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This project describes the development and piloting of a framework to assess the risk of contamination in psychological therapy trial protocols

The purpose of this study was to examine subjective cognitive and psychiatric functioning in post-deployed military Veterans who underwent the Veterans Health Administration's Traumatic Brain Injury (TBI) Screening and Evaluation Program and enrolled in the VA's Million Veteran Program (MVP). Veterans (N=7483) were classified into three groups based on outcomes from the TBI Screening and Evaluation Program: (1) negative TBI screen ('Screen-'), (2) positive TBI screen but no TBI diagnosis ('Screen+/TBI-'), or (3) positive TBI screen and TBI diagnosis ('Screen+/TBI+'). Chi-square analyses revealed significant group differences across all self-reported cognitive and psychiatric health conditions (e.g., memory loss, depression), and ANCOVAs similarly showed a significant association between group and subjective symptom reporting. Specifically, the relationship between TBI group and clinical outcome (i.e., health conditions and symptoms) was such that the Screen+/TBI+group fared the worst, followed by the Screen+/TBI- group, and finally the Screen- group. However, evaluation of effect sizes suggested that Veterans in the two Screen+groups (Screen+/TBI+ and Screen+/TBI-) are faring similarly to one another on subjective cognitive and psychiatric functioning, but that both Screen+groups are faring significantly worse than the Screen- group. Our results have meaningful clinical implications and suggest that Veterans who screen positive for TBI, regardless of ultimate TBI diagnosis, be eligible for similar clinical services so that both groups can benefit from valuable treatments and therapeutics. Finally, this research sets the stage for follow-up work to be conducted within MVP that will address the neurobiological underpinnings of cognitive and psychiatric distress in this population.

Contemporary wildlife trade is massively facilitated by the Internet. By design, the dark web is one layer of the Internet that is difficult to monitor and lacks thorough investigation. Here, we accessed a comprehensive database of dark web marketplaces to search across c. 2 million dark web advertisements over 5 years using c. 7k wildlife trade-related search terms. We found 153 species traded in 3,332 advertisements (c. 600 advertisements per year). We characterized a highly specialized wildlife trade market, where c. 90% of dark-web wildlife advertisements were for recreational drugs. We verified that 68 species contained chemicals with drug properties. Species advertised as drugs mostly comprised of plant species, however, fungi and animals were also traded as drugs. Most species with drug properties were psychedelics (45 species), including one genera of fungi, Psilocybe, with 19 species traded on the dark web. The native distribution of plants with drug properties were clustered in Central and South America. A smaller proportion of trade was for purported medicinal properties of wildlife, clothing, decoration, and as pets. Our results greatly expand on what species are currently traded on the dark web and provide a baseline to track future changes. Given the low number of advertisements, we assume current conservation and biosecurity risks of the dark web are low. While wildlife trade is rampant on other layers of the Internet, particularly on e-commerce and social media sites, trade on the dark web may increase if these popular platforms are rendered less accessible to traders (e.g., via an increase in enforcement). We recommend focussing on surveillance of e-commerce and social media sites, but we encourage continued monitoring of the dark web periodically, to evaluate potential shifts in wildlife trade across this more occluded layer of the Internet.

Additional file 1: Supplementary Material. Search Strategies

We examined the association between cognitive functioning and health-related quality of life (HR-QOL) in military veterans with a history of mild traumatic brain injury (mTBI) using two methods to assess cognition: mean performance on cognitive composite scores and across-test intraindividual variability (IIV). The sample included 73 veterans (84.9% male; age, mean = 32.47 years) who completed neuropsychological testing and self-report questionnaires ∼7 years post-injury. Three cognitive composite scores representing mean performance were computed, including memory, attention/processing speed (A/PS), and executive functioning (EF). Three IIV indices were also calculated reflecting degree of dispersion across the same cognitive domains: memory-IIV, A/PS-IIV, and EF-IIV. The Posttraumatic Stress Disorder (PTSD) Checklist-Military Version (PCL-M) was used to assess current PTSD symptoms, and the World Health Organization Quality of Life Short Version Physical Health domain was used to assess HR-QOL. Hierarchical linear regressions adjusting for PTSD symptoms demonstrated that IIV indices, but not mean cognitive composite scores, significantly predicted HR-QOL. Specifically, memory-IIV, A/PS-IIV, and EF-IIV, when taken together, made an independent and significant contribution to the prediction of HR-QOL. Examination of the standardized coefficients showed that the A/PS-IIV index was uniquely associated with HR-QOL, such that higher A/PS-IIV scores significantly predicted poorer HR-QOL. Our results are the first to show that, in veterans with remote mTBI histories, greater fluctuations in cognitive performance significantly contribute to poorer HR-QOL, even after accounting for PTSD symptom severity. Moreover, findings suggest that, compared to traditional mean cognitive performance scores, measures of IIV may represent more sensitive indicators of clinical outcome and better align with subjective experiences of distress.

Supplemental material, sj-docx-1-cpx-10.1177_21677026221100230 for Characterizing Sex Differences in Clinical and Functional Outcomes Among Military Veterans With a Comprehensive Traumatic Brain Injury Evaluation: A Million Veteran Program Study by Victoria C. Merritt, Catherine Chanfreau-Coffinier, McKenna S. Sakamoto, Amy J. Jak and Lisa Delano-Wood in Clinical Psychological Science

Supplemental material, sj-docx-2-cpx-10.1177_21677026221100230 for Characterizing Sex Differences in Clinical and Functional Outcomes Among Military Veterans With a Comprehensive Traumatic Brain Injury Evaluation: A Million Veteran Program Study by Victoria C. Merritt, Catherine Chanfreau-Coffinier, McKenna S. Sakamoto, Amy J. Jak and Lisa Delano-Wood in Clinical Psychological Science

The purpose of this study was to examine neurobehavioral symptom reporting in a large sample of military veterans (N=12,144) who completed the Comprehensive Traumatic Brain Injury Evaluation (CTBIE) and enrolled in the VA's Million Veteran Program (MVP). The CTBIE is a clinician-administered interview that assesses for historical, deployment-related traumatic brain injury (TBI) and evaluates symptoms using the Neurobehavioral Symptom Inventory (NSI). Clinicians completing the CTBIE made clinical determinations about participants' (1) TBI diagnostic status (i.e., CTBIE+or CTBIE-) and (2) current symptom etiology (i.e., Symptom Resolution, TBI, Behavioral Health, Comorbid TBI+Behavioral Health [Comorbid], or Other). We evaluated the association of TBI diagnostic status and symptom etiology group with neurobehavioral symptoms. Results showed a significant association between TBI diagnostic status and all NSI variables, with CTBIE+veterans endorsing greater symptoms than CTBIE- veterans. There was also a significant association between symptom etiology group and all NSI variables; specifically, the Comorbid and Behavioral Health groups generally endorsed significantly greater symptoms compared to the other groups. Follow-up analyses showed that relative to the Symptom Resolution group, the Comorbid and Behavioral Health groups had increased odds of severe/very severe cognitive and affective symptoms, whereas the TBI and Other groups did not. Finally, presence of psychiatric symptoms, pain, post-traumatic amnesia, loss of consciousness, and blast exposure significantly predicted Comorbid symptom etiology group membership. Findings from this large epidemiologic MVP study have relevant clinical implications and further highlight the importance of prioritizing integrated behavioral health interventions for this vulnerable population.

Alterations to cerebral white matter tracts have been associated with cognitive decline in aging and Alzheimer's disease (AD). In particular, the fornix has been implicated as especially vulnerable given that it represents the primary outflow tract of the hippocampus. Despite this, little work has focused on the fornix using a potential early marker of white matter degeneration-myelin water fraction (MWF; an in vivo marker of myelin content). Therefore, we sought to (1) clarify associations between MWF in the fornix and memory functioning, and (2) examine whether fornix MWF relates to memory performance above and beyond hippocampal volume and conventional imaging measures of white matter that may not be as specific to alterations in myelin content. Forty nondemented older adults (mean age = 72.9 years) underwent an MRI exam and neuropsychological assessment. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) was used to quantify fornix MWF and diffusion tensor imaging (DTI) was used to measure fornix fractional anisotropy (FA). Adjusting for age, sex, education, and vascular risk factors, linear regression models revealed that, lower fornix MWF was significantly associated with poorer memory functioning (β = 0.405, p = .007) across our sample of older adults. Notably, fornix MWF remained a significant predictor of memory functioning (β = 0.380, p = .015) even after adjusting for fornix DTI FA and hippocampal volume (in addition to the above covariates). Given the observed associations between myelin and memory in older adults without dementia, MWF may be a useful early marker of dementia risk.

The original and second editions of the California Verbal Learning Test (CVLT) used nonparametric and parametric methods, respectively, to assess Total Recognition Discriminability (RD). In a previous study, we found evidence that the nonparametric formula may be more sensitive than the parametric formula to high false positive (FP) rates and provide more accurate assessments of yes/no recognition in neurodegenerative populations prone to high FP rates, including Alzheimer's disease (AD). In the present study, we extended our investigation to examine the utility of CVLT-3 nonparametric and parametric Total RD indices in the assessment and comparison of yes/no recognition in individuals with Huntington's disease (HD) and AD in mild and moderate stages of dementia. Findings suggested that the CVLT-3 nonparametric Total RD index was more sensitive than the parametric index to HD and AD differences in yes/no recognition across mild and moderate stages of dementia. Additionally, group differences on total FP errors were more closely mirrored by group differences on the nonparametric Total RD index. The present results bolster our previous findings and highlight the utility of examining nonparametric (in addition to parametric) Total RD on the CVLT-3 in assessments of yes/no recognition involving clinical populations prone to high FP rates.

BackgroundCognitively-defined subgroups are well-documented within neurodegeneration.ObjectiveWe examined such profiles in diverse non-demented older adults and considered how resulting subgroups relate to modifiable factors associated with neurodegeneration.Methods121 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.ResultsBased 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

BackgroundAge-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer's disease (AD), although their interactive effects have yet to be fully examined.ObjectiveThe current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI).MethodsThis study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1-42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified.ResultsMultiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = -1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s

Additional file 1: Table S1. Participant Demographics and Clinical Characteristics by APOE ε4 Status. Table S2. Participant Demographics and Clinical Characteristics by AD CSF Biomarker Status. Table S3. Post-hoc Exploration of Influence of Individual Vascular Risk Variables in Place of Overall Framingham Stroke Risk Profile: Results of Models Examining Main Effect of PWV on Executive Function. Table S4. Post-hoc Exploration of Influence of Individual Vascular Risk Variables in Place of Overall Framingham Stroke Risk Profile: Results of Models Examining Interaction of PWV and APOE ε4 Status on Memory. Table S5. Post-hoc Exploration of Influence of Individual Vascular Risk Variables in Place of Overall Framingham Stroke Risk Profile: Results of Models Examining Interaction of PWV and CSF AD Biomarker Status on Memory.

Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor-prediabetes-impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100-125 mg/dL) and 520 normoglycemic individuals (age range: 55-91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2-6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-181/amyloid-β1-42 ratio (p-tau181/Aβ1-42), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau181/Aβ1-42, memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.

Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.

ObjectiveTo determine the cognitive consequences of anticholinergic medications (aCH) in cognitively normal older adults as well as interactive effects of genetic and CSF Alzheimer disease (AD) risk factors.MethodsA total of 688 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative were evaluated (mean age 73.5 years, 49.6% female). Cox regression examined risk of progression to mild cognitive impairment (MCI) over a 10-year period and linear mixed effects models examined 3-year rates of decline in memory, executive function, and language as a function of aCH. Interactions with APOE ε4 genotype and CSF biomarker evidence of AD pathology were also assessed.ResultsaCH+ participants had increased risk of progression to MCI (hazard ratio [HR] 1.47, p = 0.02), and there was a significant aCH × AD risk interaction such that aCH+/ε4+ individuals showed greater than 2-fold increased risk (HR 2.69, p < 0.001) for incident MCI relative to aCH-/ε4-), while aCH+/CSF+) individuals demonstrated greater than 4-fold (HR 4.89, p < 0.001) increased risk relative to aCH-/CSF-. Linear mixed effects models revealed that aCH predicted a steeper slope of decline in memory (t = -2.35, p = 0.02) and language (t = -2.35, p = 0.02), with effects exacerbated in individuals with AD risk factors.ConclusionsaCH increased risk of incident MCI and cognitive decline, and effects were significantly enhanced among individuals with genetic risk factors and CSF-based AD pathophysiologic markers. Findings underscore the adverse impact of aCH medications on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD.

Alternative water management practices for rice (Oryza sativa) production have been developed for water conservation purposes, such as the furrow-irrigated rice production system, which results in variable volumetric water content (VWC), temperature, and oxidation-reduction (redox) potential conditions. The spatial and temporal variations in environmental factors can affect greenhouse gas (GHG) emissions.

Supplemental Digital Content is available in the text, Background: Increasing prevalence of atrial fibrillation has a significant impact on health, society, and healthcare resource utilization, due to increased morbidity, mortality, risk of stroke, and reduction in quality of life. Early diagnosis allows for treatment initiation, a reduction in complications and associated costs, and so innovation to improve screening and enable easy access are needed Developments in digital technology have significantly contributed to the availability of screening tools. The single-lead electrocardiogram AliveCor (Mountainview, CA) device offers the opportunity to provide heart rhythm screening and has been used extensively in clinical practice and research studies. Methods: This review investigates the feasibility, validity, and utility of the AliveCor device as a tool for atrial fibrillation detection in clinical practice and in wider research. Databases searched included PUBMED, CINAHL, MEDLINE, and World of Science, plus grey literature search. Search terms related to atrial fibrillation, screening, and AliveCor with adults >18 years. Feasibility metrics were applied including process, resource, management, and scientific outcomes. Studies not written in the English language were excluded. Validity of AliveCor was explored by extracting sensitivity and specificity data from eligible studies and overall effectiveness analyzed by incorporating the above, with wider issues surrounding screening approaches, cost effectiveness and appropriateness of AliveCor as a screening tool. Results: The AliveCor device screening was reviewed in 11 studies matching inclusion criteria. Atrial fibrillation detection rates ranged from 0.8% to 36% and this largely correlated to the study population, where wider age inclusion and mass/population screening represented lower atrial fibrillation detection. Recruitment from higher-risk groups (older age, targeted localities, chronic disease) identified higher numbers with atrial fibrillation. Feasibility metrics demonstrated AliveCor as an effective tool of choice in terms of process, resources, and management. Duration of screening time had an impact on rates of atrial fibrillation detection. There was however significant heterogeneity between studies reviewed. Conclusion: The AliveCor device offers a convenient, valid, and feasible means of monitoring for atrial fibrillation. Further analysis of electrocardiograms produced by AliveCor may be necessary in some circumstances. The AliveCor electrocardiogram device can be successfully implemented into both opportunistic and systematic screening strategies for atrial fibrillation.

White matter hyperintensities (WMHs), a marker of small-vessel cerebrovascular disease, increase risk for mild cognitive impairment (MCI). Less is known about whether regional WMHs distinguish MCI subtypes and predict decline in everyday functioning. About 618 Alzheimer's Disease Neuroimaging Initiative participants (301 cognitively normal [CN]; 232 amnestic MCI [aMCI]; 85 nonamnestic MCI [naMCI]) underwent neuropsychological testing, MRI, and assessment of everyday functioning. aMCI participants showed greater temporal (p= 0.002) and occipital WMHs (p= 0.030) relative to CN whereas naMCI participants had greater frontal (p= 0.045), temporal (p= 0.003), parietal (p= 0.018), and occipital (p < 0.001) WMH compared with CN. Relative to those with aMCI, individuals with naMCI showed greater occipital WMH (p= 0.013). Greater WMH in temporal (p= 0.001) and occipital regions (p= 0.006) was associated with faster decline in everyday functioning across the sample. Temporal lobe WMHs were disproportionately associated with accelerated functional decline among naMCI (p= 0.045). Regional WMH volumes vary across cognitive groups and predict functional decline. Cerebrovascular markers may help identify individuals at risk for decline and distinguish subtypes of cognitive impairment.

The amyloid cascade model of Alzheimer's disease posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer's continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is frequently observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled 'primary age-related tauopathy'. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to Alzheimer's disease. We used positron emission tomography imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer's pathogenesis. Five hundred twenty-three individuals from the Alzheimer's Disease Neuroimaging Initiative who had undergone flortaucipir positron emission tomography imaging were selected to derive positron emission tomography positivity thresholds using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. those with normal cognition or mild cognitive impairment) had also undergone florbetapir positron emission tomography imaging within 12 months and were categorized into one of the four groups based on cortical amyloid and Braak stage I/II tau positivity: A-/T-, A+/T-, A-/T+, or A+/T+. Tau positivity in the absence of amyloid beta positivity (i.e. A-/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T-, and the remainder of the sample fell into A-/T- (22%) or A+/T+ (27%) categories. A-/T- and A+/T- groups had the best cognitive performances across memory, language and executive function; the A-/T+ group showed small-to-moderate relative decreases in cognition; and the A+/T+ group had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau values and all cognitive domains only in the A-/T+ and A+/T+ groups, with strongest associations for the A+/T+ group. Among our sample of older adults across the Alzheimer's pathological spectrum, 7-fold fewer individuals have positron emission tomography evidence of amyloid beta pathology in the absence of tau pathology than the converse, challenging prevailing models of amyloid beta's primacy in Alzheimer's pathogenesis. Given that cognitive performance in the A-/T+ group was poorer than in individuals without either pathology, our results suggest that medial temporal lobe tau without cortical amyloid beta may reflect an early stage on the Alzheimer's pathological continuum.

To investigate the biological, cognitive, and psychological presentations of combat-exposed Veterans with a history of mild traumatic brain injury (mTBI) and/or posttraumatic stress disorder (PTSD) using a novel white matter imaging technique and comprehensive neuropsychological assessment. 74 Iraq and Afghanistan Veterans (mean age 33.89, 90.5% male) with history of mTBI (average 7.25 years since injury), PTSD, both, or neither underwent magnetic resonance imaging (MRI) exams including acquisition of a novel imaging technique, multicomponent-driven equilibrium single-pulse observation of T1/T2 (mcDESPOT) to quantify myelin water fraction (MWF), a surrogate measure of myelin content. Participants also underwent comprehensive neuropsychological assessment and three cognitive composite scores (memory, working memory/processing speed, and executive functioning) were created. There were no significant group differences on the neuropsychological composite scores. ANCOVAs revealed a main effect of PTSD across all a priori regions of interest (ROI) in which PTSD was associated with higher MWF. There was no main effect of mTBI history or TBI by PTSD interaction on any ROI. Significant positive associations were observed between myelin and PTSD symptoms, but no significant associations were found between myelin and neurobehavioral symptoms. No significant associations were found between myelin in the a priori ROIs and the cognitive composite scores. This study did not find neuropsychological or MWF differences in combat Veterans with a remote history of mTBI but did find myelin alterations related to PTSD. Psychological trauma should be a primary target for intervention in Veterans with comorbid PTSD and mTBI reporting subjective complaints, given its salience.

ObjectiveAlmost half of patients with heart failure (HF) have cognitive impairment. While exercise relates to better cognitive health, a hallmark of HF is exercise intolerance. The study objective was to explore whether light-to-moderate exercise improves cognitive function in patients with HF.MethodsThis was an exploratory parallel design study of 69 patients with symptomatic HF (mean age=65, SD=10), recruited from VA and University of California, San Diego Healthcare Systems. Participants were randomized to Tai Chi (TC) (n=24), resistance band (RB) exercise (n=22) or treatment as usual (TAU) (n=23). The primary outcome was change in Montreal Cognitive Assessment (MoCA) scores. We further explored if changes in Beck Depression Inventory - IA (BDI-IA) scores or inflammation biomarkers, CRP, TNFα and IL-6 related to altered cognitive function.ResultsThere was a fixed effect of group for MoCA scores changes (F=8.07, p=.001). TC and RB groups had greater MoCA score increases versus TAU, but no differences were found between TC and RB. Depression symptom changes predicted altered MoCA scores (ΔR2=0.15, Β=-0.413, p=.001). However, group did not interact with depression symptom levels for MoCA alterations (p=.392). Changes in CRP levels predicted MoCA scores (ΔR2=0.078, Β=-0.283, p=.01), but group did not interact with CRP levels for MoCA alterations (p=.689).ConclusionsLight-to-moderate exercises, TC and RB may improve cognitive function. However, the mechanisms remain unclear. ClinicalTrials.gov: NCT01625819.

ObjectiveTo determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups.MethodA total of 747 Alzheimer's Disease Neuroimaging Initiative participants (305 CN, 153 Obj-SCD, 289 MCI) underwent neuropsychological testing and serial amyloid PET and structural MRI examinations. Linear mixed effects models examined 4-year rate of change in cortical 18F-florbetapir PET, entorhinal cortex thickness, and hippocampal volume in those classified as Obj-SCD and MCI relative to CN.ResultAmyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants.ConclusionRelative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.

Supplemental material, JCB897443 Supplemental Material for Repetitive mTBI is associated with age-related reductions in cerebral blood flow but not cortical thickness by Alexandra L Clark, Alexandra J Weigand, Katherine J Bangen, Victoria C Merritt, Mark W Bondi and Lisa Delano-Wood in Journal of Cerebral Blood Flow & Metabolism

ObjectiveThe current study examined the interactive effect of type 2 diabetes and Alzheimer disease (AD) risk factors on the rate of functional decline in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative.MethodsParticipants underwent annual assessments that included the Functional Activities Questionnaire, an informant-rated measure of everyday functioning. Multilevel modeling, controlling for demographic variables and ischemic risk, examined the interactive effects of diabetes status (diabetes, n=69; no diabetes, n=744) and AD risk factors in the prediction of 5-year longitudinal change in everyday functioning. One model was run for each AD risk factor, including: objectively-defined subtle cognitive decline (Obj-SCD), and genetic susceptibility [apolipoprotein E ε4 (APOE ε4) as well as cerebrospinal fluid β-amyloid (Aβ), total tau (tau), and hyperphosphorylated tau (p-tau).ResultsThe 3-way diabetes×AD risk factor×time interaction predicted increased rates of functional decline in models that examined Obj-SCD, APOE ε4, tau, and p-tau positivity, but not Aβ positivity.ConclusionsParticipants with both diabetes and at least 1 AD risk factor (ie, Obj-SCD, APOE ε4, tau, and p-tau positivity) demonstrated faster functional decline compared with those without both risk factors (diabetes or AD). These findings have implications for early identification of, and perhaps earlier intervention for, diabetic individuals at risk for future functional difficulty.

Population assessment techniques for soft-sediment infauna (invertebrates within the substrate) requires excavation of specimens, damaging or killing the specimen and surrounding habitat, while being time-consuming and costly. Rapid population assessments of some marine burrowing decapods have been possible by counting burrow openings to estimate abundance, and while they may be used as indicator species, these decapods are not ubiquitous to environments requiring monitoring. Additionally, the presence of other burrowing macrofauna (invertebrates living in the sediment and retained on 1mm mesh such as clams or large worms) may reduce the efficacy of burrow openings in estimating macrofauna abundance. As such, we assessed mudflats along the north coast of British Columbia, Canada, during summer 2017 to determine if macrofauna abundances could be estimated from burrow openings on the sediment surface in regions of low (n = 1 species) and high (n = 8 species) biodiversity. Abundance could not be estimated at the low diversity sites where only one macrofaunal species created burrows. At the high diversity site, species-specific models estimating abundance from burrow openings could not be constructed; however, the total number of burrow openings observed was useful in estimating total infaunal community abundance. As such, burrow openings may not be an effective tool in assessing species-specific abundances, but may be appropriate to estimate overall community changes.

INTRODUCTION:The low mild cognitive impairment (MCI) to cognitively normal (CN) reversion rate in the Alzheimer's Disease Neuroimaging Initiative (2-3%) suggests the need to examine reversion by other means. We applied comprehensive neuropsychological criteria (NP criteria) to determine the resulting MCI to CN reversion rate. METHODS:Participants with CN (n=641) or MCI (n=569) were classified at baseline and year 1 using NP criteria. Demographic, neuropsychological, and Alzheimer's disease biomarker variables as well as progression to dementia were examined across stable CN, reversion, and stable MCI groups. RESULTS:NP criteria produced a one-year reversion rate of 15.8%. Reverters had demographics, Alzheimer's disease biomarkers, and risk-of-progression most similar to the stable CN group and showed the most improvement on neuropsychological measures from baseline to year1. DISCUSSION:NP criteria produced a reversion rate that is consistent with, albeit modestly improved from, reversion rates in meta-analyses. Reverters' biomarker profiles and progression rates suggest that NP criteria accurately tracked with underlying pathophysiologic status.

ObjectivesResearch has shown that analyzing intrusion errors generated on verbal learning and memory measures is helpful for distinguishing between the memory disorders associated with Alzheimer's disease (AD) and other neurological disorders, including Huntington's disease (HD). Moreover, preliminary evidence suggests that certain clinical populations may be prone to exhibit different types of intrusion errors.MethodsWe examined the prevalence of two new California Verbal Learning Test-3 (CVLT-3) intrusion subtypes - across-trial novel intrusions and across/within trial repeated intrusions - in individuals with AD or HD. We hypothesized that the encoding/storage impairment associated with medial-temporal involvement in AD would result in a greater number of novel intrusions on the delayed recall trials of the CVLT-3, whereas the executive dysfunction associated with subcortical-frontal involvement in HD would result in a greater number of repeated intrusions across trials.ResultsThe AD group generated significantly more across-trial novel intrusions than across/within trial repeated intrusions on the delayed cued-recall trials, whereas the HD group showed the opposite pattern on the delayed free-recall trials.ConclusionsThese new intrusion subtypes, combined with traditional memory analyses (e.g., recall versus recognition performance), promise to enhance our ability to distinguish between the memory disorders associated with primarily medial-temporal versus subcortical-frontal involvement.

Background:\ud Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.\ud \ud Methods:\ud The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).\ud \ud Findings:\ud Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).\ud \ud Interpretation:\ud These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.

INTRODUCTION:The Alzheimer's Disease Neuroimaging Initiative (ADNI) separates "early" and "late" mild cognitive impairment (MCI) based on a single memory test. We compared ADNI's MCI classifications to our neuropsychological approach, which more broadly assesses cognitive abilities. METHODS:Three hundred thirty-six ADNI-2 participants were classified as "early" or "late" MCI. Cluster analysis was performed on neuropsychological test data, and participants were reclassified based on cluster results. These two staging approaches were compared on progression rates, cerebrospinal fluid biomarkers, and cortical thickness profiles. RESULTS:There was little correspondence between the two staging methods. ADNI's early MCI group included a large proportion of false-positive diagnostic errors. The reclassified neuropsychological MCI groups showed steeper survival curves and more abnormal biomarkers. CONCLUSIONS:Our novel neuropsychological approach improved the staging of MCI by (1) capturing individuals at an early symptomatic stage, (2) minimizing false-positive cases, and (3) identifying a late MCI group further along the disease trajectory.

IntroductionWe examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodsCN and MCI participants were identified as remaining stable, progressing, or reverting at 1-year of follow-up (Year 1). Application of ADNI's MCI criteria at Year 1 in addition to Alzheimer's disease biomarkers by group were examined.ResultsThe MCI-to-CN reversion rate was 3.0%. When specific components were examined, 22.5% of stable MCI participants had normal memory performance at Year 1 and their Alzheimer's disease biomarkers were consistent with the stable CN group. At Year 1, when all MCI criteria were not met, the more subjective Clinical Dementia Rating rather than objective memory measure appeared to drive continuation of the MCI diagnosis.DiscussionResults demonstrate an artificially low 1-year MCI-to-CN reversion rate in ADNI-diagnosed participants. If the Logical Memory cutoffs had been consistently applied, the reversion rate would have been at least 21.8%.

Traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), and depressive symptoms each increase the risk for cognitive impairment in older adults. We investigated whether TBI has long-term associations with cognition in late middle-aged men, and examined the role of current PTSD/depressive symptoms. Participants were 953 men (ages 56-66) from the Vietnam Era Twin Study of Aging (VETSA), who were classified by presence or absence of (1) history of TBI and (2) current elevated psychiatric symptoms (defined as PTSD or depressive symptoms above cutoffs). TBIs had occurred an average of 35 years prior to assessment. Participants completed cognitive testing examining nine domains. In mixed-effects models, we tested the effect of TBI on cognition including for interactions between TBI and elevated psychiatric symptoms. Models adjusted for age, pre-morbid cognitive ability assessed at average age 20 years, apolipoprotein E genotype, and substance abuse; 33% (n = 310) of participants had TBI, mostly mild and remote; and 23% (n = 72) of those with TBI and 18% (n = 117) without TBI had current elevated psychiatric symptoms. TBI and psychiatric symptoms had interactive effects on cognition, particularly executive functioning. Group comparison analyses showed that men with both TBI and psychiatric symptoms demonstrated deficits primarily in executive functioning. Cognition was largely unaffected in men with either risk factor in isolation. Among late middle-aged men, the combination of even mild and very remote TBI with current elevated psychiatric symptoms is associated with deficits in executive function and related abilities. Future longitudinal studies should investigate how TBI and psychiatric factors interact to impact brain aging.

Supplemental material, QHR_appendix for Psychologists’ Perspectives on the implementation of Psychological Therapy for Psychosis in the Acute Psychiatric Inpatient Setting by Lisa Wood, Claire Williams, Jo Billings and Sonia Johnson in Qualitative Health Research

Table S1. Trial Registration Data. All details pertaining to the Australian New Zealand Clinical Trial Registry are provided in this file. (DOCX 23 kb)

As few studies have examined the relationship between the apolipoprotein E (APOE) gene and clinical outcomes after military-related traumatic brain injury (TBI), we aimed to determine whether the ε4 allele of the APOE gene influences neuropsychiatric symptoms in veterans with a history of mild-to-moderate TBI. Participants included 133 veterans (TBI = 79; military controls [MC] = 54) who underwent APOE genotyping and were divided into ε4+ (TBI = 18; MC = 15) and ε4- (TBI = 61; MC = 39) groups. All participants underwent evaluation of psychological distress using the Beck Depression Inventory-II, Beck Anxiety Inventory, and PTSD Checklist-Military Version. Two-way analyses of variance were conducted to examine the effect of group (TBI vs. MC) and APOE-ε4 status (ε4+ vs. ε4-) across symptom measures. There was a significant main effect of group across all symptom measures (TBI > MC; all p values

OBJECTIVES:The third edition of the California Verbal Learning Test (CVLT-3) includes a new index termed List A versus Novel/Unrelated recognition discriminability (RD) on the Yes/No Recognition trial. Whereas the Total RD index incorporates false positive (FP) errors associated with all distractors (including List B and semantically related items), the new List A versus Novel/Unrelated RD index incorporates only FP errors associated with novel, semantically unrelated distractors. Thus, in minimizing levels of source and semantic interference, the List A versus Novel/Unrelated RD index may yield purer assessments of yes/no recognition memory independent of vulnerability to source memory difficulties or semantic confusion, both of which are often seen in individuals with primarily frontal-system dysfunction (e.g., early Huntington's disease [HD]). METHODS:We compared the performance of individuals with Alzheimer's disease (AD) and HD in mild and moderate stages of dementia on CVLT-3 indices of Total RD and List A versus Novel/Unrelated RD. RESULTS:Although AD and HD subgroups exhibited deficits on both RD indices relative to healthy comparison groups, those with HD generally outperformed those with AD, and group differences were more robust on List A versus Novel/Unrelated RD than on Total RD. CONCLUSIONS:Our findings highlight the clinical utility of the new CVLT-3 List A versus Novel/Unrelated RD index, which (a) maximally assesses yes/no recognition memory independent of source and semantic interference; and (b) provides a greater differentiation between individuals whose memory disorder is primarily at the encoding/storage level (e.g., as in AD) versus at the retrieval level (e.g., as in early HD). (JINS, 2018, 24, 833-841).

ObjectiveOur objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.MethodsWe used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively.ResultsAt time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%).InterpretationAge-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Background/aimsMild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study.MethodsA total of 347 adults (ages 79-102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia.ResultsMCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria.ConclusionsOur findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals.

IntroductionWe examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up.MethodsFramingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified.ResultsBaseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up.DiscussionBaseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.