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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 (β=-0.65, 95% CI -1.15 to -0.15; P=.01) and simple motor (β=-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., (©Samia C Akhter-Khan, Qiushan Tao, Ting Fang Alvin Ang, Cody Karjadi, Indira Swetha Itchapurapu, David J Libon, Michael Alosco, Jesse Mez, Wei Qiao Qiu, Rhoda Au. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.07.2024.)

The clock drawing test (CDT) is a neuropsychological assessment tool to screen an individual's cognitive ability. In this study, we developed a Fair and Interpretable Representation of Clock drawing test (FaIRClocks) to evaluate and mitigate classification bias against people with less than 8 years of education, while screening their cognitive function using an array of neuropsychological measures. In this study, we represented clock drawings by a priorly published 10-dimensional deep learning feature set trained on publicly available data from the National Health and Aging Trends Study (NHATS). These embeddings were further fine-tuned with clocks from a preoperative cognitive screening program at the University of Florida to predict three cognitive scores: the Mini-Mental State Examination (MMSE) total score, an attention composite z-score (ATT-C), and a memory composite z-score (MEM-C). ATT-C and MEM-C scores were developed by averaging z-scores based on normative references. The cognitive screening classifiers were initially tested to see their relative performance in patients with low years of education (< = 8 years) versus patients with higher education (> 8 years) and race. Results indicated that the initial unweighted classifiers confounded lower education with cognitive compromise resulting in a 100% type I error rate for this group. Thereby, the samples were re-weighted using multiple fairness metrics to achieve sensitivity/specificity and positive/negative predictive value (PPV/NPV) balance across groups. In summary, we report the FaIRClocks model, with promise to help identify and mitigate bias against people with less than 8 years of education during preoperative cognitive screening., (© 2024. The Author(s).)

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., Competing Interests: DL and RS consult Linus Health, Inc.; DL receives royalties from Linus Health, Inc.; DL and RS receive royalties from Oxford University Press. ST, AJ, and RB are employees of Linus Health, Inc., and receive shares or share options from Linus Health. ST, AP-L, and AJ are listed as inventors on a pending patent assessing central nervous system functionality using a digital tablet and stylus. AP-L serves as a paid member of the scientific advisory boards for Neuroelectrics, Magstim Inc., TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant. He is a co-founder of TI Solutions and the chief medical officer of Linus Health, and he receives shares or share options from Linus Health. AP-L is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, applications of non-invasive brain stimulation in various neurological disorders, as well as digital biomarkers of cognition and digital assessments for early diagnosis of dementia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Libon, Swenson, Price, Lamar, Cosentino, Bezdicek, Kling, Tobyne, Jannati, Banks and Pascual-Leone.)

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., Competing Interests: DL and RS consult to Linus Health, Inc. and receive royalties from Oxford University Press. DL receives royalties from Linus Health, Inc. DS, ST, AJ, and AP-L were employees of Linus Health, Inc. and receive shares or share options from Linus Health. AP-L serves as a paid member of the scientific advisory boards for Neuroelectrics, Magstim Inc., TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant. He is co-founder of TI Solutions and co-founder and chief medical officer of Linus Health and receives shares or share options from Linus Health. He is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and applications of noninvasive brain stimulation in various neurological disorders, as well as digital biomarkers of cognition and digital assessments for early diagnosis of dementia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Libon, Swenson, Tobyne, Jannati, Schulman, Price, Lamar and Pascual-Leone.)

Graphomotor and time-based variables from the digital Clock Drawing Test (dCDT) characterize cognitive functions. However, no prior publications have quantified the strength of the associations between digital clock variables as they are produced. We hypothesized that analysis of the production of clock features and their interrelationships, as suggested, will differ between the command and copy test conditions. Older adults aged 65+ completed a digital clock drawing to command and copy conditions. Using a Bayesian hill-climbing algorithm and bootstrapping (10,000 samples), we derived directed acyclic graphs (DAGs) to examine network structure for command and copy dCDT variables. Although the command condition showed moderate associations between variables ( μ | β z | = 0.34) relative to the copy condition ( μ | β z | = 0.25), the copy condition network had more connections (18/18 versus 15/18 command). Network connectivity across command and copy was most influenced by five of the 18 variables. The direction of dependencies followed the order of instructions better in the command condition network. Digitally acquired clock variables relate to one another but differ in network structure when derived from command or copy conditions. Continued analyses of clock drawing production should improve understanding of quintessential normal features to aid in early neurodegenerative disease detection., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Smartphone-based cognitive assessments have emerged as promising tools, bridging gaps in accessibility and reducing bias in Alzheimer disease and related dementia research. However, their congruence with traditional neuropsychological tests and usefulness in diverse cohorts remain underexplored., Methods and Results: A total of 406 FHS (Framingham Heart Study) and 59 BHS (Bogalusa Heart Study) participants with traditional neuropsychological tests and digital assessments using the Defense Automated Neurocognitive Assessment (DANA) smartphone protocol were included. Regression models investigated associations between DANA task digital measures and a neuropsychological global cognitive Z score (Global Cognitive Score [GCS]), and neuropsychological domain-specific Z scores. FHS participants' mean age was 57 (SD, 9.75) years, and 44% (179) were men. BHS participants' mean age was 49 (4.4) years, and 28% (16) were men. Participants in both cohorts with the lowest neuropsychological performance (lowest quartile, GCS1) demonstrated lower DANA digital scores. In the FHS, GCS1 participants had slower average response times and decreased cognitive efficiency scores in all DANA tasks ( P <0.05). In BHS, participants in GCS1 had slower average response times and decreased cognitive efficiency scores for DANA Code Substitution and Go/No-Go tasks, although this was not statistically significant. In both cohorts, GCS was significantly associated with DANA tasks, such that higher GCS correlated with faster average response times ( P <0.05) and increased cognitive efficiency (all P <0.05) in the DANA Code Substitution task., Conclusions: Our findings demonstrate that smartphone-based cognitive assessments exhibit concurrent validity with a composite measure of traditional neuropsychological tests. This supports the potential of using smartphone-based assessments in cognitive screening across diverse populations and the scalability of digital assessments to community-dwelling individuals.

Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1-42) (Aβ42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood., Objective: To test the hypothesis that chronic extravasation of bloodborne Aβ42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model., Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aβ42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes., Results: Mice injected with both PT and Aβ42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls., Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.

Introduction: Screening for neurocognitive impairment and psychological distress in ambulatory primary and specialty care medical settings is an increasing necessity. The Core Cognitive Evaluation™ (CCE) is administered/scored using an iPad, requires approximately 8 min, assesses 3- word free recall and clock drawing to command and copy, asks questions about lifestyle and health, and queries for psychological distress. This information is linked with patients' self- reported concerns about memory and their cardiovascular risks., Methods: A total of 199 ambulatory patients were screened with the CCE as part of their routine medical care. The CCE provides several summary indices, and scores on 44 individual digital clock variables across command and copy tests conditions., Results: Subjective memory concerns were endorsed by 41% of participants. Approximately 31% of participants reported psychological distress involving loneliness, anxiety, or depression. Patients with self-reported memory concerns scored lower on a combined delay 3- word/ clock drawing index ( p < 0.016), the total summary clock drawing command/ copy score ( p < 0.050), and clock drawing to command Drawing Efficiency ( p < 0.036) and Simple and Complex Motor ( p < 0.029) indices. Patients treated for diabetes and atherosclerotic cardiovascular disease (ASCVD) scored lower on selected CCE outcome measures ( p < 0.035). Factor analyses suggest that approximately 10 underlying variables can explain digital clock drawing performance., Discussion: The CCE is a powerful neurocognitive assessment tool that is sensitive to patient's subjective concerns about possible decline in memory, mood symptoms, possible cognitive impairment, and cardiovascular risk. iPad administration ensures total reliability for test administration and scoring. The CCE is easily deployable in outpatient ambulatory primary care settings., Competing Interests: DL and RS were consultants to Linus Health, Inc., and received royalties from Oxford University Press. DL received royalties from Linus Health Inc. ST and JG-O were employees of Linus Health, Inc. AP-L served as a paid member of the scientific advisory boards for Neuroelectrics, Magstim Inc., TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant and he was co-founder of TI solutions and co-founder and chief medical officer of Linus Health and also he was listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and applications of noninvasive brain stimulation in various neurological disorders; as well as digital biomarkers of cognition and digital assessments for early diagnosis of dementia. None of these companies have any interest in or have contributed to the present work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Libon, Matusz, Cosentino, Price, Swenson, Vermeulen, Ginsberg, Okoli-Umeweni, Powell, Nagele, Tobyne, Gomes-Osman and Pascual-Leone.)

Background: Functional impairments are a necessary requirement for the diagnosis of a dementia along with observed cognitive impairment. Comparatively, functional abilities are often relatively intact in those with mild cognitive impairment (MCI)., Objective: The current research examined the associations between memory clinic participants classified as cognitively intact, amnestic MCI, and mixed/dysexecutive MCI, using Jak-Bondi criteria, and Instrumental Activities of Daily Living - Compensation Scale (IADL-C) abilities, an informant-based questionnaire that quantifies functional abilities. The associations between functional abilities as assessed with the IADL-C and performance on neuropsychological tests were also investigated., Methods: IADLC scores were obtained along with a comprehensive neuropsychological protocol on memory clinic participants (n = 100) classified as cognitively normal (CN), amnestic MCI (aMCI), or a combined mixed/dysexecutive (mixed/dys) MCI. Regression analyses were employed to determine how the IADLC related to neuropsychological test performance., Results: On the IADLC, greater functional impairment was commonly observed in the mixed/dys MCI group compared to CN participants. Furthermore, the mixed/dys MCI group had lower scores on activities such as Money and Self-Management, Travel and Event Memory subscales compared to the CN group. Linear regression analyses found greater functional impairment in relation to lower scores on executive and episodic memory tests., Conclusions: Greater functional impairment as assessed with the IADL-C appears to be disproportionately associated with dysexecutive difficulty, and to a lesser degree, episodic memory.

The clock drawing test is a simple and inexpensive method to screen for cognitive frailties, including dementia. In this study, we used the relevance factor variational autoencoder (RF-VAE), a deep generative neural network, to represent digitized clock drawings from multiple institutions using an optimal number of disentangled latent factors. The model identified unique constructional features of clock drawings in a completely unsupervised manner. These factors were examined by domain experts to be novel and not extensively examined in prior research. The features were informative, as they distinguished dementia from non-dementia patients with an area under receiver operating characteristic (AUC) of 0.86 singly, and 0.96 when combined with participants' demographics. The correlation network of the features depicted the "typical dementia clock" as having a small size, a non-circular or "avocado-like" shape, and incorrectly placed hands. In summary, we report a RF-VAE network whose latent space encoded novel constructional features of clocks that classify dementia from non-dementia patients with high performance., (© 2023. The Author(s).)

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.

Background: Sensory deficits can result in limitations regarding how well neuropsychological test findings can be interpreted. Only a few studies have investigated the influence of vision alteration on neuropsychological tests. In 2012 the Czech Republic experienced mass methanol poisoning. Methanol metabolites cause histotoxic hypoxia to the optic nerve., Objective: In the current study, the effect of the toxic damage on the parts of the visual pathway on visual and non-visual neuropsychological measures was investigated using electrophysiological methods (visual evoked potential (VEP) and optical coherence tomography (OCT) with retinal nerve fibre layer (RNFL) thickness measurement., Methods: 53 individuals who experienced methanol poisoning participated in this research (76% men; ages 24 to 74 years, mean = 43.8±14.6 years; education 11.9±1.4 years). Each participant underwent comprehensive neurological, ophthalmological, and neuropsychological examinations., Results: The results of mixed-effect models revealed significant small to a medium association between the Stroop test weak interference and Grooved Pegboard with the left eye global, nasal and temporal RNFL thickness. Also, medium associations between the Finger Tapping test and the Stroop test weak interference and left eye temporal RNFL, right eye temporal RNFL, and the latency P1 of VEP in the left eye were significant., Conclusion: The results of this study found a small to medium association (r = .15- .33; p = .010- .046) between RNFL thickness and cognitive visual test performance. Careful interpretation is suggested regarding results obtained from visual tests of the executive or motor functioning with participants with RNFL decrease or other types of early visual processing damage.

Background: Individuals with Alzheimer's disease (AD) often present with coexisting vascular pathology that is expressed to different degrees and can lead to clinical heterogeneity., Objective: To examine the utility of unsupervised statistical clustering approaches in identifying neuropsychological (NP) test performance subtypes that closely correlate with carotid intima-media thickness (cIMT) in midlife., Methods: A hierarchical agglomerative and k-means clustering analysis based on NP scores (standardized for age, sex, and race) was conducted among 1,203 participants (age 48±5.3 years) from the Bogalusa Heart Study. Regression models assessed the association between cIMT ≥50th percentile and NP profiles, and global cognitive score (GCS) tertiles for sensitivity analysis., Results: Three NP profiles were identified: Mixed-low performance [16%, n = 192], scores ≥1 SD below the mean on immediate, delayed free recall, recognition verbal memory, and information processing; Average [59%, n = 704]; and Optimal [26%, n = 307] NP performance. Participants with greater cIMT were more likely to have a Mixed-low profile [OR = 3.10, 95% CI (2.13, 4.53), p < 0.001] compared to Optimal. After adjusting for education and cardiovascular (CV) risks, results remained. The association with GCS tertiles was more attenuated [lowest (34%, n = 407) versus highest (33%, n = 403) tertile: adjusted OR = 1.66, 95% CI (1.07, 2.60), p = 0.024]., Conclusion: As early as midlife, individuals with higher subclinical atherosclerosis were more likely to be in the Mixed-low profile, underscoring the potential malignancy of CV risk as related to NP test performance, suggesting that classification approaches may aid in identifying those at risk for AD/vascular dementia spectrum illness.

Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis., Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages., Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves., Results: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78-0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93-0.99) and overall accuracy (93.0%)., Conclusion: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD.

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.

Background: Greater cardiovascular burden and peripheral inflammation are associated with dysexecutive neuropsychological profiles and a higher likelihood of conversion to vascular dementia. The digital clock drawing test (dCDT) is useful in identifying neuropsychological dysfunction related to vascular etiology. However, the specific cognitive implications of the combination of cardiovascular risk, peripheral inflammation, and brain integrity remain unknown., Objective: We aimed to examine the role of cardiovascular burden, inflammation, and MRI-defined brain integrity on dCDT latency and graphomotor metrics in older adults., Methods: 184 non-demented older adults (age 69±6, 16±3 education years, 46% female, 94% white) completed dCDT, vascular assessment, blood draw, and brain MRI. dCDT variables of interest: total completion time (TCT), pre-first hand latency, digit misplacement, hour hand distance from center, and clock face area. Cardiovascular burden was calculated using the Framingham Stroke Risk Profile (FSRP-10). Peripheral inflammation markers included interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha, and high sensitivity C-reactive protein. Brain integrity included bilateral entorhinal cortex volume, lateral ventricular volume, and whole brain leukoaraiosis., Results: FSRP-10, peripheral inflammation, and brain integrity explained an additional 14.6% of the variance in command TCT, where FSRP-10 was the main predictor. FSRP-10, inflammatory markers, and brain integrity explained an additional 17.0% in command digit misplacement variance, with findings largely driven by FSRP-10., Conclusion: Subtle graphomotor behavior operationalized using dCDT metrics (i.e., TCT and digit misplacement) is partly explained by cardiovascular burden, peripheral inflammation, and brain integrity and may indicate vulnerability to a disease process.

We examined the construct of mental planning by quantifying digital clock drawing digit placement accuracy in command and copy conditions, and by investigating its underlying neuropsychological correlates and functional connectivity. We hypothesized greater digit misplacement would associate with attention, abstract reasoning, and visuospatial function, as well as functional connectivity from a major source of acetylcholine throughout the brain: the basal nucleus of Meynert (BNM). Participants ( n = 201) included non-demented older adults who completed all metrics within 24 h of one another. A participant subset met research criteria for mild cognitive impairment (MCI; n = 28) and was compared to non-MCI participants on digit misplacement accuracy and expected functional connectivity differences. Digit misplacement and a comparison dissociate variable of total completion time were acquired for command and copy conditions. a priori fMRI seeds were the bilateral BNM. Command digit misplacement is negatively associated with semantics, visuospatial, visuoconstructional, and reasoning ( p 's < 0.01) and negatively associated with connectivity from the BNM to the anterior cingulate cortex (ACC; p = 0.001). Individuals with MCI had more misplacement and less BNM-ACC connectivity ( p = 0.007). Total completion time involved posterior and cerebellar associations only. Findings suggest clock drawing digit placement accuracy may be a unique metric of mental planning and provide insight into neurodegenerative disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dion, Tanner, Formanski, Davoudi, Rodriguez, Wiggins, Amin, Penney, Davis, Heilman, Garvan, Libon and Price.)

The clock drawing test (CDT) is an inexpensive tool to screen for dementia. In this study, we examined if a variational autoencoder (VAE) with only two latent variables can capture and encode clock drawing anomalies from a large dataset of unannotated CDTs (n = 13,580) using self-supervised pre-training and use them to classify dementia CDTs (n = 18) from non-dementia CDTs (n = 20). The model was independently validated using a larger cohort consisting of 41 dementia and 50 non-dementia clocks. The classification model built with the parsimonious VAE latent space adequately classified dementia from non-dementia (0.78 area under receiver operating characteristics (AUROC) in the original test dataset and 0.77 AUROC in the secondary validation dataset). The VAE-identified atypical clock features were then reviewed by domain experts and compared with existing literature on clock drawing errors. This study shows that a very small number of latent variables are sufficient to encode important clock drawing anomalies that are predictive of dementia., (© 2022. The Author(s).)

Background and Objectives: Carotid intima-media thickness (c-IMT) is a measurement of atherosclerosis, a progressive disease that develops as early as childhood and has been linked with cognitive impairment and dementia in the elderly. However, the relationship between c-IMT and midlife cognitive function and the race and social disparities in this relationship remain unclear. We examined the association between c-IMT and cognitive function in midlife among Black and White participants from a semirural community-based cohort in Bogalusa, Louisiana., Methods: In this cross-sectional analysis of participants from the Bogalusa Heart Study, linear regression models were used to determine the association between c-IMT dichotomized above the 50th percentile (>0.87 mm), an a demographically standardized global cognitive score (GCS), and individual cognitive domain-based z scores. Stratified analyses were performed to evaluate the impact of race and the individual's education status., Results: A total of 1,217 participants (age 48 ± 5.28 years) were included; 66% (804) self-identified as White, and 34% (413) self-identified as Black. Of those, 58% (708) were women, and 42% (509) were men. Having a c-IMT ≥50th percentile was inversely associated with GCS ( B ± SE -0.39 ± 0.18, p = 0.03), independently of cardiovascular risk factors (CVRFs) and achieved education. The effect remained significant in Black and White participants after adjustment for CVRFs (Black participants: B ± SE -1.25 ± 0.45, p = 0.005; White participants: B ± SE -0.92 ± 0.35, p = 0.008) but not for education. The interaction between c-IMT ≥50th percentile and education was significant ( p = 0.03), and stratified analysis showed an association with GCS among those with lower achieved education ( B ± SE -0.81 ± 0.33, p = 0.013) independently of major CVRFs., Discussion: Subclinical atherosclerosis, measured as c-IMT, was associated with worse midlife cognitive function, independently of major CVRFs. The association was buffered by education and may be stronger among Black than White participants, likely due to corresponding structural and social determinants. These findings underscore the importance of establishing preventive measures in midlife and suggest subclinical atherosclerosis as a potential target to prevent cognitive decline., (© 2022 American Academy of Neurology.)

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., (©Jing Yuan, Rhoda Au, Cody Karjadi, Ting Fang Ang, Sherral Devine, Sanford Auerbach, Charles DeCarli, David J Libon, Jesse Mez, Honghuang Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 15.04.2022.)

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.

Objective: The Boston Naming Test (BNT) is the most widely used test to assess visual confrontation naming in both research and clinical settings. Recently, an abbreviated Czech version of the BNT was described. The purpose of this study is to assess the validity of this new test at the item level with advanced psychometric methods to assess its equivalence with the original test. The rationale was to help busy clinicians in the differential diagnosis of language disorders., Method: We administered the BNT-30 (odd item form of BNT-60) ( N = 535; 75.61 ± 9.11; 60-96 years) and shortened the BNT-15 ( N = 754; 71.94 ± 7.88; 60-96 years) to a large sample of healthy older adults., Results: Significant but low associations between BNT performance and age, education, and sex were found. We found strong evidence for the unidimensionality of both BNT-15/BNT-30 versions in healthy adults ( p 's < .001)., Conclusion: In-depth psychometric analysis of the BNT-15 and BNT-30 Czech versions show that test stimuli function in a similar fashion as the original BNT. Normative values adjusting for the influence of age, education, and sex are provided for use in clinical settings and future cross-cultural comparisons.

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.

Background: The Clock Drawing Test (CDT) has been widely used in clinic for cognitive assessment. Recently, a digital Clock Drawing Text (dCDT) that is able to capture the entire sequence of clock drawing behaviors was introduced. While a variety of domain-specific features can be derived from the dCDT, it has not yet been evaluated in a large community-based population whether the features derived from the dCDT correlate with cognitive function., Objective: We aimed to investigate the association between dCDT features and cognitive performance across multiple domains., Methods: Participants from the Framingham Heart Study, a large community-based cohort with longitudinal cognitive surveillance, who did not have dementia were included. Participants were administered both the dCDT and a standard protocol of neuropsychological tests that measured a wide range of cognitive functions. A total of 105 features were derived from the dCDT, and their associations with 18 neuropsychological tests were assessed with linear regression models adjusted for age and sex. Associations between a composite score from dCDT features were also assessed for associations with each neuropsychological test and cognitive status (clinically diagnosed mild cognitive impairment compared to normal cognition)., Results: The study included 2062 participants (age: mean 62, SD 13 years, 51.6% women), among whom 36 were diagnosed with mild cognitive impairment. Each neuropsychological test was associated with an average of 50 dCDT features. The composite scores derived from dCDT features were significantly associated with both neuropsychological tests and mild cognitive impairment., Conclusions: The dCDT can potentially be used as a tool for cognitive assessment in large community-based populations., (©Jing Yuan, David J Libon, Cody Karjadi, Alvin F A Ang, Sherral Devine, Sanford H Auerbach, Rhoda Au, Honghuang Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.06.2021.)

Background: When performing the clock-drawing test healthy participants often draw the clock face using a counter clockwise movement. The reason for this circular directional bias is not known. These actions may be related to the development of motor or attentional programs that associate leftward with downward movements, and rightward with upward movements., Methods: To further examine this down-left, up-right programming hypothesis, we examined the direction of circular movements made during cursive writing by dividing the first curved movements into the following pairs, up versus down, and leftward versus rightward., Results and Conclusions: With almost all the letters analyzed, when initially moving upward there was a simultaneous rightward movement and when initially moving downward a leftward movement. The results suggest that there appears to be a relationship between downward and leftward movements as well as between upward and right rightward movements. In addition, there is some evidence to suggest that the right-upward movements may be mediated by the left hemisphere and left-downward movements by the right hemisphere. Although our results suggest motor or spatial attentional programs may account for counter clockwise face drawing, activities such as learned writing direction may influence this spatial bias. Therefore, additional research is needed to better understand if these spatial biases are learned or intrinsic and the neuropsychological mechanisms that might account for these asymmetries., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We sought to determine if Parkinson's disease (PD) with mild cognitive impairment (MCI) is associated with a greater SERIAL-ORDER (mental manipulation) than ANY-ORDER (auditory span, storage) deficit in working memory (WM). We investigated WM combining neuropsychological measures with the study of brain functional connectivity. A cohort of 160 patients with idiopathic PD, classified as PD-MCI (n = 87) or PD with normal cognition (PD-NC; n = 73), and 70 matched healthy controls were studied. Verbal WM was assessed with the Backward Digit Span Task (BDT; Lamar et al., 2007, Neuropsychologia, 45, 245), measuring SERIAL-ORDER and ANY-ORDER recall. Resting-state MRI data were collected for 15 PD-MCI, 15 PD-NC and 30 controls. Hypothesis-driven seed-based functional connectivity of the dorsolateral prefrontal cortex (DLPFC) was compared between the three groups and correlated with BDT performance. We found the main effect of the test (impairment in SERIAL ORDER > ANY ORDER) and group ((NC = PD-NC) > PD-MCI) in BDT performance that was even more pronounced in SERIAL ORDER when controlling for ANY ORDER variability but not vice versa. Furthermore, PD-MCI compared to other groups were characterized by the functional disconnection between the bilateral DLPFC and the cerebellum. In functional correlations, DLPFC connectivity was positively related to both SERIAL- and ANY-ORDER performance. In conclusion, PD-MCI patients evidenced greater SERIAL-ORDER (manipulation and cognitive control) than ANY-ORDER (storage) working memory impairment than PD-NC and controls with a disrupted DLPFC resting-state connectivity that was also related to the verbal WM performance., (© 2020 The British Psychological Society.)

Aims: Reduced pre-operative cognitive functioning in older adults is a risk factor for postoperative complications, but it is unknown if preoperative digitally-acquired clock drawing test (CDT) cognitive screening variables, which allow for more nuanced examination of patient performance, may predict lengthier hospital stay and greater cost of hospital care. This issue is particularly relevant for older adults undergoing transcatheter aortic valve replacement (TAVR), as this surgical procedure is chosen for intermediate-risk older adults needing aortic replacement. This proof of concept research explored if specific latency and graphomotor variables indicative of planning from digitally-acquired command and copy clock drawing would predict post-TAVR duration and cost of hospitalization, over and above age, education, American Society of Anesthesiologists (ASA) physical status classification score, and frailty., Methods: Form January 2018 to December 2019, 162 out of 190 individuals electing TAVR completed digital clock drawing as part of a hospital wide cognitive screening program. Separate hierarchical regressions were computed for the command and copy conditions of the CDT and assessed how a-priori selected clock drawing metrics (total time to completion, ideal digit placement difference, and hour hand distance from center; included within the same block) incrementally predicted outcome, as measured by R 2 change significance values., Results: Above and beyond age, education, ASA physical status classification score, and frailty, only digitally-acquired CDT copy performance explained significant variance for length of hospital stay (9.5%) and cost of care (8.9%)., Conclusions: Digital variables from clock copy condition provided predictive value over common demographic and comorbidity variables. We hypothesize this is due to the sensitivity of the copy condition to executive dysfunction, as has been shown in previous studies for subtypes of cognitive impairment. Individuals undergoing TAVR procedures are often frail and executively compromised due to their cerebrovascular disease. We encourage additional research on the value of digitally-acquired clock drawing within different surgery types. Type of cognitive impairment and the value of digitally-acquired CDT command and copy parameters in other surgeries remain unknown., Competing Interests: Conflicts of interest Drs. Dana Penney and Randall Davis are the creators of the digital CDT and previously owned stock in this company, and Dr. David Libon previously owned stock in Digital Cognition Technology.

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.

Background: A companion paper (Crowley et al., 2020) reports on the neuroimaging and neuropsychological profiles of statistically determined idiopathic non-dementia Parkinson's disease (PD)., Objective: The current investigation sought to further examine subtle behavioral clock drawing differences within the same PD cohort by comparing 1) PD to non-PD peers on digitally acquired clock drawing latency and graphomotor metrics, and 2) PD memory, executive, and cognitively well phenotypes on the same variables., Methods: 230 matched participants (115 PD, 115 non-PD) completed neuropsychological tests and dCDT. Statistically-derived PD cognitive phenotypes characterized PD participants as PD low executive (PDExe; n = 25), PD low memory (PDMem; n = 34), PD cognitively well (PDWell; n = 56). Using a Bayesian framework and based on apriori hypotheses, we compared groups on: total completion time (TCT), pre-first hand latency (PFHL), post-clock face latency (PCFL), total clock face area (TCFA), and total number of pen strokes., Results: Fewer strokes and slower performance to command were associated with higher odds of PD diagnosis, while a larger clock face in the copy condition was associated with lower odds of PD diagnosis. Within PD cognitive phenotypes, slower performance (TCT, PCFL) and smaller clock face to command were associated with higher odds of being PDExe than PDWell, whereas larger clock faces associated with higher odds of being PDMem than PDWell. Longer disease duration, more pen strokes (command) and smaller clocks (command) associated with higher odds of being PDExe than PDWell., Conclusion: Digitally-acquired clock drawing profiles differ between PD and non-PD peers, and distinguish PD cognitive phenotypes.

Background: Cognitively-defined subgroups are well-documented within neurodegeneration., Objective: We examined such profiles in diverse non-demented older adults and considered how resulting subgroups relate to modifiable factors associated with neurodegeneration., Methods: 121 non-demented (MMSE = 28.62) diverse (46%non-Latino Black, 40%non-Latino White, 15%Latino) community-dwelling adults (age = 67.7 years) completed cognitive, cardiovascular, physical activity, and diet evaluations. Latent profile analyses (LPA) employed six cognitive scores (letter fluency, letter-number sequencing, confrontational naming, 'animal' fluency, list-learning delayed recall, and recognition discriminability) to characterize cognitively-defined subgroups. Differences between resulting subgroups on cardiovascular (composite scores of overall health; specific health components including fasting blood levels) and lifestyle (sedentary behavior; moderate-to-vigorous physical activity; Mediterranean diet consumption) factors were examined using ANCOVAs adjusting for relevant confounders., Results: Based on sample means across cognitive scores, LPA resulted in the following cognitive subgroups: 1) high-average cognition, 55%non-Latino White and 64%female participants; 2) average cognition, 58%non-Latino Black and 68%male participants; 3) lower memory, 58%non-Latino Black participants; and 4) lower executive functioning, 70%Latinos. The high-average subgroup reported significantly higher Mediterranean diet consumption than the average subgroup (p = 0.001). The lower executive functioning group had higher fasting glucose and hemoglobin A1c than all other subgroups (p-values<0.001)., Conclusion: LPA revealed two average subgroups reflecting level differences in cognition previously reported between non-Latino White and Black adults, and two lower cognition subgroups in domains similar to those documented in neurodegeneration. These subgroups, and their differences, suggest the importance of considering social determinants of health in cognitive aging and modifiable risk.

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.

Background: The model of executive attention proposes that temporal organization, i.e., the time necessary to bring novel tasks to fruition is an important construct that modulates executive control. Subordinate to temporal organization are the constructs of working memory, preparatory set, and inhibitory control., Objective: The current research operationally-defined the constructs underlying the theory of executive attention using intra-component latencies (i.e., reaction times) from a 5-span backward digit test from patients with suspected mild cognitive impairment (MCI)., Methods: An iPad-version of the Backward Digit Span Test (BDT) was administered to memory clinic patients. Patients with (n = 22) and without (n = 36) MCI were classified. Outcome variables included intra-component latencies for all correct 5-span serial order responses., Results: Average total time did not differ. A significant 2-group by 5-serial order latency interaction revealed the existence of distinct time epochs. Non-MCI patients produced slower latencies on initial (position 2-working memory/preparatory set) and latter (position 4-inhibitory control) correct serial order responses. By contrast, patients with MCI produced a slower latency for middle serial order responses (i.e., position 3-preparatory set). No group differences were obtained for incorrect 5-span test trials., Conclusion: The analysis of 5-span BDT serial order latencies found distinct epochs regarding how time was allocated in the context of successful test performance. Intra-component latencies obtained from tests assessing mental re-ordering may constitute useful neurocognitive biomarkers for emergent neurodegenerative illness.

Background: Relative to the abundance of publications on dementia and clock drawing, there is limited literature operationalizing 'normal' clock production., Objective: To operationalize subtle behavioral patterns seen in normal digital clock drawing to command and copy conditions., Methods: From two research cohorts of cognitively-well participants age 55 plus who completed digital clock drawing to command and copy conditions (n = 430), we examined variables operationalizing clock face construction, digit placement, clock hand construction, and a variety of time-based, latency measures. Data are stratified by age, education, handedness, and number anchoring., Results: Normative data are provided in supplementary tables. Typical errors reported in clock research with dementia were largely absent. Adults age 55 plus produce symmetric clock faces with one stroke, with minimal overshoot and digit misplacement, and hands with expected hour hand to minute hand ratio. Data suggest digitally acquired graphomotor and latency differences based on handedness, age, education, and anchoring., Conclusion: Data provide useful benchmarks from which to assess digital clock drawing performance in Alzheimer's disease and related dementias.

Background: Advantages of digital clock drawing metrics for dementia subtype classification needs examination., Objective: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer's disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer's disease (AD) versus vascular dementia (VaD)., Methods: Healthy, community-dwelling control participants (n = 175), patients diagnosed clinically with Alzheimer's disease (n = 29), and vascular dementia (n = 27) completed the dCDT to command and copy clock drawing conditions. Thirty-seven dCDT command and 37 copy dCDT features were extracted and used with Random Forest classification models., Results: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC = 91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, achieved with models that combined both command and copy features (AUC = 76.94%). Subsequent follow-up analyses of a corpus of 10 variables of interest determined using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features., Conclusion: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide additional neurocognitive biomarkers that may be able to identify and tract dementia syndromes.

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.

Aging is associated with normal and abnormal brain and cognitive changes. Due to the expected increase in older adults requiring surgery, perioperative clinicians will be increasingly encountering patients with neurodegenerative disease. To help perioperative clinicians understand signs of abnormal behaviors that may mark an undiagnosed neurodegenerative disorder and alert additional patient monitoring, The Society for Perioperative Assessment and Quality Improvement (SPAQI) worked with experts in dementia, neuropsychology, geriatric medicine, neurology, and anesthesiology to provide a summary of cognitive and behavioral considerations for patients with common neurodegenerative disorders being evaluated at preoperative centers. Patients with neurodegenerative disorders are at high risk for delirium due to known neurochemical disruptions, medication interactions, associated frailty, or vascular risk profiles presenting risk for repeat strokes. We provide basic information on the expected cognitive changes with aging, most common neurodegenerative disorders, a list of behavioral features and considerations to help differentiate neurodegenerative disorders. Finally, we propose screening recommendations intended for a multidisciplinary team in the perioperative setting., Competing Interests: Individual Contribution/ Conflict of Interest/Financial Disclosures: Margaret Wiggins, M.S.- Manuscript preparation and revisions - Has no conflict of interest to disclose. Franchesca Arias, PhD.- manuscript preparation and revisions - Has no conflict of interest to disclose. Bobbie Jean Sweitzer, M.D.- Manuscript reviews - Has no conflict of interest to disclose. Deborah C. Richman, M.B., Ch.B., F.F.A.(S.A.)- Manuscript review - Has no conflict of interest to disclose. Angela F. Edwards, MD – Manuscript reviews – Has no conflict of interest to disclose Melissa Armstrong, M.D., MSc – Manuscript reviews – Has no conflict of interest to disclose. Anita Chopra, M.D. – manuscript reviews – has no conflict of interest to disclose. David J. Libon, Ph.D., ABN, FACPN – Manuscript revisions – Has no conflict of interest to report. Richard D. Urman, M.D., M.B.A.- Manuscript preparation and review- Has no conflict of interest to disclose. Catherine C. Price, Ph.D. ABPP-CN- Concept, manuscript preparation and review- Has no conflict of interest to disclose.

The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals ( n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults.

Background: This pilot study explored differences in distribution of white matter hyperintensities (called leukoaraiosis; LA) in older adults (mean age = 67 years) with atrial fibrillation (AF) vs. non-AF peers measured by: (1) depth distribution; (2) anterior-posterior distribution; (3) associations between LA and cortical thickness; and (4) presence of lacunae and stroke., Methods: Participant data (AF n = 17; non-AF peers n = 17) were acquired with the same magnetic resonance imaging protocols. LA volume was quantified by cortical depth (periventricular, deep, infracortical) and in anterior and posterior regions. Cortical thickness by lobe was assessed relative to LA load., Results: Relative to non-AF peers, the AF group had twice the total LA volume (AF = 2.1% vs. Non-AF = 0.9%), over 10 times greater infracortical LA (AF = 0.72% vs. Non-AF = 0.07%), and three times greater deep LA (AF = 2.1% vs. Non-AF = 0.6%). Examinations of the extent of LA in anterior vs. posterior regions revealed a trend for more posterior relative to anterior LA. In the entire sample, total LA and infracortical LA were negatively associated with temporal lobe thickness. Only those with AF presented with lacunae or stroke., Conclusion: Aging adults with AF had more total white matter disease than those without AF, particularly near the cortical mantle and deep within the cortex. Total and infracortical white matter disease in the entire sample negatively associated with temporal lobe thickness. Results suggest that those with AF have a distinct pattern of LA relative to those without AF, and that LA severity for all individuals may associate with structural changes in the cortex., (Copyright © 2020 Wiggins, Jones, Tanner, Schmalfuss, Hossein Aalaei-Andabili, Heilman, Libon, Beaver and Price.)

Objective: To determine how well machine learning algorithms can classify mild cognitive impairment (MCI) subtypes and Alzheimer's disease (AD) using features obtained from the digital Clock Drawing Test (dCDT)., Methods: dCDT protocols were administered to 163 patients diagnosed with AD(n = 59), amnestic MCI (aMCI; n = 26), combined mixed/dysexecutive MCI (mixed/dys MCI; n = 43), and patients without MCI (non-MCI; n = 35) using standard clock drawing command and copy procedures, that is, draw the face of the clock, put in all of the numbers, and set the hands for "10 after 11." A digital pen and custom software recorded patient's drawings. Three hundred and fifty features were evaluated for maximum information/minimum redundancy. The best subset of features was used to train classification models to determine diagnostic accuracy., Results: Neural network employing information theoretic feature selection approaches achieved the best 2-group classification results with 10-fold cross validation accuracies at or above 83%, that is, AD versus non-MCI = 91.42%; AD versus aMCI = 91.49%; AD versus mixed/dys MCI = 84.05%; aMCI versus mixed/dys MCI = 84.11%; aMCI versus non-MCI = 83.44%; and mixed/dys MCI versus non-MCI = 85.42%. A follow-up two-group non-MCI versus all MCI patients analysis yielded comparable results (83.69%). Two-group classification analyses were achieved with 25-125 dCDT features depending on group classification. Three- and four-group analyses yielded lower but still promising levels of classification accuracy., Conclusion: Early identification of emergent neurodegenerative illness is criterial for better disease management. Applying machine learning to standard neuropsychological tests promises to be an effective first line screening method for classification of non-MCI and MCI subtypes.

The Clock Drawing Test, where the participant is asked to draw a clock from memory and copy a model clock, is widely used for screening of cognitive impairment. The digital version of the clock test, the digital clock drawing test (dCDT), employs accelerometer and pressure sensors of a digital pen to capture time and pressure information from a participant's performance in a granular digital format. While visual features of the clock drawing test have previously been studied, little is known about the relationship between demographic and cognitive impairment characteristics with dCDT latency and graphomotor features. Here, we examine dCDT feature clusters with respect to sociodemographic and cognitive impairment outcomes. Our results show that the clusters are not significantly different in terms of age and gender, but did significantly differ in terms of education, Mini-Mental State Exam scores, and cognitive impairment diagnoses.This study shows that features extracted from digital clock drawings can provide important information regarding cognitive reserve and cognitive impairments.

There are few cognitive screening tools appropriate for fast-paced settings with limited staffing, and particularly in preoperative evaluation clinics. The Society for Perioperative Assessment and Quality Improvement (SPAQI) convened experts in neuropsychology, geriatric medicine, and anesthesiology to conduct a review of the literature and compile a comprehensive list of cognitive screening tools used within primary care and preoperative settings. This Recommendations Statement: 1. summarizes a review of the literature on existing cognitive screening tools used within preoperative settings; 2. discusses factors to consider when selecting cognitive screening tools in a preoperative environment; and 3. includes a work flow diagram to guide use of these screening measures. Methodology involved searching peer-reviewed literature for 29 cognitive screening tools which were identified from the literature that fit inclusion criteria. Of these 29, seven tests have been used in preoperative settings and are discussed. These seven had an average administration time ranging from one to ten minutes. Memory, language, and attention were the most commonly evaluated cognitive domains. Most had adequate sensitivity and specificity to detect cognitive impairment/dementia. While information on the psychometric properties of these tools is limited, the tools discussed are appropriate for lay examiners, are short in duration, and accessible for free or at a low cost. We describe factors that must be considered prior to instrument selection., (Copyright © 2020. Published by Elsevier Inc.)

There are few cognitive screening tools appropriate for fast-paced settings with limited staffing, and particularly in preoperative evaluation clinics. The Society for Perioperative Assessment and Quality Improvement (SPAQI) convened experts in neuropsychology, geriatric medicine, and anesthesiology to conduct a review of the literature and compile a comprehensive list of cognitive screening tools used within primary care and preoperative settings. This Recommendations Statement: 1. summarizes a review of the literature on existing cognitive screening tools used within preoperative settings; 2. discusses factors to consider when selecting cognitive screening tools in a preoperative environment; and 3. includes a work flow diagram to guide use of these screening measures. Methodology involved searching peer-reviewed literature for 29 cognitive screening tools which were identified from the literature that fit inclusion criteria. Of these 29, seven tests have been used in preoperative settings and are discussed. These seven had an average administration time ranging from one to ten minutes. Memory, language, and attention were the most commonly evaluated cognitive domains. Most had adequate sensitivity and specificity to detect cognitive impairment/dementia. While information on the psychometric properties of these tools is limited, the tools discussed are appropriate for lay examiners, are short in duration, and accessible for free or at a low cost. We describe factors that must be considered prior to instrument selection., Competing Interests: Individual Contribution/Conflict of Interest/Financial Disclosures: Franchesca Arias, Ph.D.-Study concept, data acquisition, data analyses, manuscript drafts- No conflict of interest to disclose. Margaret Wiggins, M.S.- Manuscript preparation and review- No conflict of interest to disclose. Richard D. Urman, M.D., M.B.A.- Study concept & manuscript draft- No conflict of interest to disclose. Rebecca Armstrong, B.A.- Data collection and manuscript review- No conflict of interest to disclose. Kurt Pfeifer M.D., F.A.C.P.- Manuscript draft- No conflict of interest to disclose. Angela M. Bader M.D., MPH.- Manuscript drafts- No conflict of interest to disclose. David J. Libon, Ph.D., ABN, FACPN – Manuscript drafts – No conflicts of interest to disclose. Anita Chopra, M.D. - Manuscript draft- No conflict of interest to disclose. Catherine C. Price, Ph.D. ABPP-CN - Study concept and manuscript drafts- No conflict of interest to disclose.

Introduction: The Oblique Effect denotes superior performance for perceiving horizontal or vertical rather than diagonal or oblique stimuli. The current research investigated responding to oblique test stimuli in patients with mild cognitive impairment (MCI). Method : Four statistically-determined groups (n = 112) were studied; patients with little to no cognitive impairment (non-MCI, n = 39); subtle cognitive impairment (SCI, n = 15); amnestic MCI (aMCI, n = 28); and a combined mixed/dysexecutive MCI (mixed/dys MCI, n = 30). The ability to respond to oblique versus non-oblique test stimuli was assessed using the Judgment of Line Orientation Test (JOLO). Comprehensive neuropsychological assessment was also obtained. Between-group differences for JOLO oblique and non-oblique test stimuli were analyzed. Hierarchical linear regression models were constructed to identify relations between accuracy for oblique and non-oblique test items and neurocognitive domains. Results : The mixed/dys MCI group demonstrated lower accuracy for oblique test items compared to non-MCI patients. Accurate responding to oblique test items was associated with better performance on tests measuring executive control, processing speed, naming/lexical retrieval, and verbal concept formation. No between-group differences were seen for non-oblique items and these items were not associated with cognition. Conclusions: Significant impairment on oblique test items distinguished patients with multi-domain/dysexecutive MCI from non-MCI patients. Accurate responding to oblique test items was associated with a complex array of neuropsychological tests suggesting that multidimensional neuropsychological skills underlie the visuospatial reasoning abilities necessary for successful oblique line identification. Research associating responding to oblique versus non-oblique test stimuli using additional neuropsychological test paradigms, and MRI-defined neuroanatomical regions of interest may provide additional information about the brain-behavior relations that underlie MCI subtypes.

A cognitive assessment strategy that is not limited to examining a set of summary test scores may be more helpful for early detection of emergent illness such as Alzheimer's disease (AD) and may permit a better understanding of cognitive functions and dysfunctions in those with AD and other dementia disorders. A revisit of the work already undertaken by Kaplan and colleagues using the Boston Process-Approach provides a solid basis for identifying new opportunities to capture data on neurocognitive processes, test-taking strategies and response styles. Thus, this critical review will combine traditional process-based assessment strategies with support provided or offered by newer technologies that have the potential to add value to data collection and interpretation. There is now considerable interest in neuropsychological test administration using computer/digital technology, both in research and in clinical settings. To add value, any computerized version of an existing cognitive test should respect the administration procedure for which normative data were obtained, should be time-saving in terms of scoring and interpretation, and should, we argue, facilitate gathering information about the processes and strategies followed in test completion. This article will offer an overview of the steps needed when implementing computerization of neuropsychological tests using a Process-Based Approach (PBA) to these technology-based adaptations and will discuss further developments in this area by linking it to future technological developments that may be possible in the area of neuropsychological assessment. Additionally, an overview of neuropsychological tests that may benefit from computerization will be presented, together with suggestions on the specific processes, strategies and features that may be captured with the aid of such computerization. Finally, hypotheses on how virtual reality could be an asset for the future of the PBA to neuropsychological assessment will also be discussed., (Copyright © 2020 Diaz-Orueta, Blanco-Campal, Lamar, Libon and Burke.)

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.

Background: A digital version of the clock drawing test (dCDT) provides new latency and graphomotor behavioral measurements. These variables have yet to be validated with external neuropsychological domains in non-demented adults., Objective: The current investigation reports on cognitive constructs associated with selected dCDT latency and graphomotor variables and compares performances between individuals with mild cognitive impairment (MCI) and non-MCI peers., Methods: 202 non-demented older adults (age 68.79 ± 6.18, 46% female, education years 16.02 ± 2.70) completed the dCDT and a comprehensive neuropsychological protocol. dCDT variables of interest included: total completion time (TCT), pre-first hand latency (PFHL), post-clock face latency (PCFL), and clock face area (CFA). We also explored variables of percent time drawing (i.e., 'ink time') versus percent time not drawing (i.e., 'think time'). Neuropsychological domains of interest included processing speed, working memory, language, and declarative memory., Results: Adjusting for age and premorbid cognitive reserve metrics, command TCT positively correlated with multiple cognitive domains; PFHL and PCFL negatively associated with worse performance on working memory and processing speed tests. For Copy, TCT, PCFL, and PFHL negatively correlated with processing speed, and CFA negatively correlated with language. Between-group analyses show MCI participants generated slower command TCT, produced smaller CFA, and required more command 'think' (% Think) than 'ink' (% Ink) time., Conclusion: Command dCDT variables of interest were primarily processing speed and working memory dependent. MCI participants showed dCDT differences relative to non-MCI peers, suggesting the dCDT may assist with classification. Results document cognitive construct validation to digital metrics of clock drawing.

The oblique effect (OE) describes the visuospatial advantage for identifying stimuli oriented horizontally or vertically rather than diagonally; little is known about brain aging and the OE. We investigated this relationship using the Judgment of Line Orientation (JLO) in 107 older adults (∼age = 67.8 ± 6.6; 51% female) together with neuropsychological tests of executive functioning (EF), attention/information processing (AIP), and neuroimaging. Only JLO lines falling between 36-54° or 126-144° were considered oblique. To quantify the oblique effect, we calculated z-scores for oblique errors (zOblique = #oblique errors/#oblique lines), and similarly, horizontal + vertical line errors (zHV), and a composite measure of oblique relative to HV errors (zOE). Composite z-scores of EF and AIP reflected domains associated with JLO performance. Graph theory analysis integrated T1-derived volumetry and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for select network properties. Participants produced more zOblique than zHV errors (p < 0.001). Age was not associated with zOE adjusting for sex, education, and MMSE. Similarly adjusted linear regression models revealed that lower EF was associated with a larger oblique effect (p < 0.001). Modular analyses of neural connectivity revealed a differential patterns of network affiliation that varied by high versus low group status determined via median split of zOblique and zHV errors, separately. Older adults exhibit the oblique effect and it is associated with specific cognitive processes and regional brain networks that may facilitate future investigations of visuospatial preference in aging., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Previous research in mild cognitive impairment (MCI) suggests that visual episodic memory impairment may emerge before analogous verbal episodic memory impairment. The current study examined working memory (WM) test performance in MCI to assess whether patients present with greater visual versus verbal WM impairment. WM performance was also assessed in relation to hippocampal occupancy (HO), a ratio of hippocampal volume to ventricular dilation adjusted for demographic variables and intracranial volume., Methods: Jak et al. (2009) (The American Journal of Geriatric Psychiatry, 17, 368-375) and Edmonds, Delano-Wood, Galasko, Salmon, & Bondi (2015) (Journal of Alzheimer's Disease, 47(1), 231-242) criteria classify patients into four groups: little to no cognitive impairment (non-MCI); subtle cognitive impairment (SCI); amnestic MCI (aMCI); and a combined mixed/dysexecutive MCI (mixed/dys MCI). WM was assessed using co-normed Wechsler Adult Intelligence Scale-IV (WAIS-IV) Digit Span Backwards and Wechsler Memory Scale-IV (WMS-IV) Symbol Span Z-scores., Results: Between-group analyses found worse WMS-IV Symbol Span and WAIS-IV Digit Span Backwards performance for mixed/dys MCI compared to non-MCI patients. Within-group analyses found no differences for non-MCI patients; however, all other groups scored lower on WMS-IV Symbol Span than WAIS-IV Digit Span Backwards. Regression analysis with HO as the dependent variable was statistically significant for WMS-IV Symbol Span performance. WAIS-IV Digit Span Backwards performance failed to reach statistical significance., Conclusions: Worse WMS-IV Symbol Span performance was observed in patient groups with measurable neuropsychological impairment and better WMS-IV Symbol Span performance was associated with higher HO ratios. These results suggest that visual WM may be particularly sensitive to emergent illness compared to analogous verbal WM tests.

Frontal lobe-executive functions are heavily dependent on distal white matter connectivity. Even with healthy aging there is an increase in leukoaraiosis that might interrupt this connectivity. The goal of this study is to learn 1) the location, depth, and percentage of leukoaraiosis in white matter among a sample of non-demented older adults and 2) associations between these leukoarioasis metrics and composites of cognitive efficiency (processing speed, working memory, and inhibitory function), and episodic memory. Participants were 154 non-demented older adults (age range 60-85) who completed a brain MRI and neuropsychological testing on the same day. Brain MRIs were segmented via Freesurfer and white matter leukoaraiosis depth segmentations was based on published criteria. On average, leukoaraiosis occupied 1 % of total white matter. There was no difference in LA distribution in the frontal (1.12%), parietal (1.10%), and occipital (0.95%) lobes; there was less LA load within the temporal lobe (0.23%). For cortical depth, leukoaraiosis was predominantly in the periventricular region (3.39%; deep 1.46%, infracortical 0.15%). Only increasing frontal lobe and periventricular leukoaraiosis were associated with a reduction in processing speed, working memory, and inhibitory function. Despite the general presence of LA throughout the brain, only frontal and periventricular LA contributed to the speeded and mental manipulation of executive functioning. This study provides a normative description of LA for non-demented adults to use as a comparison to more disease samples.