Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults.

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-ß (Aß) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aß deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aß-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aß-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aß pathology.

White Noise-Is Anxiety in Late-Life Associated With White Matter Hyperintensity Burden?

OBJECTIVE: We investigated the relationship between anxiety phenotypes (global anxiety, worry, and rumination) and white matter hyperintensities (WMH), with special consideration for the roles of age and executive function (EF). Our hypotheses were 1) anxiety phenotypes would be associated with WMH and 2) EF would moderate this relationship. DESIGN: Cross-sectional. SETTING: Participants were recruited from the local community (Pittsburgh, PA). PARTICIPANTS: We recruited 110 older adults (age ≥ 50) with varying worry severity and clinical comorbidity. INTERVENTIONS: Not applicable. MEASUREMENTS: Demographics (age, sex, race, education), clinical measures (cumulative illness burden, global anxiety, worry, and rumination), EF, and WMH quantified with magnetic resonance imaging. RESULTS: Lower global anxiety and worry severity were significantly correlated with higher WMH volume, though the global anxiety relationship was not significant after controlling for age. Rumination as not associated with WMH burden. EF was not correlated with either global anxiety, worry, rumination, or WMH. However, in those with advanced age and/or greater WMH burden, there was an association between worry and EF as well as EF and WMH. CONCLUSION: Longitudinal studies are needed in order to clarify the complex interactions between anxiety phenotypes, WMH, and EF.

Characterizing the emergence of amyloid and tau burden in Down syndrome.

INTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aß) trajectories were modeled to provide individual-level estimates of Aß-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0-2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. HIGHLIGHTS: Longitudinal amyloid trajectories reveal rapid Aß accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5-5 years after reaching A.

Astrocyte biomarker signatures of amyloid-ß and tau pathologies in Alzheimer's disease.

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-ß (Aß) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aß ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aß-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aß-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aß and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aß and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

In Pre-Clinical AD Small Vessel Disease is Associated With Altered Hippocampal Connectivity and Atrophy.

OBJECTIVE: Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aß) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume. METHODS: This study included 61 cognitively normal older adults (age range: 65-93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aß, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity. RESULTS: We found that, in WMH (+) older adults greater Aß burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aß burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy. CONCLUSION: These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aß positivity to neurodegeneration, and subsequent AD.

Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals.

INTRODUCTION: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-ß (Aß) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aß and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODS: We assessed 138 CU and 87 CI with available plasma p-tau231, 217+ , and 181, Aß42/40, GFAP and Aß- and tau-PET. RESULTS: In CU, only plasma p-tau231 and p-tau217+ significantly improved the performance of the demographics in detecting Aß-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217+ and GFAP significantly contributed to demographics to identify both Aß-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity. DISCUSSION: Our results support plasma p-tau231 and p-tau217+ as state markers of early Aß deposition, but in later disease stages they inform on tau tangle accumulation. HIGHLIGHTS: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex). Plasma p-tau231 and p-tau217+ contribute to demographic information to identify brain Aß pathology in preclinical AD. In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217+ and GFAP inform on both Aß deposition and tau pathology.

Blood-brain barrier integrity impacts the use of plasma amyloid-ß as a proxy of brain amyloid-ß pathology.

INTRODUCTION: Amyloid-ß (Aß) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers. METHODS: We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography Aß, p-tau, and albumin measures. RESULTS: Plasma Aß42/40 better identified CSF Aß42/40 and Aß-PET positivity in individuals with high BBB permeability. An interaction between plasma Aß42/40 and BBB permeability on CSF Aß42/40 was observed. Voxel-wise models estimated that the association of positron emission tomography (PET), with plasma Aß was most affected by BBB permeability in AD-related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p-tau levels. DISCUSSION: These findings suggest that BBB integrity may influence the performance of plasma Aß, but not p-tau, biomarkers in research and clinical settings. HIGHLIGHTS: BBB permeability affects the association between brain and plasma Aß levels. BBB integrity does not affect the association between brain and plasma p-tau levels. Plasma Aß was most affected by BBB permeability in AD-related brain regions. BBB permeability increases with age but not according to cognitive status.

Longitudinal 18F-MK-6240 tau tangles accumulation follows Braak stages.

Tracking longitudinal tau tangles accumulation across the Alzheimer's disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-ß-negative, 22 cognitively unimpaired elderly amyloid-ß-positive, 21 mild cognitive impairment amyloid-ß-positive and 17 Alzheimer's disease dementia amyloid-ß-positive individuals) with baseline amyloid-ß 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90-110 min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer's disease dementia who died after the PET scans. We found that the cognitively unimpaired amyloid-ß-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-ß-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer's dementia amyloid-ß-positive exhibited tau accumulation in Braak regions III-VI but not I-II. Cognitively impaired amyloid-ß-positive individuals that were Braak II-IV at baseline displayed a 4.6-7.5% annual increase in tau accumulation in the Braak III-IV regions, whereas those who were cognitively impaired amyloid-ß-positive Braak V-VI at baseline showed an 8.3-10.7% annual increase in the Braak regions V-VI. Neuropathological assessments confirmed PET-based Braak stages V-VI in the two brain donors. Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer's disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual's baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer's disease.

PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimer's disease progression in Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aß) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aß throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aß to better characterize the natural history of Aß accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. METHODS: Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aß burden was quantified using the amyloid load metric (AßL). Modeled PiB images were generated from the longitudinal AßL data to visualize which regions are most susceptible to Aß accumulation in DS. AßL change was evaluated across Aß(-), Aß-converter, and Aß(+) groups to assess longitudinal Aß trajectories during different stages of AD-pathology progression. AßL change values were used to identify Aß-accumulators within the Aß(-) group prior to reaching the Aß(+) threshold (previously reported as 20 AßL) which would have resulted in an Aß-converter classification. With knowledge of trajectories of Aß(-) accumulators, a new cutoff of Aß(+) was derived to better identify subthreshold Aß accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aß change with 80% power (alpha 0.01) were determined for different groups of Aß-status. RESULTS: Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aß accumulation in DS. The Aß(-) group had a mean AßL change of 0.38 (0.58) AßL/year, while the Aß-converter and Aß(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AßL/year, respectively. Within the Aß(-) group, Aß-accumulators showed no significant difference in AßL change values when compared to Aß-converter and Aß(+) groups. An Aß(+) cutoff for subthreshold Aß accumulation was derived as 13.3 AßL. The estimated sample size necessary to detect a 25% reduction in Aß was 79 for Aß(-) accumulators and 59 for the Aß-converter/Aß(+) group in DS. CONCLUSION: Longitudinal AßL changes were capable of distinguishing Aß accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aß accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aß deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.

A multi-scanner neuroimaging data harmonization using RAVEL and ComBat.

Modern neuroimaging studies frequently combine data collected from multiple scanners and experimental conditions. Such data often contain substantial technical variability associated with image intensity scale (image intensity scales are not the same in different images) and scanner effects (images obtained from different scanners contain substantial technical biases). Here we evaluate and compare results of data analysis methods without any data transformation (RAW), with intensity normalization using RAVEL, with regional harmonization methods using ComBat, and a combination of RAVEL and ComBat. Methods are evaluated on a unique sample of 16 study participants who were scanned on both 1.5T and 3T scanners a few months apart. Neuroradiological evaluation was conducted for 7 different regions of interest (ROI's) pertinent to Alzheimer's disease (AD). Cortical measures and results indicate that: (1) RAVEL substantially improved the reproducibility of image intensities; (2) ComBat is preferred over RAVEL and the RAVEL-ComBat combination in terms of regional level harmonization due to more consistent harmonization across subjects and image-derived measures; (3) RAVEL and ComBat substantially reduced bias compared to analysis of RAW images, but RAVEL also resulted in larger variance; and (4) the larger root mean square deviation (RMSD) of RAVEL compared to ComBat is due mainly to its larger variance.

Relationships Between Executive Control Circuit Activity, Amyloid Burden, and Education in Cognitively Healthy Older Adults.

INTRODUCTION: In cognitively healthy older adults, amyloid-beta (Aß) burden is associated with greater activity on task-based functional magnetic resonance imaging. Higher levels of functional activation are associated with other factors along with amyloid and the authors investigated these relationships as well as how they relate to Aß in cognitively healthy older adults. METHODS: The authors recruited cognitive healthy older adults (N = 50) from the Pittsburgh community that underwent extensive cognitive batteries, activation during a working memory (digit symbol substitution task, DSST), positron emission tomography scan for Pittsburgh Compound B (PiB, measuring amyloid), and other demographic measures. The authors tested the association between DSST activation and global PiB, neurocognitive batteries, and education. RESULTS: The authors found that the DSST robustly activated expected structures involved in working memory. The authors found that greater global Aß deposition was associated with greater DSST activation in the right calcarine, precuneus, middle temporal as well as the left insula and inferior frontal gyrus. The authors also found that greater education was associated with lower DSST activation - however this was not significant after adjusting for Aß. DISCUSSION: Greater amyloid was associated with greater activation, which may represent compensatory activation. Greater education was associated with lower activation, which may represent more efficient activation (i.e., less activation for the same task). After adjusting for amyloid, education was not significantly associated with activation suggesting that during the preclinical stage amyloid is the primary determinant of activation. Further, activation was not associated with cognitive function. Compensatory activation in the preclinical stage may help maintain cognitive function.

Adenosine Administration With a Stopcock Technique Delivers Lower-Than-Intended Drug Doses.

STUDY OBJECTIVE: Adenosine administration with a stopcock is the recommended treatment for pediatric patients with acute supraventricular tachycardia. Recent reports suggest that many infants do not respond to the first dose of adenosine administered. Our aim is to determine whether administration of adenosine with a stopcock delivers lower-than-expected drug doses in patients weighing less than 10 kg, corresponding to weights of infants. METHODS: We developed an in vitro model of adenosine delivery. Doses of adenosine corresponding to weights 2 to 25 kg were calculated, using a dose of 0.1 mg/kg, and administered through one port of a stopcock. Distilled water was administered through the second port. The adenosine concentration of the output was measured with mass spectrometry and results were confirmed with spectrophotometry of Evans blue. RESULTS: The mean doses of adenosine delivered through the stopcock increased as weight increased. The mean dose of adenosine delivered was 0.08 mg/kg for weights 2 to 9 kg and 0.1 mg/kg for weights 10 to 25 kg (95% confidence interval for difference of means -0.03 to -0.009). The median dose of adenosine delivered was 0.07 mg/kg (interquartile range [IQR] 0.06 to 0.07 mg/kg), 0.09 mg/kg (IQR 0.08 to 0.09 mg/kg), and 0.1 mg/kg (IQR 0.09 to 0.1 mg/kg) for weights 2 to 5, 6 to 9, and 10 to 25 kg, respectively (rank difference=100; P<.05 for 2 to 5 kg versus 10 to 25 kg). Similar results were obtained with spectrophotometry. CONCLUSION: Administration of adenosine through a stopcock delivers doses lower than intended in patients weighing less than 10 kg, which may account for the decreased response of infants to the first dose of adenosine.

Acute Management of Refractory and Unstable Pediatric Supraventricular Tachycardia.

OBJECTIVE: To characterize the management of acute pediatric supraventricular tachycardia (SVT), placing special emphasis on infants, patients refractory to adenosine (refractory SVT), and patients with hypotension, poor perfusion, or altered mental status (unstable SVT). STUDY DESIGN: Retrospective cohort study of patients 0-18 years of age without congenital heart disease who presented to our pediatric hospital from January 2003 to December 2012 for the treatment of acute SVT. Multiple logistic regression was applied to identify whether age was a risk factor for different SVT therapies. Model fit and residuals also were examined. RESULTS: We identified 179 episodes for SVT. First dose of adenosine was effective in 72 (56%) episodes, and a second dose was effective in 27 of 54 (50%) episodes, leaving 27 (15%) episodes with refractory SVT. The response to the first dose of adenosine increased proportionally with age (OR 1.13, 95% CI 1.05-1.2). Only 1 of 17 episodes in infants responded to the first dose of adenosine. Refractory SVT was more frequent in infants vs older children (χ2 = 5.9 [1 df], P = .01). Unstable SVT was present in 13 episodes and was treated with adenosine and antiarrhythmics. Synchronized cardioversion was performed on 3 patients, 2 patients with unstable SVT, and 1 with refractory SVT. CONCLUSION: In children with SVT, young age is associated with decreased response to the first dose of adenosine and increased odds of adenosine-refractory SVT. In the treatment of unstable SVT, medical management with various antiarrhythmics before cardioversion may have a role in a subset of patients. Synchronized cardioversion rarely is performed for acute SVT.

[18 F]Nifene test-retest reproducibility in first-in-human imaging of α4ß2* nicotinic acetylcholine receptors.

The aim of this study was to examine the suitability of [18 F]nifene, a novel α4ß2* nicotinic acetylcholine receptor (nAChR) radiotracer, for in vivo brain imaging in a first-in-human study. METHODS: Eight healthy subjects (4 M,4 F;21-69,44 ± 21 yrs) underwent a [18 F]nifene positron emission tomography scan (200 ± 3.7 MBq), and seven underwent a second scan within 58 ± 31 days. Regional estimates of DVR were measured using the multilinear reference tissue model (MRTM2) with the corpus callosum as reference region. DVR reproducibility was evaluated with test-retest variability (TRV) and intraclass correlation coefficient (ICC). RESULTS: The DVR ranged from 1.3 to 2.5 across brain regions with a TRV of 0-7%, and did not demonstrate a systematic difference between test and retest. The ICCs ranged from 0.2 to 0.9. DVR estimates were stable after 40 min. CONCLUSION: The binding profile and tracer kinetics of [18 F]nifene make it a promising α4ß2* nAChR radiotracer for scientific research in humans, with reliable DVR test-retest reproducibility.

Serotonin transporter genotype affects serotonin 5-HT1A binding in primates.

Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding using in vivo imaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor binding at the 5-HT(1A) receptor site has been reported in humans, suggesting the 5-HTTLPR polymorphism may play a role in serotonin (5-HT) function. Rhesus monkeys possess a 5-HTTLPR length polymorphism similar to humans and serve as an excellent model for studying the effects of this orthologous genetic variation on behaviors and neurochemical functions related to the 5-HT system. In this study, PET imaging of [(18)F]mefway was performed on 58 rhesus monkeys (33 l/l, 25 s-carriers) to examine the relation between 5-HT(1A) receptor-specific binding and 5-HTTLPR genotypes. Significantly lower 5-HT(1A) binding was found in s-carrier subjects throughout both cortical brain regions and the raphe nuclei. These results demonstrate that the underlying 5-HT neurochemical system is influenced by this functional polymorphism and illustrate the strong potential for extending the nonhuman primate model into investigating the role of this genetic variant on behavior and gene-environment interactions.

Breathing-based meditation decreases posttraumatic stress disorder symptoms in U.S. military veterans: a randomized controlled longitudinal study.

Given the limited success of conventional treatments for veterans with posttraumatic stress disorder (PTSD), investigations of alternative approaches are warranted. We examined the effects of a breathing-based meditation intervention, Sudarshan Kriya yoga, on PTSD outcome variables in U.S. male veterans of the Iraq or Afghanistan war. We randomly assigned 21 veterans to an active (n = 11) or waitlist control (n = 10) group. Laboratory measures of eye-blink startle and respiration rate were obtained before and after the intervention, as were self-report symptom measures; the latter were also obtained 1 month and 1 year later. The active group showed reductions in PTSD scores, d = 1.16, 95% CI [0.20, 2.04], anxiety symptoms, and respiration rate, but the control group did not. Reductions in startle correlated with reductions in hyperarousal symptoms immediately postintervention (r = .93, p < .001) and at 1-year follow-up (r = .77, p = .025). This longitudinal intervention study suggests there may be clinical utility for Sudarshan Kriya yoga for PTSD.

Hippocampal subfield volume in older adults with and without mild cognitive impairment: Effects of worry and cognitive reappraisal.

Studies have confirmed that anxiety, especially worry and rumination, are associated with increased risk for cognitive decline, including Alzheimer's disease and related dementias (ADRD). Hippocampal atrophy is a hallmark of ADRD. We investigated the association between hippocampus and its subfield volumes and late-life global anxiety, worry, and rumination, and emotion regulation strategies. We recruited 110 participants with varying worry severity who underwent magnetic resonance imaging and clinical interviews. We conducted cross-sectional regression analysis between each subfield and anxiety, worry, rumination, reappraisal, and suppression while adjusting for age, sex, race, education, cumulative illness burden, stress, neuroticism, and intracranial volume. We imputed missing data and corrected for multiple comparisons across regions. Greater worry was associated with smaller subiculum volume, whereas greater use of reappraisal was associated with larger subiculum and CA1 volume. Greater worry may be detrimental to the hippocampus and to subfields involved in early ADRD pathology. Use of reappraisal appears protective of hippocampal structure. Worry and reappraisal may be modifiable targets for ADRD prevention.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting.

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aß]40, Aß42, Aß42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies.

5-HT1A sex based differences in Bmax, in vivo KD, and BPND in the nonhuman primate.

UNLABELLED: Serotonin (5-HT) dysfunction has been implicated in neuropsychiatric illnesses and may play a pivotal role in the differential prevalence of depression between the sexes. Previous PET studies have revealed sex-based differences in 5-HT1A binding potential (BPND). The binding potential is a function of the radioligand-receptor affinity (1/KDapp), and receptor density (Bmax). In this work, we use a multiple-injection (MI) PET protocol and the 5-HT1A receptor antagonist, [(18)F]mefway, to compare sex-based differences of in vivo affinity, Bmax, and BPND in rhesus monkeys. METHODS: PET [(18)F]mefway studies were performed on 17 (6m, 11f) rhesus monkeys using a 3-injection protocol that included partial saturation injections of mefway. Compartmental modeling was performed using a model to account for non-tracer doses of mefway for the estimation of KDapp and Bmax. BPND estimates were also acquired from the first injection (high specific activity [(18)F]mefway, 90-minute duration) for comparison using the cerebellum (CB) as a reference region. Regions of interest were selected in 5-HT1A binding regions of the hippocampus (Hp), dorsal anterior cingulate cortex (dACC), amygdala (Am), and raphe nuclei (RN). RESULTS: Female subjects displayed significantly (*p<0.05) lower KDapp in the Hp (-32%), Am (-38%), and RN (-37%). Only the Hp displayed significant differences in Bmax with females having a Bmax of -29% compared to males. Male subjects demonstrated significantly lower BPND measurements in the Am (14%) and RN (29%). CONCLUSION: These results suggest that the higher BPND values found in females are the result of lower [(18)F]mefway KDapp. Although a more experimentally complex measurement, separate assay of KDapp and Bmax provides a more sensitive measure than BPND to identify the underlying differences between females and males in 5-HT1A function.