Classification of Mild Cognitive Impairment and Alzheimer's Disease Using Manual Motor Measures.

INTRODUCTION: Manual motor problems have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the specific aspects that are affected, their neuropathology, and potential value for classification modeling is unknown. The current study examined if multiple measures of motor strength, dexterity, and speed are affected in MCI and AD, related to AD biomarkers, and are able to classify MCI or AD. METHODS: Fifty-three cognitively normal (CN), 33 amnestic MCI, and 28 AD subjects completed five manual motor measures: grip force, Trail Making Test A, spiral tracing, finger tapping, and a simulated feeding task. Analyses included: 1) group differences in manual performance; 2) associations between manual function and AD biomarkers (PET amyloid ß, hippocampal volume, and APOE ε4 alleles); and 3) group classification accuracy of manual motor function using machine learning. RESULTS: amnestic MCI and AD subjects exhibited slower psychomotor speed and AD subjects had weaker dominant hand grip strength than CN subjects. Performance on these measures was related to amyloid ß deposition (both) and hippocampal volume (psychomotor speed only). Support vector classification well-discriminated control and AD subjects (area under the curve of 0.73 and 0.77 respectively), but poorly discriminated MCI from controls or AD. CONCLUSION: Grip strength and spiral tracing appear preserved, while psychomotor speed is affected in amnestic MCI and AD. The association of motor performance with amyloid ß deposition and atrophy could indicate that this is due to amyloid deposition in- and atrophy of motor brain regions, which generally occurs later in the disease process. The promising discriminatory abilities of manual motor measures for AD emphasize their value alongside other cognitive and motor assessment outcomes in classification and prediction models, as well as potential enrichment of outcome variables in AD clinical trials.

The Quick Dementia Rating System and Its Relationship to Biomarkers of Alzheimer's Disease and Neuropsychological Performance.

INTRODUCTION: The Quick Dementia Rating System (QDRS) is a brief, patient-reported dementia staging tool that has approximated scores on the Clinical Dementia Rating Scale in patients with Alzheimer's disease (AD). However, no studies have examined its relationship with AD-related biomarkers. METHODS: One-hundred twenty-one older adults (intact, amnestic mild cognitive impairment, mild AD) completed the QDRS, and three biomarkers (amyloid deposition via positron emission tomography, hippocampal volume via magnetic resonance imaging, and apolipoprotein [APOE] ε4 status). RESULTS: The Total score on the QDRS was statistically significantly related to all three biomarkers (after controlling for age, education, sex, and race), with greater levels of dementia severity being associated with greater amyloid deposition, smaller hippocampi, and having copies of APOE ε4 allele. DISCUSSION: In participants across the cognitive spectrum, the QDRS showed modest relationships with amyloid deposition, hippocampal volumes, and APOE status. Therefore, the QDRS may offer a cost-effective screening method for clinical trials in AD.

Efficacy of Corsi Block Tapping Task training for improving visuospatial skills: a non-randomized two-group study.

Even though impaired visuospatial abilities can negatively affect daily functioning, there are very few training programs that attempt to improve visuospatial abilities. The purpose of this study was to examine if a single training session with a computerized version of the Corsi Block Tapping Task could improve mental rotation skills. Fifty-three young adults were assigned to one of two groups: (1) control group (mean age = 21.4; 10 females), who had 20 min of rest after their baseline assessment, or (2) training group (mean age = 21.5; 17 females), who had 20 min of training on the Corsi Block Tapping Task after their baseline assessment. The primary outcome was reaction time on a computer-based mental rotation task, and it was assessed both before and after the rest or training. There was a significant interaction between time (pre vs. post) and group (control vs. training) on mental rotation performance (p = 0.04), with the training group performing on average 124 ms faster on accurate trials than the control group at post-test. This preliminary study suggested that improving mental rotation may be feasible through targeted cognitive training. Future studies will consider multiple sessions of Corsi Block Tapping Task training to maximize training benefits (i.e., dose-response), as well as longer term retention in cognitively intact and impaired individuals.

Computerized Cognitive Training in Amnestic Mild Cognitive Impairment: A Randomized Clinical Trial.

OBJECTIVE: Computerized cognitive training has been successful in healthy older adults, but its efficacy has been mixed in patients with amnestic Mild Cognitive Impairment (MCI). METHODS: In a randomized, placebo-controlled, double-blind, parallel clinical trial, we examined the short- and long-term efficacy of a brain-plasticity computerized cognitive training in 113 participants with amnestic MCI. RESULTS: Immediately after 40-hours of training, participants in the active control group who played computer games performed better than those in the experimental group on the primary cognitive outcome (p = 0.02), which was an auditory memory/attention composite score. There were no group differences on 2 secondary outcomes (global cognitive composite and rating of daily functioning). After 1 year, there was no difference between the 2 groups on primary or secondary outcomes. No adverse events were noted. CONCLUSIONS: Although the experimental cognitive training program did not improve outcomes in those with MCI, the short-term effects of the control group should not be dismissed, which may alter treatment recommendations for these patients.

Predicting daily functioning with the modified Telephone Interview for Cognitive Status.

BACKGROUND: The modified Telephone Interview for Cognitive Status (mTICS) is a frequently used telephone-based cognitive screening measure that can distinguish between normal aging, mild cognitive impairment (MCI), and dementia. Although it has been used to predict current and future cognitive function in older adults, no studies have examined if the mTICS can predict daily functioning. AIMS: The current study sought to examine the relationship between the mTICS and a performance-based measure of daily functioning. METHODS: The mTICS and demographic information (age, sex, education) were collected during a telephone screening visit for 149 older adults (65-91 years in age) with amnestic MCI. Three subscales of the Independent Living Scales (ILS; Managing Money, Managing Home and Transportation, Health and Safety) were collected during a baseline visit and during a 16 month follow-up visit in a subsample of 93 individuals. RESULTS: Using simple hierarchical regression, baseline mTICS total score combined with demographic variables significantly predicted 19-22% of baseline ILS subscale scores. Similarly, in a subsample of 93 participants with 16 month follow-up data, baseline mTICS and demographic information predicted 9-31% of ILS subscale scores at follow-up. CONCLUSIONS: The mTICS appears able to predict daily functioning in older individuals with MCI. Remote tracking of cognition and daily functioning in this at-risk group seems particularly beneficial to geriatricians and other providers, especially during COVID-19.

The ONETEP linear-scaling density functional theory program.

We present an overview of the onetep program for linear-scaling density functional theory (DFT) calculations with large basis set (plane-wave) accuracy on parallel computers. The DFT energy is computed from the density matrix, which is constructed from spatially localized orbitals we call Non-orthogonal Generalized Wannier Functions (NGWFs), expressed in terms of periodic sinc (psinc) functions. During the calculation, both the density matrix and the NGWFs are optimized with localization constraints. By taking advantage of localization, onetep is able to perform calculations including thousands of atoms with computational effort, which scales linearly with the number or atoms. The code has a large and diverse range of capabilities, explored in this paper, including different boundary conditions, various exchange-correlation functionals (with and without exact exchange), finite electronic temperature methods for metallic systems, methods for strongly correlated systems, molecular dynamics, vibrational calculations, time-dependent DFT, electronic transport, core loss spectroscopy, implicit solvation, quantum mechanical (QM)/molecular mechanical and QM-in-QM embedding, density of states calculations, distributed multipole analysis, and methods for partitioning charges and interactions between fragments. Calculations with onetep provide unique insights into large and complex systems that require an accurate atomic-level description, ranging from biomolecular to chemical, to materials, and to physical problems, as we show with a small selection of illustrative examples. onetep has always aimed to be at the cutting edge of method and software developments, and it serves as a platform for developing new methods of electronic structure simulation. We therefore conclude by describing some of the challenges and directions for its future developments and applications.

Long-term Changes in 18F-Flutemetamol Uptake in Nondemented Older Adults.

PURPOSE: Longitudinal studies into the variability of F-Flutemetamol uptake are lacking. METHODS/PATIENTS: Therefore, the current study examined change in F-Flutemetamol uptake in 19 nondemented older adults (65 to 82 y old) who were either cognitively intact or had Mild Cognitive Impairment (MCI) who were scanned twice across 3.6 years. RESULTS: Baseline and follow-up composite SUVRs were significantly correlated (0.96, P<0.001). Significant increases in the composite SUVR from baseline to follow-up were observed (P=0.002). For the total sample, the average difference over this time period when using the composite SUVR was 6.8%. Similar results were seen in subsets of the total sample (MCI vs. cognitively intact, amyloid positive vs. negative). Finally, a Reliable Change Index that exceeded ±0.046 SUVR units would indicate a significant change of F-Flutemetamol. CONCLUSIONS: The current results extend the limited literature on longitudinal variability of F-Flutemetamol uptake across 3.6 years, which should give clinicians and researchers more confidence in the stability of this amyloid imaging agent in longer therapeutic and prevention trials in cognitive decline in MCI and Alzheimer disease.

RBANS Validity Indices: a Systematic Review and Meta-Analysis.

Neuropsychology practice organizations have highlighted the need for thorough evaluation of performance validity as part of the neuropsychological assessment process. Embedded validity indices are derived from existing measures and expand the scope of validity assessment. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief instrument that quickly allows a clinician to assess a variety of cognitive domains. The RBANS also contains multiple embedded validity indicators. The purpose of this study was to synthesize the utility of those indicators to assess performance validity. A systematic search was completed, resulting in 11 studies for synthesis and 10 for meta-analysis. Data were synthesized on four indices and three subtests across samples of civilians, service members, and veterans. Sufficient data for meta-analysis were only available for the Effort Index, and related analyses indicated optimal cutoff scores of ≥1 (AUC = .86) and ≥ 3 (AUC = .85). However, outliers and heterogeneity were present indicating the importance of age and evaluation context. Overall, embedded validity indicators have shown adequate diagnostic accuracy across a variety of populations. Recommendations for interpreting these measures and future studies are provided.

Rating scales for cognition in Huntington's disease: Critique and recommendations.

Cognitive impairment is one of the main features of Huntington's disease and is present across the disease spectrum. As part of the International Parkinson's Disease and Movement Disorder Society-sponsored project to review all clinical rating scales used in Huntington's disease, a systematic review of the literature was performed to identify cognitive scales used in Huntington's disease and make recommendations for their use. A total of 17 cognitive scales were identified and evaluated. None of the scales met criteria for a "recommended" status. For assessing severity of cognitive dysfunction, the Montreal Cognitive Assessment was "recommended with caveats." The UHDRS Cognitive Assessment, the UHDRS-For Advanced Patients cognitive section, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini-Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were "suggested" for evaluating severity of cognitive impairment. The MoCA was "suggested" as a screening tool for cognitive impairment. The major challenge in the assessment of cognition in Huntington's disease is the lack of a formal definition of dementia and/or mild cognitive impairment in this disease. The committee concluded that there is a need to further validate currently available cognitive scales in Huntington's disease, but that it is premature to recommend the development of new scales. Recently developed Huntington's disease-specific scales, such as the Huntington's Disease-Cognitive Assessment Battery, hold promise but require the completion of more comprehensive clinimetric development. © 2017 International Parkinson and Movement Disorder Society.

Within-Session Practice Effects in the Jebsen Hand Function Test (JHFT).

The Jebsen Hand Function Test (JHFT) is a standardized assessment that has been used as a clinical outcome measure. To appropriately interpret the effects of an intervention on hand function (as measured by the JHFT), the extent to which this instrument shows significant practice effects must be quantified. The purpose of this study was to determine whether the JHFT is susceptible to within-session practice effects. The results showed that the dominant and nondominant hands significantly improved on the JHFT and many of its subtests over six consecutive trials. Although practice effects might complicate the interpretation of change due to intervention, we briefly relate our findings to emerging neuropsychological evidence that practice effects may indicate a person's motor learning potential or treatment responsiveness.

Cognitive changes associated with switching to frequent nocturnal hemodialysis or renal transplantation.

BACKGROUND: It is uncertain whether switching to frequent nocturnal hemodialysis improves cognitive function in well-dialyzed patients and how this compares to patients who receive a kidney transplant. METHODS: We conducted a multicenter observational study with longitudinal follow-up of the effect on cognitive performance of switching dialysis treatment modality from conventional thrice-weekly hemodialysis to frequent nocturnal hemodialysis, a functioning renal transplant or remaining on thrice-weekly conventional hemodialysis. Neuropsychological tests of memory, attention, psychomotor processing speed, executive function and fluency as well as measures of solute clearance were performed at baseline and again after switching modality. The change in cognitive performance measured by neuropsychological tests assessing multiple cognitive domains at baseline, 4 and 12 months after switching dialysis modality were analyzed using a linear mixed model. RESULTS: Seventy-seven patients were enrolled; 21 of these 77 patients were recruited from the randomized Frequent Hemodialysis Network (FHN) Nocturnal Trial. Of these, 18 patients started frequent nocturnal hemodialysis, 28 patients received a kidney transplant and 31 patients remained on conventional thrice-weekly hemodialysis. Forty-eight patients (62 %) returned for the 12-month follow-up. Despite a significant improvement in solute clearance, 12 months treatment with frequent nocturnal hemodialysis was not associated with substantial improvement in cognitive performance. By contrast, renal transplantation, which led to near normalization of solute clearance was associated with clinically relevant and significant improvements in verbal learning and memory with a trend towards improvements in psychomotor processing speed. Cognitive performance in patients on conventional hemodialysis remained stable with the exception of an improvement in psychomotor processing speed and a decline in verbal fluency. CONCLUSIONS: In patients on conventional thrice-weekly hemodialysis, receiving a functioning renal transplant was associated with improvement in auditory-verbal memory and psychomotor processing speed, which was not observed after 12 months of frequent nocturnal hemodialysis.

Cognitive predictors of understanding treatment decisions in patients with newly diagnosed brain metastasis.

BACKGROUND: Medical decision-making capacity is a higher-order functional skill that refers to a patient's ability to make informed, sound decisions related to care and treatment. In a medical context, understanding is the most cognitively demanding consent standard and refers to a patient's ability to comprehend information to the extent that informed decisions can be made. METHODS: The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board-certified radiation oncologist and were verified histologically. In total, 41 demographically matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (ie, intact or impaired). RESULTS: Results indicate that measures of simple attention, verbal fluency, verbal memory, processing speed, and executive functioning were all associated with understanding, and that verbal memory and phonemic fluency were the primary cognitive predictors. Using these two primary predictors, equations can be constructed to predict the ability to understand treatment decisions in patients with brain metastasis. CONCLUSIONS: Although preliminary, these data demonstrate how cognitive measures can estimate understanding as it relates to medical decision-making capacities in these patients. Clinically, these findings suggest that poor verbal memory and expressive language function could serve as "red flags" for reduced consent capacity in this patient population, thus signaling that a more comprehensive medical decision-making capacity evaluation is warranted.

Cognitive Predictors of Reasoning through Treatment Decisions in Patients with Newly Diagnosed Brain Metastases.

To examine the association between reasoning through medical treatment decisions and cognition in a sample of patients with brain metastasis. The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board-certified radiation oncologist and were verified histologically. In total, 41 demographically matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (i.e., intact or impaired). Results indicate that measures of episodic memory and processing speed were associated with reasoning. Using these two predictors, actuarial equations were constructed that can be used to help screen for impaired reasoning ability in patients' with brain metastasis. The equations presented in this study have clinical significance as they can be used to help identify patients at risk for possessing a diminished ability to reason through medical treatment decisions and, thus, are in need of a more comprehensive evaluation of their medical decision-making capacity.

The Modified Telephone Interview for Cognitive Status is More Predictive of Memory Abilities Than the Mini-Mental State Examination.

Although not as popular as the Mini-Mental State Examination (MMSE), the modified Telephone Interview for Cognitive Status (mTICS) has some distinct advantages when screening cognitive functioning in older adults. The current study compared these 2 cognitive screening measures in their ability to predict performance on a memory composite (ie, delayed recall of verbal and visual information) in a cohort of 121 community-dwelling older adults, both at baseline and after 1 year. Both the MMSE and the mTICS significantly correlated with the memory composite at baseline (r's of .41 and .62, respectively) and at 1 year (r's of .36 and .50, respectively). At baseline, stepwise linear regression indicated that the mTICS and gender best predicted the memory composite score (R (2) = .45, P < .001), and the MMSE and other demographic variables did not significantly improve the prediction. At 1 year, the results were very similar. Despite its lesser popularity, the mTICS may be a more attractive option when screening for cognitive abilities in this age range.

Correcting for demographic variables on the modified telephone interview for cognitive status.

OBJECTIVE: To examine the effect of demographic variables on scores on the modified Telephone Interview for Cognitive Status (mTICS) in a healthy cohort and develop demographically corrected normative data. DESIGN: Observational. SETTING: Primarily academic medical centers. PARTICIPANTS: 576 healthy older adults. MEASUREMENTS: mTICS. RESULTS: Age and education significantly correlated with mTICS score, and sex differences were also observed on this score. Ethnicity differences were not observed. Using regression equations, age, education, and sex significantly predicted mTICS total score. CONCLUSIONS: By using these corrections, an individual's cognitive status may be more accurately predicted with this telephone screening instrument, although clinical validation is needed.

Practice effects and amyloid deposition: preliminary data on a method for enriching samples in clinical trials.

Clinical trials in Alzheimer disease are moving toward prevention studies in prodromal individuals with amyloid burden. However, methods are needed to identify individuals expected to be amyloid positive for these studies to be feasible and cost-effective. The current study sought to determine whether short-term practice effects on cognitive tests can identify those with notable uptake on amyloid imaging. Twenty-five, nondemented older adults (15 cognitively intact, 10 with mild cognitive impairment) underwent amyloid imaging through F-flutemetamol and 2 cognitive testing sessions across 1 week to determine practice effects on a visual memory test. Results indicated that, whereas F-flutemetamol uptake showed little association with baseline performance on a visual memory test (r=-0.04, P=0.85), it was significantly correlated with practice effects across 1 week on that same memory measure (r=-0.45, P=0.02), with greater uptake being associated with lower practice effects. The odds ratio of notable F-flutemetamol uptake was 5 times higher in individuals with low practice effects compared with high practice effects. Although these preliminary results need to be replicated in larger samples, short-term practice effects on cognitive tests may provide an affordable screening method to identify individuals who are amyloid positive, which could enrich samples for preventative clinical trials in Alzheimer disease.

Revisiting reliable change with Iverson (2001).

Objective: Iverson (2001) expanded on reliable change methodology by accounting for the variability in scores at Time 2 in the calculation of change scores. However, due to limitations in available data, an incomplete picture of variables affecting change was presented. The current paper sought to address some of these limitations and clarify the methodology for assessing reliable change. Method: Using one-year test-retest data on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in older adults who were cognitively intact or had mild Alzheimer's disease (AD), change scores were calculated, and various models, consistent with or divergent from Iverson, were presented. Results: Across the RBANS, individuals with intact cognition tended to show less variable scores, especially at Time 2, which resulted in larger change scores than those with AD. When applied to an independent sample, different patterns of change were observed, with: (1) models that used intact data showed more cognitive change than those using AD data; (2) the model that corrected for practice effects and used intact data showed the most decline; and (3) the model that corrected for practice effects and used AD data showed the most improvement. The models that showed the strongest association in classifying independent cases as decline/stable/improve were those that used intact data and were discordant on the use of practice effects. Conclusions: Overall, findings highlight the complexity of calculating reliable change, and they lend additional caution to Iverson's original limitations. However, the use of data from individuals classified as cognitively intact and a correction for practice effects seems warranted.

A Closer Look at Practice Effects in Mild Cognitive Impairment and Alzheimer's Disease.

Practice effects have become a potentially important variable regarding the diagnosis, prognosis, and treatment recommendations in mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the understanding of these short-term changes in test scores remains unclear. The current observational study sought to examine variables that influence the magnitude of short-term practice effects in MCI and AD, including demographic information, cognitive performance, daily functioning, and medical comorbidities. One hundred sixty-six older adults classified as cognitively intact, amnestic MCI, or mild AD were tested twice across 1 week with a brief battery of neuropsychological tests. Correlational and regression analyses examined the relationship of practice effects with demographic and clinical variables. Results indicated that practice effects were minimally related to demographic variables and medical comorbidities, but they were significantly related to cognitive variables, depressive symptoms, and daily functioning. These findings expand our understanding of practice effects in MCI and AD, and they may allow a better appreciation of how they could affect clinical care and research.

Short-Term Practice Effects on Cognitive Tests Across the Late Life Cognitive Spectrum and How They Compare to Biomarkers of Alzheimer's Disease.

Background: Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD) remain understudied, especially with how they compare to biomarkers of AD. Objective: The current study sought to add to this growing literature. Methods: Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 status. Results: The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons. Conclusion: Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.

The African American Dementia and Aging Project (AADAPt): An Oregon-based Longitudinal Study.

Objectives: The vast majority of studies on aging, cognition, and dementia focus on non-Hispanic white subjects. This paper adds to the extant literature by providing insight into the African American aging experience. Here we describe the study design and baseline characteristics of the African American Dementia and Aging Project (AADAPt) study, which is exploring aging and cognition in African American older adults in Oregon. Methods: African American older adults (n=177) participated in AADAPt, a longitudinal study that collected data on cognitive, physical, and social functioning in annual visits since 2000. Results: AADAPt participants had risk factors for developing dementia in future, such as hypertension and hyperlipidemia, but also reported protective factors such as high social engagement. Conclusions: The AADAPt project offers new insights into aging in older African Americans that includes data on cognition, social engagement, and physical health, which are crucial for understanding the experience of under-represented groups and making future studies more inclusive. These findings reflect a window of time for a geographically-focused cohort, and the lessons learned from this study likely have broader implications for shaping the health of these older African American adults. Keywords: African American, Dementia, Observational Study.