Cerebral Microbleeds in Different Brain Regions and Their Associations With the Digital Clock-Drawing Test: Secondary Analysis of the Framingham Heart Study.

BACKGROUND: Cerebral microbleeds (CMB) increase the risk for Alzheimer disease. Current neuroimaging methods that are used to detect CMB are costly and not always accessible. OBJECTIVE: This study aimed to explore whether the digital clock-drawing test (DCT) may provide a behavioral indicator of CMB. METHODS: In this study, we analyzed data from participants in the Framingham Heart Study offspring cohort who underwent both brain magnetic resonance imaging scans (Siemens 1.5T, Siemens Healthcare Private Limited; T2*-GRE weighted sequences) for CMB diagnosis and the DCT as a predictor. Additionally, paper-based clock-drawing tests were also collected during the DCT. Individuals with a history of dementia or stroke were excluded. Robust multivariable linear regression models were used to examine the association between DCT facet scores with CMB prevalence, adjusting for relevant covariates. Receiver operating characteristic (ROC) curve analyses were used to evaluate DCT facet scores as predictors of CMB prevalence. Sensitivity analyses were conducted by further including participants with stroke and dementia. RESULTS: The study sample consisted of 1020 (n=585, 57.35% female) individuals aged 45 years and older (mean 72, SD 7.9 years). Among them, 64 (6.27%) participants exhibited CMB, comprising 46 with lobar-only, 11 with deep-only, and 7 with mixed (lobar+deep) CMB. Individuals with CMB tended to be older and had a higher prevalence of mild cognitive impairment and higher white matter hyperintensities compared to those without CMB (P<.05). While CMB were not associated with the paper-based clock-drawing test, participants with CMB had a lower overall DCT score (CMB: mean 68, SD 23 vs non-CMB: mean 76, SD 20; P=.009) in the univariate comparison. In the robust multiple regression model adjusted for covariates, deep CMB were significantly associated with lower scores on the drawing efficiency (ß=-0.65, 95% CI -1.15 to -0.15; P=.01) and simple motor (ß=-0.86, 95% CI -1.43 to -0.30; P=.003) domains of the command DCT. In the ROC curve analysis, DCT facets discriminated between no CMB and the CMB subtypes. The area under the ROC curve was 0.76 (95% CI 0.69-0.83) for lobar CMB, 0.88 (95% CI 0.78-0.98) for deep CMB, and 0.98 (95% CI 0.96-1.00) for mixed CMB, where the area under the ROC curve value nearing 1 indicated an accurate model. CONCLUSIONS: The study indicates a significant association between CMB, especially deep and mixed types, and reduced performance in drawing efficiency and motor skills as assessed by the DCT. This highlights the potential of the DCT for early detection of CMB and their subtypes, providing a reliable alternative for cognitive assessment and making it a valuable tool for primary care screening before neuroimaging referral.

Dissociating Statistically Determined Normal Cognitive Abilities and Mild Cognitive Impairment Subtypes with DCTclock.

OBJECTIVE: To determine whether the DCTclock can detect differences across groups of patients seen in the memory clinic for suspected dementia. METHOD: Patients (n = 123) were classified into the following groups: cognitively normal (CN), subtle cognitive impairment (SbCI), amnestic cognitive impairment (aMCI), and mixed/dysexecutive cognitive impairment (mx/dysMCI). Nine outcome variables included a combined command/copy total score and four command and four copy indices measuring drawing efficiency, simple/complex motor operations, information processing speed, and spatial reasoning. RESULTS: Total combined command/copy score distinguished between groups in all comparisons with medium to large effects. The mx/dysMCI group had the lowest total combined command/copy scores out of all groups. The mx/dysMCI group scored lower than the CN group on all command indices (p < .050, all analyses); and lower than the SbCI group on drawing efficiency (p = .011). The aMCI group scored lower than the CN group on spatial reasoning (p = .019). Smaller effect sizes were obtained for the four copy indices. CONCLUSIONS: These results suggest that DCTclock command/copy parameters can dissociate CN, SbCI, and MCI subtypes. The larger effect sizes for command clock indices suggest these metrics are sensitive in detecting early cognitive decline. Additional research with a larger sample is warranted.

Associations Between the Digital Clock Drawing Test and Brain Volume: Large Community-Based Prospective Cohort (Framingham Heart Study).

BACKGROUND: The digital Clock Drawing Test (dCDT) has been recently used as a more objective tool to assess cognition. However, the association between digitally obtained clock drawing features and structural neuroimaging measures has not been assessed in large population-based studies. OBJECTIVE: We aimed to investigate the association between dCDT features and brain volume. METHODS: This study included participants from the Framingham Heart Study who had both a dCDT and magnetic resonance imaging (MRI) scan, and were free of dementia or stroke. Linear regression models were used to assess the association between 18 dCDT composite scores (derived from 105 dCDT raw features) and brain MRI measures, including total cerebral brain volume (TCBV), cerebral white matter volume, cerebral gray matter volume, hippocampal volume, and white matter hyperintensity (WMH) volume. Classification models were also built from clinical risk factors, dCDT composite scores, and MRI measures to distinguish people with mild cognitive impairment (MCI) from those whose cognition was intact. RESULTS: A total of 1656 participants were included in this study (mean age 61 years, SD 13 years; 50.9% women), with 23 participants diagnosed with MCI. All dCDT composite scores were associated with TCBV after adjusting for multiple testing (P value <.05/18). Eleven dCDT composite scores were associated with cerebral white matter volume, but only 1 dCDT composite score was associated with cerebral gray matter volume. None of the dCDT composite scores was associated with hippocampal volume or WMH volume. The classification model for differentiating MCI and normal cognition participants, which incorporated age, sex, education, MRI measures, and dCDT composite scores, showed an area under the curve of 0.897. CONCLUSIONS: dCDT composite scores were significantly associated with multiple brain MRI measures in a large community-based cohort. The dCDT has the potential to be used as a cognitive assessment tool in the clinical diagnosis of MCI.

Digital assessment of cognition in neurodegenerative disease: a data driven approach leveraging artificial intelligence.

Introduction: A rapid and reliable neuropsychological protocol is essential for the efficient assessment of neurocognitive constructs related to emergent neurodegenerative diseases. We developed an AI-assisted, digitally administered/scored neuropsychological protocol that can be remotely administered in ~10 min. This protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illnesses. Methods: The protocol was administered to 77 ambulatory care/memory clinic patients (56.40% women; 88.50% Caucasian). The protocol includes a 6-word version of the Philadelphia (repeatable) Verbal Learning Test [P(r)VLT], three trials of 5 digits backward from the Backwards Digit Span Test (BDST), and the "animal" fluency test. The protocol provides a comprehensive set of traditional "core" measures that are typically obtained through paper-and-pencil tests (i.e., serial list learning, immediate and delayed free recall, recognition hits, percent correct serial order backward digit span, and "animal" fluency output). Additionally, the protocol includes variables that quantify errors and detail the processes used in administering the tests. It also features two separate, norm-referenced summary scores specifically designed to measure executive control and memory. Results: Using four core measures, we used cluster analysis to classify participants into four groups: cognitively unimpaired (CU; n = 23), amnestic mild cognitive impairment (MCI; n = 17), dysexecutive MCI (n = 23), and dementia (n = 14). Subsequent analyses of error and process variables operationally defined key features of amnesia (i.e., rapid forgetting, extra-list intrusions, profligate responding to recognition foils); key features underlying reduced executive abilities (i.e., BDST items and dysexecutive errors); and the strength of the semantic association between successive responses on the "animal" fluency test. Executive and memory index scores effectively distinguished between all four groups. There was over 90% agreement between how cluster analysis of digitally obtained measures classified patients compared to classification using a traditional comprehensive neuropsychological protocol. The correlations between digitally obtained outcome variables and analogous paper/pencil measures were robust. Discussion: The digitally administered protocol demonstrated a capacity to identify patterns of impaired performance and classification similar to those observed with standard paper/pencil neuropsychological tests. The inclusion of both core measures and detailed error/process variables suggests that this protocol can detect subtle, nuanced signs of early emergent neurodegenerative illness efficiently and comprehensively.

Dysexecutive difficulty and subtle everyday functional disabilities: the digital Trail Making Test.

Background: Digital neuropsychological tests reliably capture real-time, process-based behavior that traditional paper/pencil tests cannot detect, enabling earlier detection of neurodegenerative illness. We assessed relations between informant-based subtle and mild functional decline and process-based features extracted from the digital Trail Making Test-Part B (dTMT-B). Methods: A total of 321 community-dwelling participants (56.0% female) were assessed with the Functional Activities Questionnaire (FAQ) and the dTMT-B. Three FAQ groups were constructed: FAQ = 0 (unimpaired); FAQ = 1-4 (subtle impairment); FAQ = 5-8 (mild impairment). Results: Compared to the FAQ-unimpaired group, other groups required longer pauses inside target circles (p < 0.050) and produced more total pen strokes to complete the test (p < 0.016). FAQ-subtle participants required more time to complete the entire test (p < 0.002) and drew individual lines connecting successive target circles slower (p < 0.001) than FAQ-unimpaired participants. Lines connecting successive circle targets were less straight among FAQ-mild, compared to FAQ-unimpaired participants (p < 0.044). Using stepwise nominal regression (reference group = FAQ-unimpaired), pauses inside target circles classified other participants into their respective groups (p < 0.015, respectively). Factor analysis using six dTMT-B variables (oblique rotation) yielded a two-factor solution related to impaired motor/cognitive operations (48.96% variance explained) and faster more efficient motor/cognitive operations (28.88% variance explained). Conclusion: Digital assessment technology elegantly quantifies occult, nuanced behavior not previously appreciated, operationally defines critical underlying neurocognitive constructs related to functional abilities, and yields selected process-based scores that outperform traditional paper/pencil test scores for participant classification. When brought to scale, the dTMT-B test could be a sensitive tool to detect subtle-to-mild functional deficits in emergent neurodegenerative illnesses.

Neurocognitive Operations Underlying Working Memory Abilities: An Analysis of Latency and Time-Based Parameters.

BACKGROUND: The theory of executive attention (Fuster, 2015) suggests considerable plasticity regarding when specific neurocognitive operations are recruited to bring executive tasks to fruition. OBJECTIVE: We tested the hypothesis that differing neurocognitive operations are recruited upon the initiation of a response, but that other distinct neurocognitive operations are recruited towards the middle or end of a response. METHODS: The Backward Digit Span Test (BDST) was administered to 58 memory clinic patients (MCI, n = 22; no-MCI, n = 36). Latency to generate all correct 5-span responses was obtained. Statistical analyses found that optimal group classification was achieved using the first and third digit backward. First and third response latencies were analyzed in relation to verbal working memory (WM), visual WM, processing speed, visuospatial operations, naming/lexical access, and verbal episodic memory tests. RESULTS: For the first response, slower latencies were associated with better performance in relation to verbal WM and visuospatial test performance. For the third response, faster latencies were associated with better processing speed and visuospatial test performance. CONCLUSION: Consistent with the theory of executive attention, these data show that the neurocognitive operations underlying successful executive test performance are not monolithic but can be quite nuanced with differing neurocognitive operations associated with specific time epochs. Results support the efficacy of obtaining time-based latency parameters to help disambiguate successful executive neurocognitive operations in memory clinic patients.

The Boston Process Approach and Digital Neuropsychological Assessment: Past Research and Future Directions.

Neuropsychological assessment using the Boston Process Approach (BPA) suggests that an analysis of the strategy or the process by which tasks and neuropsychological tests are completed, and the errors made during test completion convey much information regarding underlying brain and cognition and are as important as overall summary scores. Research over the last several decades employing an analysis of process and errors has been able to dissociate between dementia patients diagnosed with Alzheimer's disease, vascular dementia associated with MRI-determined white matter alterations, and Parkinson's disease; and between mild cognitive impairment subtypes. Nonetheless, BPA methods can be labor intensive to deploy. However, the recent availability of digital platforms for neuropsychological test administration and scoring now enables reliable, rapid, and objective data collection. Further, digital technology can quantify highly nuanced data previously unobtainable to define neurocognitive constructs with high accuracy. In this paper, a brief review of the BPA is provided. Studies that demonstrate how digital technology translates BPA into specific neurocognitive constructs using the Clock Drawing Test, Backward Digit Span Test, and a Digital Pointing Span Test are described. Implications for using data driven artificial intelligence-supported analytic approaches enabling the creation of more sensitive and specific detection/diagnostic algorithms for putative neurodegenerative illness are also discussed.

Digital Neuropsychological Assessment: New Technology for Measuring Subtle Neuropsychological Behavior.

Technology has transformed the science and practice of medicine. In this special mini-forum, data using digital neuropsychological technology are reported. All of these papers demonstrate how coupling digital technology with standard paper and pencil neuropsychological tests are able to extract behavior not otherwise obtainable. As digital assessment methods mature, early identification of persons with emergent neurodegenerative and other neurological illness may be possible.

Digital Technology Differentiates Graphomotor and Information Processing Speed Patterns of Behavior.

BACKGROUND: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition. OBJECTIVE: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST). METHODS: A subset of Long Life Family Study participants (n = 1,594) completed the DSST. Total time to draw each symbol was divided into 'writing' and non-writing or 'thinking' time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90 s test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores. RESULTS: Clustering revealed four 'thinking' time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of 'writing' time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores. CONCLUSION: Digital data identified previously unrecognized patterns of 'writing' and 'thinking' time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions.

Features and psychometric properties of the Montreal Cognitive Assessment: Review and proposal of a process-based approach version (MoCA-PA).

The current study presents a rapid review of the psychometric features of the standard Montreal Cognitive Assessment (MoCA), and the proposal for a modified version of the test, informed by the methodology of the Boston Process Approach to neuropsychological assessment. In order to aid the process of identification of the primary underlying neurocognitive mechanism responsible for defective test performance, the MoCA-Process-Based Approach (MoCA-PA) adds complementary or satellite test conditions in some of its subtests, includes "new" qualitative indices to capture the cognitive processes involved in each cognitive task, and incorporates new qualitative classifications of error subtypes. It provides concurrent assessment of multiple cognitive processes within each task, without significantly increasing administration time or placing significant additional burden upon the respondent. We present preliminary results obtained from an initial sample of 45 community-dwelling older adults attending a University program for seniors. Results suggest the usefulness of additional indices in providing additional information on cognitive deterioration that may be overlooked with the only consideration of quantitative scores. Future research will aim to collect normative data for different clinical populations using the newly developed indices in order to determine the validity and clinical utility of the relatively novel qualitative process-based methods used in the MoCA-PA.

The development, validation and normative data study of the English in Ireland adaption of the Philadelphia repeatable Verbal Learning Test (EirPrVLT-12) for use in an older adult population.

OBJECTIVE: Cultural adaptations of verbal serial list-learning tests such as the California Verbal Learning Test (CVLT) and the Philadelphia (repeatable) Verbal Learning Test (P(r)VLT) have been shown to be clinically necessary. This paper aimed to culturally adapt, validate and provide normative data for an English in Ireland adaptation of the P(r)VLT, i.e. the EirPrVLT-12, in order to improve episodic memory assessments for Irish adults. Method: EirPrVLT-12 word lists were constructed using a word frequency study of Irish adults (n = 58). Two twelve-word, four-trial forms were constructed (standard and alternate form). A normative study included 145 participants who met strict inclusion criteria. Results: EirPrVLT-12 performance varied depending on age, gender, education, estimated IQ and socioeconomic status. Construct validity was established by correlations with other cognitive tests. Principal component analysis yielded a three-factor solution relating to general verbal learning, intrusions and interference. Normed EirPrVLT-12 scaled scores and percentiles stratified by age are available on the Open Science Framework at https://osf.io/vjzsp/, as are regression equations to predict individual scores based on age, gender and education. Conclusions: The data obtained underscores the clinical ultility of the EirPrVLT-12 to assess episodic memory in Irish older adults. Future research was recommended to validate the EirPrVLT-12 in a clinical population, extend normative data to younger populations and develop norms for the alternate form.

Assessing Working Memory in Mild Cognitive Impairment with Serial Order Recall.

BACKGROUND: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined. OBJECTIVE: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI). METHODS: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied. RESULTS: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients. CONCLUSIONS: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.

Age and Graphomotor Decision Making Assessed with the Digital Clock Drawing Test: The Framingham Heart Study.

BACKGROUND: Digital Clock Drawing Test (dCDT) technology enables the examination of detailed neurocognitive behavior as behavior unfolds in real time; a capability that cannot be obtained using a traditional pen and paper testing format. OBJECTIVE: Parameters obtained from the dCDT were used to investigate neurocognitive constructs related to higher-order neurocognitive decision making and information processing speed. The current research sought to determine the effect of age as related to combined motor and non-motor components of drawing, and higher-order decision making latencies. METHODS: A large group of stroke- and dementia- free Framingham Heart Study participants were administered the dCDT to command and copy with hands set for "10 after 11". Six age groups (age range 28-98) were constructed. RESULTS: Differences between age groups were found for total time to completion, total pen stroke count, and higher-order decision making latencies in both command and copy test conditions. CONCLUSION: Longer age-related decision making latencies may reflect a greater need for working memory and increased self-monitoring in older subjects. These latency measures have potential to serve as neurocognitive biomarkers of Alzheimer's disease and other insidious neurodegenerative disorders.

Visuoconstructional Impairment in Subtypes of Mild Cognitive Impairment.

Clock Drawing Test performance was examined alongside other neuropsychological tests in mild cognitive impairment (MCI). We tested the hypothesis that clock-drawing errors are related to executive impairment. The current research examined 86 patients with MCI for whom, in prior research, cluster analysis was used to sort patients into dysexecutive (dMCI, n = 22), amnestic (aMCI, n = 13), and multidomain (mMCI, n = 51) subtypes. First, principal components analysis (PCA) and linear regression examined relations between clock-drawing errors and neuropsychological test performance independent of MCI subtype. Second, between-group differences were assessed with analysis of variance (ANOVA) where MCI subgroups were compared to normal controls (NC). PCA yielded a 3-group solution. Contrary to expectations, clock-drawing errors loaded with lower performance on naming/lexical retrieval, rather than with executive tests. Regression analyses found increasing clock-drawing errors to command were associated with worse performance only on naming/lexical retrieval tests. ANOVAs revealed no differences in clock-drawing errors between dMCI versus mMCI or aMCI versus NCs. Both the dMCI and mMCI groups generated more clock-drawing errors than the aMCI and NC groups in the command condition. In MCI, language-related skills contribute to clock-drawing impairment.

Verbal memory and brain aging: an exploratory analysis of the role of error responses in the Framingham Study.

OBJECTIVE: Analysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements. METHODS: The LM immediate (LM-I) and LM delay (LM-D) free recall correct responses and related and unrelated errors were scored. Principal components analysis yielded a 3-factor solution: LM-I and LM-D correct responses, LM-I and LM-D-unrelated errors, and LM-I/-D-related errors. The MRI total cerebral brain volume, frontal brain volume, temporal horn volume (THV), and white matter hyperintensities volume (WMHIV) were obtained. RESULTS: Increasing THV (suggesting greater regional atrophy) was associated with lower scores on the LM-correct responses factor. Extensive WMHIV was associated with higher scores on the LM-related errors factor. CONCLUSION: These results suggest that LM-correct responses could relate to emerging brain alterations. Longitudinal research might enhance the sensitivity of this test to identify preclinical impairment and persons at risk of mild cognitive impairment and dementia.

Development, validity, and normative data study for the 12-word Philadelphia Verbal Learning Test [czP(r)VLT-12] among older and very old Czech adults.

The aim of the present study was to assess the validity of a 12-word Czech version of the Philadelphia (repeatable) Verbal Learning Test [czP(r)VLT-12]. The construction of the czP(r)VLT-12 was modeled after the California Verbal Learning Test (CVLT) and the nine-word Philadelphia (repeatable) Verbal Learning Test [P(r)VLT]. The czP(r)VLT-12 was constructed from a large corpus of old (60-74) and very old (75-96) Czech adults (n = 540). Participants met strict inclusion criteria for the absence of any active or past neurodegenerative disorders and performed within normal limits on other neuropsychological measures. Principal component analysis (PCA) and correlations between czP(r)VLT-12 factor structure and other memory tests were conducted. The czP(r)VLT-12 produced a four-factor solution, accounting for 70.90% of variance, with factors related to: (1) recall, (2) extra-list intrusion errors/recognition foils, (3) interference, and (4) acquisition rate; a solution similar to the CVLT and P(r)VLT. Increasing age resulted in a decline in most czP(r)VLT-12 indices, women outperformed men, and higher education led to higher scores. Memory performance in normal aging did not correlate with instrumental activities of daily living. Low, but significant, correlations were seen with other tests of cognitive performance (divergent validity). Appendices are available that provide normed percentile estimates of individual czP(r)VLT-12 performance stratified by age, education, and gender. In accordance with previous studies, these results demonstrate the usefulness of czP(r)VLT-12 in assessing declarative memory in older adults.