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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.

Background and ObjectivesCerebrovascular 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.MethodsThe sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3,Consortium to Establish a Registry for Alzheimer's Diseasescore ≥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.ResultsOf 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 (β = −0.93, 95% CI −1.35, −0.51, Bayes factor [BF] 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = −0.08, 95% CI −0.12, −0.05, BF 18.11). Effects ranged from weak (BFs DiscussionIn 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.

Introduction: Misophonia is marked by abnormal negative reactions to specific and idiosyncratic sounds. Despite unclear etiology and diagnostic conceptualization, neuropsychology may be abl...

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-tau(181) 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-tau(181) had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau(181) for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

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.

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: 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.

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.

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.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 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.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.

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., This work was partially supported by a research award to the first author (O.F.G.) from the Brain Imaging Network Grid/FCT (Portugal). Jorge Leite (SFRH/BPD/86027/2012) and Sandra Carvalho (SFRH/BPD/86041/2012) are supported by grants from the Portuguese Foundation for Science and Technology (FCT) and European Union (FSE-POPH).

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).