 provided similar discriminative ability to tests in UDS V2 to distinguish categories of cognitive impairment. Optimal cut‐points calculated in this study will be useful for clinical diagnosis.

In real-world networks, information from source to destination does not only flow along the shortest path connecting them, but can flow along any alternative route. Communicability is a network metric that accounts for this issue and, especially in diffusion-like processes, provides a reliable measure of the ease of communication between node pairs. Accordingly, communicability appears to be promising for highlighting the disruption of connectivity among brain regions, caused by the white matter degeneration due to Alzheimer's disease (AD). Such a degeneration can be captured by digital imaging techniques, in particular diffusion tensor imaging (DTI), which allow to build the brain connectivity network through tractography algorithms and studying its complexity through graph theory. In this study, a cohort of 122 DTI scans, composed by 52 healthy control (HC) subjects, 40 AD patients and 30 mild cognitive impairment (MCI) converter subjects, from Alzheimer's Disease Neuroimaging Initiative (ADNI) database, has been employed to study the suitability of communicability to serve as discriminant factor for AD. We developed a two-fold investigation. On one hand, a statistical analysis has been carried out to ascertain the information content provided by communicability to detect the brain regions mostly affected by the disease: node pairs with statistical significant different communicability have been found, corresponding to some well-known AD-related brain regions. On the other hand, heterogeneous groups of network features (which include/not include communicability) were input to a support vector machine, to assess the impact of communicability on the classification performances in the HC/AD and the HC/AD/MCI discrimination. The best performances, i.e., AUC = 0.82 in the HC/AD case and multiclass AUC = 0.77 in the HC/AD/MCI task, were obtained by using the values of communicability, outperforming the performance obtained with the other network metrics. In summary, this article suggests that communicability can be promising for an automatized AD diagnosis.

OBJECTIVES:Although financial ability has been well-studied in mild cognitive impairment (MCI) and Alzheimer's disease (AD) using performance-based financial capacity assessment instruments, research is limited investigating everyday financial problems and declines in persons with AD and MCI and the insight of people with MCI to recognize that financial capacity declines are occurring. To address this gap in the research, we investigated everyday financial activities and skills in a sample of older adults representing the dementia spectrum.METHODS:Participants were 186 older adults in three diagnostic classifications: cognitively healthy, MCI likely due to AD, and mild AD dementia. Everyday financial ability was assessed using the Current Financial Activities Report (CFAR). The CFAR is a standardized report-based measure which elicits participant and study partner ratings about a participant's everyday financial abilities.RESULTS:Results showed that both CFAR self- and study partner-report distinguished diagnostic groups on key financial capacity variables in a pattern consistent with level of clinical pathology. Study partner-report indicated higher levels of financial skill difficulties in study participants than did the self-report of the same study participants. Study partner-ratings were more highly correlated with participant scores on a performance-based measure of financial capacity than were participant self-ratings. Results also showed that loss of awareness of financial decline is emerging at the MCI stage of AD.CONCLUSIONS:People with MCI represent a group of older adults at particular risk for financial missteps and-similar to people with AD-are in need of supervision of their financial skills and activities.