A Network Analysis of Digital Clock Drawing for Command and Copy Conditions.

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|ßz|= 0.34) relative to the copy condition (µ|ßz| = 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.

Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease.

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

Nodes of the default mode network implicated in the quality of empathic responses: A clinical perspective of the empathic response.

The ability to empathize with another person's inner experience is believed to be a central element of our social interactions. Previous research has focused on cognitive (e.g., theory of mind) and emotional (e.g., emotional contagion) empathy, and less on behavioral factors (i.e., the ability to respond empathically). Recent studies suggest that the Default Mode Network (DMN) mediates individual variability in distinct empathy-related behaviors. However, little is known about DMN activity during actual empathic responses, understood in this study as the ability to communicate our understanding of the others' experience back to them. This study used an empathy response paradigm with 28 participants (22-37 years old) to analyze the relationship between the quality of empathic responses to 14 empathy-eliciting vignettes and patterns of attenuation in the DMN. Overall, the results suggest that high levels of empathic response, are associated with sustained activation of the DMN when compared with lower levels of empathy. Our results demonstrate that the DMN becomes increasingly involved in empathy-related behavior, as our level of commitment to the other's experience increases. This study represents a first attempt to understand the relation between the capacity for responding in a supportive way to others' needs and the intra-individual variability of the pattern of the DMN attenuation. Here we underline the critical role that the DMN plays in high-level social cognitive processes and corroborate the DMN role in different psychiatric disorders associated with a lack of empathy.

Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy.

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease.

BACKGROUND AND OBJECTIVES: Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors. METHODS: The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3, Consortium to Establish a Registry for Alzheimer's Disease score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes. RESULTS: Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (ß = -0.93, 95% CI -1.35, -0.51, Bayes factor [BF] 130.75), working memory (ß = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (ß = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (ß = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (ß = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (ß = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (ß = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (ß = 0.45, 95% CI 0.01, 0.89, BF 0.33). DISCUSSION: In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.

Plasma p-tau181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau.

INTRODUCTION: We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). METHODS: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. RESULTS: Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

Normative References for Graphomotor and Latency Digital Clock Drawing Metrics for Adults Age 55 and Older: Operationalizing the Production of a Normal Appearing Clock.

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.

Mental health mediators of subjective cognitive concerns among World Trade Center responders.

Decline in cognitive functioning among rescue and recovery workers who responded in the aftermath of the September 11, 2001, World Trade Center (WTC) attacks is of emerging interest. Responders are vulnerable to cognitive decline from exposure to airborne toxins present at the WTC site, as well as from WTC-related mental and physical health conditions. To better understand the relationship between occupational WTC exposure, mental health, physical health and subjective cognitive functioning, we examined the mediating role of health status in the association between exposure and subjective cognitive concerns in a multi-site, longitudinal investigation of the WTC General Responder cohort (n = 16,380 responders; n = 58,575 visits) for the period 2002-2015. Through latent class analyses, we identified a four-level marker of cognitive concerns based on information from a Self-Administered Mental Health Questionnaire. Using generalized linear mixed models with random intercepts, we observed that a higher intensity WTC exposure composite was associated with greater cognitive concerns, and that this association was operating almost entirely through mental health comorbidities, not physical health comorbidities. In fully adjusted models, the inclusion of probable depression, anxiety, PTSD and use of psychotropic medications attenuated the association between highest WTC exposure and greatest cognitive concerns. Physical health did not appear to be on the pathway between WTC exposure and cognitive concerns. Understanding the underlying sources of cognitive concerns may help identify vulnerable members of the General Responder cohort and potentially aid clinical decision-making, such as treatment choice and enhanced screening options. Earlier diagnosis and symptom treatment may help preserve functional independence.

Parkinson's Disease Cognitive Phenotypes Show Unique Clock Drawing Features when Measured with Digital Technology.

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.

Inattention in misophonia: Difficulties achieving and maintaining alertness.

Introduction: Misophonia is marked by abnormal negative reactions to specific and idiosyncratic sounds. Despite unclear etiology and diagnostic conceptualization, neuropsychology may be able to help characterize the syndrome. In the current study, we administered the Attention Network Test (ANT) under symptom provocation conditions, as well as secondary measures of concept formation, perseveration, processing speed, and frustration tolerance. We assessed treatment seeking individuals with misophonia and non-clinical controls. We hypothesized higher alerting, orienting, and conflict effects on the ANT suggesting overall poorer performance for the misophonia group.Methods: The sample consisted of symptomatic individuals recruited from a randomized treatment trial prior to the mandatory waitlist (n = 11) and age, gender matched controls (n = 11). Symptomatic individuals were screened with the Misophonia Questionnaire, as well as a number of additional self-report and diagnostic measures.Results: Robust Bayesian estimation in multi-level models suggested worse alerting attention for symptomatic individuals, ßMedian = 2.766, ßSD = 1.253, 95% CI [0.322, 5.2876], Bayes factor = 31.41. There were no effects respective to block (i.e., blocks before versus during and after symptom provocation) or interaction effects. There were also no effects particular to executive functioning measures but some evidence this domain should be further explored (e.g., ANT conflict effects, perseveration, and serial math accuracy).Conclusions: We propose that symptom provocation alone does not explain the observed group difference in alerting attention, which could reflect a long-standing neuropsychological weakness. Future studies should attempt to characterize misophonia with more comprehensive neuropsychological batteries and larger samples.

Machine learning as a new paradigm for characterizing localization and lateralization of neuropsychological test data in temporal lobe epilepsy.

In this study, we employed a kernel support vector machine to predict epilepsy localization and lateralization for patients with a diagnosis of epilepsy (n = 228). We assessed the accuracy to which indices of verbal memory, visual memory, verbal fluency, and naming would localize and lateralize seizure focus in comparison to standard electroencephalogram (EEG). Classification accuracy was defined as models that produced the least cross-validated error (CVϵ). In addition, we assessed whether the inclusion of norm-based standard scores, demographics, and emotional functioning data would reduce CVϵ. Finally, we obtained class probabilities (i.e., the probability of a particular classification for each case) and produced receiver operating characteristic (ROC) curves for the primary analyses. We obtained the least error assessing localization data with the Gaussian radial basis kernel function (RBF; support vectors = 157, CVϵ = 0.22). There was no overlap between the localization and lateralization models, such that the poorest localization model (the hyperbolic tangent kernel function; support vectors = 91, CVϵ = 0.36) outperformed the strongest lateralization model (RBF; support vectors = 201, CVϵ = 0.39). Contrary to our hypothesis, the addition of norm, demographics, and emotional functioning data did not improve the accuracy of the models. Receiver operating characteristic curves suggested clinical utility in classifying epilepsy lateralization and localization using neuropsychological indicators, albeit with better discrimination for localizing determinations. This study adds to the existing literature by employing an analytic technique with inherent advantages in generalizability when compared to traditional single-sample, not cross-validated models. In the future, class probabilities extracted from these and similar analyses could supplement neuropsychological practice by offering a quantitative guide to clinical judgements.

Empathy by default: Correlates in the brain at rest.

BACKGROUND: Empathy, defined as the ability to access and respond to the inner world of another person, is a multidimensional construct involving cognitive, emotional and self-regulatory mechanisms. Neuroimaging studies report that empathy recruits brain regions which are part of the social cognition network. Among the different resting state networks, the Default Mode Network (DMN) may be of particular interest for the study of empathy since it has been implicated in social cognition tasks. METHOD: The current study compared the cognitive and emotional empathy scores, as measured by the Interpersonal Reactivity Index, with the patterns of activation within the DMN, through the neuroimaging methodology of resting-state functional magnetic resonance. RESULTS: Results suggest a significant positive correlation between cognitive empathy and activation of the bilateral superior medial frontal cortex nodes of the DMN. Contrastingly, a negative correlation was found between emotional empathy and the same brain region. CONCLUSIONS: Overall, this data highlights a critical role of the medial cortical regions of the DMN, specifically its anterior node, for both cognitive and emotional domains of the empathic process.

Ecological momentary analysis of the relations among stressful events, affective reactivity, and smoking among smokers with high versus low depressive symptoms during a quit attempt.

AIMS: To assess whether individuals trying to quit smoking who have high depressive symptoms (HD), compared with low depressive symptoms (LD): (1) report more frequent stressful events (SEs), (2) are more likely to smoke after SEs, (3) experience greater acute or persistent changes in affect after an SE, and (4) are at greater risk of smoking following affective changes. DESIGN: Smoking cessation data were analyzed using multi-level path modeling to examine the moderating effects of depressive symptoms on relations among SEs, subsequent affect, and smoking. SETTING: An academic research center in Central New Jersey, USA. PARTICIPANTS: Seventy-one adult treatment-seeking daily smokers recruited from 2010 to 2012. MEASUREMENTS: Baseline depressive symptoms [HD: Center for Epidemiological Studies Depression Scale (CES-D) ≥ 16 versus LD: CES-D < 16]; and real-time ecological momentary assessment (EMA) reports of SEs, affect, and smoking assessed during 21 days post-quit. FINDINGS: Multi-level models indicated that HD smokers were more likely than LD smokers to report stressful events [odds ratio (OR) = 2.323, P = 0.009], but had similar post-stress acute affective changes (negative affect: b = -0.117, P = 0.137, positive affect: b = 0.020, P = 0.805). Only HD smokers reported increased negative affect (NA) (b = 0.199, P = 0.030) and decreased positive affect (PA) up to 12 hours later (b = -0.217, P = 0.021), and greater lapse risk up to 24 hours after an SE (OR = 3.213, P = 0.017). The persistence of elevated NA and suppressed PA was partially explained by increased odds of subsequent SEs among HD smokers. However, the heightened stress-lapse association over 24 hours found in HD smokers was not fully explained by sustained aversive affect or subsequent SEs. CONCLUSIONS: Depressed and non-depressed smokers trying to quit appear to experience similar acute affective changes following stress: however, depressed smokers experience higher rates of exposure to stress, longer-lasting post-stress affective disturbance and greater risk of smoking lapse 12-24 hours after a stressful event than non-depressed smokers.

A theoretical and empirical modeling of anxiety integrated with RDoC and temporal dynamics.

The newly launched Research Domain Criteria (RDoC) emphasize specific mechanisms over diagnostic categories of psychopathology. In our view, RDoC provides a useful heuristic for mental health disorders, but does not capture the complexity of psychological data when proposed mechanisms are viewed as static entities. However, temporal and complex system dynamics may advance RDoC's utility. By investigating temporal patterns within trajectories and the interaction of complex networks, we propose that dynamic modeling provides comprehensive methods with which to investigate the etiopathology and maintenance of mental health disorders. We examine applications of dynamical systems to periphery physiology, an RDoC construct that has been widely used in psychological science. A review of the literature suggests methodological problems with aggregate and reductive models. We present a dynamical systems modeling of anxiety which suggests avenues for future biomarker research. This model appears congruent with RDoC and recent learning theory.

Inferior frontal gyrus white matter abnormalities in obsessive-compulsive disorder.

The aim of the present study is to explore obsessive-compulsive disorder (OCD)-related abnormalities in white matter connectivity in OCD for a core region associated with inhibitory control [i.e. inferior frontal gyrus (IFG)]. Fifteen patients with OCD (11 men) and 15 healthy controls (nine men) underwent diffusion tensor imaging scanning to study four diffusivity indexes of white matter integrity [fractional anisotropy, mean diffusivity (MD), axial diffusivity and radial diffusivity (RD)]. The results showed that persons with OCD manifested significantly lower fractional anisotropy levels in the bilateral IFG as well as its parcellations in the pars opercularis, pars triangularis, and pars orbitalis. Significantly higher levels of MD, RD were evident for the OCD group in the IFG as a whole as well as in the bilateral subregions of the pars triangularis and pars opercularis (for MD and RD), the right side of the pars orbitalis (for RD), and the left side of the pars triangularis and right side pars opercularis (for axial diffusivity). Overall, the results suggest significant alterations in structural connectivity, probably associated with myelination and axonal abnormalities in the IFG of OCD patients.

Brain activation of the defensive and appetitive survival systems in obsessive compulsive disorder.

Several studies have shown that basic emotions are responsible for a significant enhancement of early visual processes and increased activation in visual processing brain regions. It may be possible that the cognitive uncertainty and repeated behavioral checking evident in Obsessive Compulsive Disorder (OCD) is due to the existence of abnormalities in basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional-laden stimuli. The objective of the present study was to test if patients with OCD show evidence of altered basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional stimuli. Fifteen patients with OCD and 12 healthy controls underwent functional magnetic resonance imaging acquisition while being exposed to emotional pictures, with different levels of arousal, intended to trigger the defensive and appetitive basic survival circuits. Overall, the present results seem to indicate dissociation in the activity of the defense and appetitive survival systems in OCD. Results suggest that the clinical group reacts to basic threat with a strong activation of the defensive system mobilizing widespread brain networks (i.e., frontal, temporal, occipital-parietal, and subcortical nucleus) and blocking the activation of the appetitive system when facing positive emotional triggers from the initial stages of visual processing (i.e., superior occipital gyrus).