Publications by authors named "Ruben Smith"

107 Publications

Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease.

Brain 2021 Jul 14. Epub 2021 Jul 14.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden.

Although recent clinical trials targeting amyloid-β (Aβ) in Alzheimer's disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with Aβ metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to either Aβ or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 Aβ-negative cognitively unimpaired individuals, 71 Aβ-positive cognitively unimpaired individuals, 78 Aβ-positive cognitively impaired individuals, 63 Aβ-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal Aβ (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all Aβ-positive groups compared with subjects without Aβ pathology (p < 0.01). In addition, there were significant associations between plasma GFAP with higher Aβ-PET signal in all Aβ-positive groups, but also in cognitively normal individuals with normal Aβ values (p < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict Aβ-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for Aβ-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p < 0.05) and correlated with Aβ-PET only in Aβ-positive cognitively impaired individuals (p = 0.005). Finally, plasma GFAP was associated with both longitudinal Aβ-PET and cognitive decline, and mediated the effect of Aβ-PET on tau-PET burden, suggesting that astrocytosis secondary to Aβ aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain Aβ pathology but not tau aggregation, even in cognitively normal individuals with a normal Aβ status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to Aβ pathology.
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http://dx.doi.org/10.1093/brain/awab223DOI Listing
July 2021

Adverse Birth Outcomes Associated With Prepregnancy and Prenatal Electronic Cigarette Use.

Obstet Gynecol 2021 Jul;138(1):85-94

School of Public Health, Texas A&M University, College Station, Texas; the Fielding School of Public Health, University of California, Los Angeles, Los Angeles, and the School of Nursing and Health Professions, University of San Francisco, San Francisco, California; and the Division of Reproductive Health, the Office on Smoking and Health, and the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.

Objective: To evaluate the risk of adverse birth outcomes among adults who use electronic cigarettes (e-cigarettes) before and during pregnancy.

Methods: Data from the 2016-2018 PRAMS (Pregnancy Risk Assessment Monitoring System) were used to assess the association between e-cigarette use during the 3 months before and last 3 months of pregnancy among 79,176 individuals with a recent live birth and the following birth outcomes: preterm birth, small for gestational age, and low birth weight (LBW). Adjusted prevalence ratios were generated using average marginal predictions from multivariable logistic regression models. Models were stratified by prenatal combustible cigarette smoking and frequency of e-cigarette use (daily or less than daily use).

Results: In the 3 months before pregnancy, 2.7% (95% CI 2.6-2.9%) of respondents used e-cigarettes; 1.1% (95% CI 1.0-1.2%) used e-cigarettes during the last 3 months of pregnancy. Electronic cigarette use before pregnancy was not associated with adverse birth outcomes. Electronic cigarette use during pregnancy was associated with increased prevalence of LBW compared with nonuse (8.1% vs 6.1%; adjusted prevalence ratio 1.33; 95% CI 1.06-1.66). Among respondents who did not also smoke combustible cigarettes during pregnancy (n=72,256), e-cigarette use was associated with higher prevalence of LBW (10.6%; adjusted prevalence ratio 1.88; 95% CI 1.38-2.57) and preterm birth (12.4%; adjusted prevalence ratio 1.69; 95% CI 1.20-2.39). When further stratified by frequency of e-cigarette use, associations were seen only for daily users.

Conclusion: E-cigarette use during pregnancy, particularly when used daily by individuals who do not also smoke combustible cigarettes, is associated with adverse birth outcomes.
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http://dx.doi.org/10.1097/AOG.0000000000004432DOI Listing
July 2021

Tau PET correlates with different Alzheimer's disease-related features compared to CSF and plasma p-tau biomarkers.

EMBO Mol Med 2021 Aug 13;13(8):e14398. Epub 2021 Jul 13.

Clinical Memory Research Unit, Lund University, Lund, Sweden.

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([ F]RO948 in BioFINDER-2, [ F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.
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http://dx.doi.org/10.15252/emmm.202114398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350902PMC
August 2021

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison Against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging.

JAMA Neurol 2021 Aug;78(8):961-971

Clinical Memory Research Unit, Lund University, Malmö, Sweden.

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.

Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers.

Design, Setting, And Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ).

Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation.

Main Outcomes And Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations.

Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels.

Conclusions And Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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http://dx.doi.org/10.1001/jamaneurol.2021.1858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240013PMC
August 2021

Evaluation of Five Data-to-Action Workshops to Enhance Capacity for Tobacco Control.

Health Promot Pract 2021 Jun 22:15248399211019984. Epub 2021 Jun 22.

Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: Five data-to-action workshops were conducted during 2016-2019 with participants from 38 countries. The purpose of the workshops is to use data to inform and disseminate tobacco prevention and control strategies. We evaluated the workshops using the Kirkpatrick Model for evaluation of trainings.

Methods: We evaluated the data-to-action workshops in three topic areas: (1) if the workshop was clear, useful, engaging, and relevant to the participant's work, (2) self-reported knowledge and skills for tobacco control topics, and (3) intention to apply the knowledge learned. We used nonparametric tests (one-sided Wilcoxon signed-rank test) and conducted descriptive analysis to assess the difference between pre- and postworkshop scores in each topic area. Free text data from open-ended responses were analyzed in Excel using thematic content analysis.

Results: Participants reported the workshop had a clear purpose (93.6%, = 73), was well organized (94.9%, = 74), and relevant to their work (96.2%, = 76). There was a statistically significant increase in median learning scores across all three knowledge and five skills topic areas ( < 0.05); more than 95% of participants intended to apply the knowledge they obtained during the workshop and planned to perform new skills learned in the workshop.

Conclusions: Programs interested in replicating a similar successful model may incorporate a mix of modes of instruction and hands-on experiences, as well as focus on the selection of the right audience, for their workshops. These workshops pose an opportunity for countries to enhance use and dissemination of their tobacco control data.
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http://dx.doi.org/10.1177/15248399211019984DOI Listing
June 2021

Sex differences in off-target binding using tau positron emission tomography.

Neuroimage Clin 2021 29;31:102708. Epub 2021 May 29.

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden.

Purpose: Off-target binding in the skull and meninges is observed in some subjects undergoing tau positron emission tomography (PET) and could potentially differ between men and women. In this study we elucidate sex differences in tau off-target binding using three different tau PET tracers.

Methods: 541 cognitively unimpaired amyloid-β negative participants underwent tau PET using [F]flortaucipir (n = 165), [F]RO948 (n = 189) and [F]MK6240 (n = 187). Baseline SUVR-values were compared between females and males at the voxel level and using a region-of-interest (ROI) encompassing the skull/meninges. In addition, we assessed the cross-sectional relationship between baseline skull/meninges SUVR and age and assessed change in skull/meningeal SUVR values over time in a subsample with longitudinal data (n = 63).

Results: Voxel-wise analysis showed higher meningeal off-target binding in women compared to men across all three tracers. The SUVRs in the skull/meningeal ROI were highest using [F]RO948, followed by [F]MK6240 and [F]flortaucipir (p < 0.001). For all tracers, females showed higher skull/meningeal ROI retention (mean SUVR ± SD [F]flortaucipir: 0.82 ± 0.14; [F]RO948: 1.26 ± 0.30; [F]MK6240: 1.09 ± 0.19) compared to men ([F]flortaucipir: 0.70 ± 0.11; [F]RO948: 1.10 ± 0.24; [F]MK6240: 0.97 ± 0.17) (p < 0.001). For [F]flortaucipir and [F]RO948, off-target binding in the skull/meninges decreased with age.

Conclusion: There is an effect of sex on off-target retention in the meninges/skull across [F]flortaucipir, [F]RO948, and [F]MK6240 tau PET tracers.
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http://dx.doi.org/10.1016/j.nicl.2021.102708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182304PMC
September 2021

The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline.

Alzheimers Dement 2021 Jun 1. Epub 2021 Jun 1.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.

Introduction: The BIN1 rs744373 single nucleotide polymorphism (SNP) is a key genetic risk locus for Alzheimer's disease (AD) associated with tau pathology. Because tau typically accumulates in response to amyloid beta (Aβ), we tested whether BIN1 rs744373 accelerates Aβ-related tau accumulation.

Methods: We included two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 153; Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER], n = 63) with longitudinal F-Flortaucipir positron emission tomography (PET), Aβ biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of Aβ and whether faster BIN1 rs744373-associated tau-PET accumulation mediated cognitive decline.

Results: BIN1 rs744373 risk-allele carriers showed faster global tau-PET accumulation (ADNI/BioFINDER, P < .001/P < .001). We found significant Aβ by rs744373 interactions on global tau-PET change (ADNI: β/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: β/SE = -0.35/0.15, P = .021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher Aβ levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (β/SE = 0.20/0.07, P = .005).

Discussion: BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of Aβ.
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http://dx.doi.org/10.1002/alz.12371DOI Listing
June 2021

A multicenter comparison of [F]flortaucipir, [F]RO948, and [F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis.

Eur J Nucl Med Mol Imaging 2021 07 27;48(7):2295-2305. Epub 2021 May 27.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

Purpose: This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [F]flortaucipir, [F]RO948, and [F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer's disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases.

Methods: A total of 1755 participants underwent tau PET using either [F]flortaucipir (n = 975), [F]RO948 (n = 493), or [F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively.

Results: Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926-0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI.

Conclusion: The temporal meta-ROI can be used for differential diagnosis of dementia patients with [F]flortaucipir, [F]RO948, and [F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.
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http://dx.doi.org/10.1007/s00259-021-05401-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175317PMC
July 2021

Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau.

EMBO Mol Med 2021 Jun 5;13(6):e14022. Epub 2021 May 5.

Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.

Alzheimer's disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer's disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ("BioFINDER-2", N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
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http://dx.doi.org/10.15252/emmm.202114022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185545PMC
June 2021

Four distinct trajectories of tau deposition identified in Alzheimer's disease.

Nat Med 2021 05 29;27(5):871-881. Epub 2021 Apr 29.

Clinical Memory Research Unit, Lund University, Lund, Sweden.

Alzheimer's disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These 'subtypes' were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of 'typical AD' and a revisiting of tau pathological staging.
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http://dx.doi.org/10.1038/s41591-021-01309-6DOI Listing
May 2021

Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer's disease.

J Neurol Neurosurg Psychiatry 2021 Apr 13. Epub 2021 Apr 13.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

Objective: The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.

Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [F]flortaucipir or [F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).

Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05).

Conclusions: Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.
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http://dx.doi.org/10.1136/jnnp-2020-325497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292599PMC
April 2021

Early stages of tau pathology and its associations with functional connectivity, atrophy and memory.

Brain 2021 Mar 16. Epub 2021 Mar 16.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 223 62 Lund, Sweden.

In Alzheimer's disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 β-amyloid negative cognitively unimpaired, 81 β-amyloid positive cognitively unimpaired and 87 β-amyloid positive individuals with mild cognitive impairment, who each underwent [18]F-RO948 tau and [18]F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease-stage specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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http://dx.doi.org/10.1093/brain/awab114DOI Listing
March 2021

Persistent Racial/Ethnic Disparities in Supine Sleep Positioning among US Preterm Infants, 2000-2015.

J Pediatr 2021 06 4;233:51-57.e3. Epub 2021 Mar 4.

Department of Biostatistics, Colorado School of Public Health, Aurora, CO.

Objective: To assess trends in racial disparity in supine sleep positioning (SSP) across racial/ethnic groups of infants born early preterm (Early preterm; <34 weeks) and late preterm (Late preterm; 34-36 weeks) from 2000 to 2015.

Study Design: We analyzed Pregnancy Risk Assessment Monitoring System data (a population-based perinatal surveillance system) from 16 US states from 2000 to 2015 (Weighted N = 1 020 986). Marginal prevalence of SSP by year was estimated for infants who were early preterm and late preterm, adjusting for maternal and infant characteristics. After stratifying infants who were early preterm and late preterm, we compared the aOR of SSP trends across racial/ethnic groups by testing the time-race interaction.

Results: From 2000 to 2015, Non-Hispanic Black infants had lower odds of SSP compared with Non-Hispanic White infants for early preterm (aOR 0.61; 95% CI 0.47-0.78) and late preterm (aOR 0.44; 95% CI 0.34-0.56) groups. For Hispanic infants, there was no statistically significant difference for either preterm group when compared with Non-Hispanic White infants. aOR of SSP increased (on average) annually by 10.0%, 7.3%, and 7.7%, respectively, in Non-Hispanic White, Non-Hispanic Black, and Hispanic early preterm infants and by 5.8%, 5.9%, and 4.8% among Non-Hispanic White, Non-Hispanic Black, and Hispanic late preterm infants. However, there were no significant between-group differences in annual changes (Early preterm: P = .11; Late preterm: P = .25).

Conclusions: SSP increased for all racial/ethnic preterm groups from 2000 to 2015. However, the racial/ethnic disparity in SSP among early preterm and late preterm groups persists.
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http://dx.doi.org/10.1016/j.jpeds.2021.02.070DOI Listing
June 2021

Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.

Transl Psychiatry 2021 01 26;11(1):76. Epub 2021 Jan 26.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, SUS, Malmö, Sweden.

Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-β-positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([F]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau. Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau levels were associated with higher MBI-C scores (β = 0.010, SE = 0.003, p = 0.003 and β = 1.263, SE = 0.446, p = 0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (β = 0.009, p = 0.009) and CSF P-tau (β = 0.408, p = 0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.
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http://dx.doi.org/10.1038/s41398-021-01206-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838407PMC
January 2021

The accumulation rate of tau aggregates is higher in females and younger amyloid-positive subjects.

Brain 2020 12;143(12):3805-3815

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

The development of tau-PET allows paired helical filament tau pathology to be visualized in vivo. Increased knowledge about conditions affecting the rate of tau accumulation could guide the development of therapies halting the progression of Alzheimer's disease. However, the factors modifying the rate of tau accumulation over time in Alzheimer's disease are still largely unknown. Large-scale longitudinal cohort studies, adjusting for baseline tau load, are needed to establish such risk factors. In the present longitudinal study, 419 participants from four cohorts in the USA (Avid 05e, n = 157; Expedition-3, n = 82; ADNI, n = 123) and Sweden (BioFINDER, n = 57) were scanned repeatedly with tau-PET. The study participants were cognitively unimpaired (n = 153), or patients with mild cognitive impairment (n = 139) or Alzheimer's disease dementia (n = 127). Participants underwent two to four tau-PET (18F-flortaucipir) scans with a mean (± standard deviation) of 537 (±163) days between the first and last scan. The change in tau-PET signal was estimated in temporal meta- and neocortical regions of interest. Subject specific tau-PET slopes were predicted simultaneously by age, sex, amyloid status (determined by amyloid-β PET), APOE ε4 genotype, study cohort, diagnosis and baseline tau load. We found that accelerated increase in tau-PET signal was observed in amyloid-β-positive mild cognitive impairment (3.0 ± 5.3%) and Alzheimer's disease dementia (2.9 ± 5.7%), respectively, when compared to either amyloid-β-negative cognitively unimpaired (0.4 ± 2.7%), amyloid-β-negative mild cognitive impairment (-0.4 ± 2.3%) or amyloid-β-positive cognitively unimpaired (1.2 ± 2.8%). Tau-PET uptake was accelerated in females (temporal region of interest: t = 2.86, P = 0.005; neocortical region of interest: t = 2.90, P = 0.004), younger individuals (temporal region of interest: t = -2.49, P = 0.013), and individuals with higher baseline tau-PET signal (temporal region of interest: t = 3.83, P < 0.001; neocortical region of interest: t = 5.01, P < 0.001). Tau-PET slopes decreased with age in amyloid-β-positive subjects, but were stable by age in amyloid-β-negative subjects (age × amyloid-β status interaction: t = -2.39, P = 0.018). There were no effects of study cohort or APOE ε4 positivity. In a similar analysis on longitudinal amyloid-β-PET (in ADNI subjects only, n = 639), we found significant associations between the rate of amyloid-β accumulation and APOE ε4 positivity, older age and baseline amyloid-β positivity, but no effect of sex. In conclusion, in this longitudinal PET study comprising four cohorts, we found that the tau accumulation rate is greater in females and younger amyloid-β-positive individuals, while amyloid-β accumulation is greater in APOE ε4 carriers and older individuals. These findings are important considerations for the design of clinical trials, and might improve our understanding of factors associated with faster tau aggregation and spread.
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http://dx.doi.org/10.1093/brain/awaa327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805812PMC
December 2020

Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts.

Eur J Nucl Med Mol Imaging 2021 07 4;48(7):2259-2271. Epub 2021 Jan 4.

Memory and Aging Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94143, USA.

Purpose: To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer's Disease (AD) Research Framework derived from [F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181).

Methods: We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL).

Results: FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181.

Conclusion: The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.
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http://dx.doi.org/10.1007/s00259-020-05152-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178158PMC
July 2021

Opportunities to Address Men's Health During the Perinatal Period - Puerto Rico, 2017.

MMWR Morb Mortal Wkly Rep 2021 Jan 1;69(5152):1638-1641. Epub 2021 Jan 1.

Decreased use of health care services (1), increased exposure to occupational hazards, and higher rates of substance use (2) might contribute to men's poorer health outcomes when compared with such outcomes for women (3). During the transition to fatherhood, paternal health and involvement during pregnancy might have an impact on maternal and infant outcomes (4-6). To assess men's health-related behaviors and participation in fatherhood-related activities surrounding pregnancy, the Puerto Rico Department of Health and CDC analyzed data from the paternal survey of the Pregnancy Risk Assessment Monitoring System-Zika Postpartum Emergency Response (PRAMS-ZPER)* study. Fewer than one half (48.3%) of men attended a health care visit for themselves in the 12 months before their newborn's birth. However, most fathers attended one or more prenatal care visits (87.2%), were present at the birth (83.1%), and helped prepare for the newborn's arrival (e.g., by preparing the home [92.4%] or purchasing supplies [93.9%]). These findings suggest that opportunities are available for public health messaging directed toward fathers during the perinatal period to increase attention to their own health and health behaviors, and to emphasize the role they can play in supporting their families' overall health and well-being.
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http://dx.doi.org/10.15585/mmwr.mm695152a2DOI Listing
January 2021

Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease.

Brain 2021 02;144(1):310-324

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
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http://dx.doi.org/10.1093/brain/awaa395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210638PMC
February 2021

Effects of e-cigarette use on cigarette smoking among U.S. youth, 2004-2018.

Prev Med 2021 01 30;142:106316. Epub 2020 Nov 30.

Center for Tobacco Control Research and Education, University of California, San Francisco, United States; Department of Medicine, University of California, San Francisco, United States.

Objective: To determine if the declining trend in U.S. youth cigarette smoking changed after e-cigarettes were introduced, and if youth e-cigarette users would have been likely to smoke cigarettes based on psychosocial and demographic predictors of smoking.

Methods: An interrupted time series analysis was used for cross-sectional data from the 2004 to 2018 National Youth Tobacco Surveys (NYTS) to assess changes in cigarette and e-cigarette use over time. A multivariable logistic regression model used 2004-2009 NYTS data on psychosocial risk factors to predict individual-level cigarette smoking risk from 2011 to 2018. Model-predicted and actual cigarette smoking behavior were compared.

Results: The decline in current cigarette smoking slowed in 2014 (-0.75 [95% CI: -0.81, -0.68] to -0.26 [95% CI: -0.40, -0.12] percentage points per year). The decline in ever cigarette smoking accelerated after 2012 (-1.45 [95% CI: -1.59, -1.31] to -1.71 [95% CI: -1.75, -1.66]). Ever and current combined cigarette and/or e-cigarette use declined during 2011-2013 and increased during 2013-2014 with no significant change during 2014-2018 for either variable. The psychosocial model estimated that 69.0% of current cigarette smokers and 9.3% of current e-cigarette users (who did not smoke cigarettes) would smoke cigarettes in 2018.

Conclusions: The introduction of e-cigarettes was followed by a slowing decline in current cigarette smoking, a stall in combined cigarette and e-cigarette use, and an accelerated decline in ever cigarette smoking. Traditional psychosocial risk factors for cigarette smoking suggest that e-cigarette users do not fit the traditional risk profile of cigarette smokers.
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http://dx.doi.org/10.1016/j.ypmed.2020.106316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796895PMC
January 2021

Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease.

Sci Adv 2020 Nov 27;6(48). Epub 2020 Nov 27.

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.

In Alzheimer's disease (AD), the Braak staging scheme suggests a stereotypical tau spreading pattern that does, however, not capture interindividual variability in tau deposition. This complicates the prediction of tau spreading, which may become critical for defining individualized tau-PET readouts in clinical trials. Since tau is assumed to spread throughout connected regions, we used functional connectivity to improve tau spreading predictions over Braak staging methods. We included two samples with longitudinal tau-PET from controls and AD patients. Cross-sectionally, we found connectivity of tau epicenters (i.e., regions with earliest tau) to predict estimated tau spreading sequences. Longitudinally, we found tau accumulation rates to correlate with connectivity strength to patient-specific tau epicenters. A connectivity-based, patient-centered tau spreading model improved the assessment of tau accumulation rates compared to Braak stage-specific readouts and reduced sample sizes by ~40% in simulated tau-targeting interventions. Thus, connectivity-based tau spreading models may show utility in clinical trials.
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http://dx.doi.org/10.1126/sciadv.abd1327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695466PMC
November 2020

The impact of demographic, clinical, genetic, and imaging variables on tau PET status.

Eur J Nucl Med Mol Imaging 2021 07 19;48(7):2245-2258. Epub 2020 Nov 19.

Clinical Memory Research Unit, Lund University, Lund, Sweden.

Purpose: A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are tau PET-negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET-positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status.

Methods: We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [F]flortaucipir (n = 1944) or [F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model.

Results: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan.

Conclusion: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.
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http://dx.doi.org/10.1007/s00259-020-05099-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131404PMC
July 2021

Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease.

JAMA Neurol 2021 Feb;78(2):149-156

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sölvegatan, Sweden.

Importance: There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes.

Objective: To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology.

Design, Setting, And Participants: This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans.

Main Outcomes And Measures: Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures.

Results: Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02).

Conclusions And Relevance: In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.
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http://dx.doi.org/10.1001/jamaneurol.2020.4201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653537PMC
February 2021

Preventing Vector-Borne Transmission of Zika Virus Infection During Pregnancy, Puerto Rico, USA, 2016-2017.

Emerg Infect Dis 2020 11;26(11):2717-2720

We examined pregnant women's use of personal protective measures to prevent mosquito bites during the 2016-2017 Zika outbreak in Puerto Rico. Healthcare provider counseling on recommended measures was associated with increased use of insect repellent among pregnant women but not with wearing protective clothing.
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http://dx.doi.org/10.3201/eid2611.201614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588518PMC
November 2020

Derivation and utility of an Aβ-PET pathology accumulation index to estimate Aβ load.

Neurology 2020 11 19;95(21):e2834-e2844. Epub 2020 Oct 19.

From the Clinical Memory Research Unit (A.L., J.L., R.O., S.P., S.J., E.S., O.S., R.S., O.H.), Department of Clinical Sciences, Lund University, Malmö; Department of Surgical Sciences, Nuclear Medicine and PET (J.L.), Uppsala University; Hermes Medical Solutions (J.L.), Stockholm, Sweden; GE Healthcare Life Sciences (C.J.B., M.B., G.F.), Amersham, UK; VU University Medical Center (R.O.), Neuroscience Campus Amsterdam, the Netherlands; Department of Neurology (S.P., R.S.) and Memory Clinic (E.S., O.H.), Skåne University Hospital, Lund, Sweden; Department of Imaging and Pathology (D.R.T.), Laboratory of Neuropathology, and Leuven Brain Institute (D.R.T.), Campus Gasthuisberg; and Department of Pathology (D.R.T.), UZ-Leuven, Belgium.

Objective: To evaluate a novel β-amyloid (Aβ)-PET-based quantitative measure (Aβ accumulation index [Aβ index]), including the assessment of its ability to discriminate between participants based on Aβ status using visual read, CSF Aβ/Aβ, and post-mortem neuritic plaque burden as standards of truth.

Methods: One thousand one hundred twenty-one participants (with and without cognitive impairment) were scanned with Aβ-PET: Swedish BioFINDER, n = 392, [F]flutemetamol; Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 692, [F]florbetapir; and a phase 3 end-of-life study, n = 100, [F]flutemetamol. The relationships between Aβ index and standardized uptake values ratios (SUVR) from Aβ-PET were assessed. The diagnostic performances of Aβ index and SUVR were compared with visual reads, CSF Aβ/Aβ, and Aβ histopathology used as reference standards.

Results: Strong associations were observed between Aβ index and SUVR ( : BioFINDER 0.951, ADNI 0.943, end-of-life, 0.916). Both measures performed equally well in differentiating Aβ-positive from Aβ-negative participants, with areas under the curve (AUCs) of 0.979 to 0.991 to detect abnormal visual reads, AUCs of 0.961 to 0.966 to detect abnormal CSF Aβ/Aβ, and AUCs of 0.820 to 0.823 to detect abnormal Aβ histopathology. Both measures also showed a similar distribution across postmortem-based Aβ phases (based on anti-Aβ 4G8 antibodies). Compared to models using visual read alone, the addition of the Aβ index resulted in a significant increase in AUC and a decrease in Akaike information criterion to detect abnormal Aβ histopathology.

Conclusion: The proposed Aβ index showed a tight association to SUVR and carries an advantage over the latter in that it does not require the definition of regions of interest or the use of MRI. Aβ index may thus prove simpler to implement in clinical settings and may also facilitate the comparison of findings using different Aβ-PET tracers.

Classification Of Evidence: This study provides Class III evidence that the Aβ accumulation index accurately differentiates Aβ-positive from Aβ-negative participants compared to Aβ-PET visual reads, CSF Aβ/Aβ, and Aβ histopathology.
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http://dx.doi.org/10.1212/WNL.0000000000011031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734735PMC
November 2020

Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.

JAMA 2020 08;324(8):772-781

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).

Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.

Design, Setting, And Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).

Exposures: Plasma P-tau217.

Main Outcomes And Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]).

Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).

Conclusions And Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.
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http://dx.doi.org/10.1001/jama.2020.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388060PMC
August 2020

Compensating for choroid plexus based off-target signal in the hippocampus using F-flortaucipir PET.

Neuroimage 2020 11 22;221:117193. Epub 2020 Jul 22.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden; Department of Neurology, Skåne University Hospital, SE-20502 Malmö, Lund, Sweden. Electronic address:

Purpose: The hippocampus is affected by tau pathology early in Alzheimer's disease (AD) development. Accurate quantification of hippocampal tau signal using the tau-PET tracer F-flortaucipir is complicated, however, by off-target binding in the adjacent choroid plexus. We here present a new method for compensating for this off-target choroid plexus signal.

Methods: As off-target binding in the choroid plexus is known to be higher using F-flortaucipir compared to F-RO948, we created a binary hippocampal mask in template space where F-flortaucipir signal was higher than F-RO948, using data from 30 patients that underwent both F-flortaucipir and F-RO948 PET. This mask, presumably representing hippocampal voxels affected by off-target binding from the choroid plexus, was then converted to native space and applied as an exclusion mask to 145 patients across the AD-spectrum scanned with F-flortaucipir. As an alternative approach exclusion masks were generated by expanding the choroid plexus ROI in native space. Results were analysed both without and with partial volume error correction (non-PVEc/PVEc).

Results: Unmasked hippocampal standardized uptake value ratios (SUVR) were significantly correlated to choroid plexus SUVRs using both non-PVEc (p < 0.001, r = 0.28) and PVEc data (p < 0.05, r = 0.18). After applying the mask, however, these correlations disappeared. The diagnostic accuracy in separating cognitively impaired (CI) from cognitively unimpaired (CU) subjects improved after masking, from an AUC of 0.792 (95% C.I.,0.715-0.869) to 0.837 (95% C.I.,0.768-0.906) for non-PVEc data (p < 0.001), and from 0.798 (95% C.I.,0.722-0.873) to 0.834 (95% C.I.,0.766-0.903) for PVEc data (p < 0.001). The correlations to memory improved significantly for MMSE for unmasked vs. masked data both without (r = -0.440 vs. r = -0.499, p < 0.001) and with (r = -0.454 vs. r = -0.503, p < 0.001) PVEc. Similar results were found using the ADAS-Cog Delayed Word Recall test.

Conclusion: Choroid plexus off-target binding interferes with the estimation of true hippocampal retention using F-flortaucipir PET. Using a mask to correct for this off-target signal, we improved the diagnostic accuracy of F-flortaucipir in the hippocampus and the correlation between F-flortaucipir hippocampal SUVR and cognitive measures.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117193DOI Listing
November 2020

Association between Neonatal Intensive Care Unit Admission and Supine Sleep Positioning, Breastfeeding, and Postnatal Smoking among Mothers of Late Preterm Infants.

J Pediatr 2020 12 19;227:114-120.e1. Epub 2020 Jul 19.

Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.

Objective: To evaluate the association between neonatal intensive care unit (NICU) admission and breastfeeding practices, infant supine sleep positioning, and postnatal smoking among mothers of late preterm infants.

Study Design: Data from 36 states using the 2000-2013 Pregnancy Risk Assessment Monitoring System were analyzed. χ tests and 95% CI assessed infant and maternal characteristics and recommended care practices for late preterm infants based on NICU admission after birth. Adjusted prevalence ratios (APR) for breastfeeding initiation and continuation at 10 weeks, supine sleep position, and postnatal smoking were estimated using multivariable logistic regression models, controlling for infant and maternal characteristics. Analyses were weighted and SEs accounted for the complex survey design.

Results: Our sample included 62 494 late preterm infants, representing a weighted population of 1 441 451 late preterm infants. In the adjusted analysis, mothers of late preterm infants admitted to a NICU were more likely to initiate breastfeeding (APR 1.07; 95% CI 1.05-1.09) and place their infants in supine sleep position (1.04; 95% CI 1.01-1.06) than mothers of late preterm infants not admitted to a NICU. There was no significant difference between groups for breastfeeding continuation or postnatal smoking.

Conclusions: Mothers of late preterm infants admitted to a NICU were more likely to initiate breastfeeding and practice supine sleep position than mothers of late preterm infants not admitted to a NICU. Future work should seek to identify the drivers of these differences to develop effective strategies to engage mothers in these health promoting infant care practices.
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http://dx.doi.org/10.1016/j.jpeds.2020.07.053DOI Listing
December 2020

No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington's disease.

Acta Neuropathol Commun 2020 06 3;8(1):77. Epub 2020 Jun 3.

Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, 110819, Shenyang, P. R. China.

Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. We studied the gene expression levels and patterns of a number of proteins forming the cytoskeletal matrix of the presynaptic active zones in HD transgenic mice (R6/1), in hippocampal neuronal cultures overexpressing mutant huntingtin and in postmortem brain tissues of HD patients. To investigate the interactions between huntingtin and active proteins, we performed confocal microscopic imaging and immunoprecipitation in mouse and HEK 293 cell line models. The mRNA and protein levels of Bassoon were reduced in mouse and cell culture models of HD and in brain tissues of patients with HD. Moreover, a striking re-distribution of a complex of proteins including Bassoon, Piccolo and Munc 13-1 from the cytoplasm and synapses into intranuclear huntingtin aggregates with loss of active zone proteins and dendritic spines. This re-localization was age-dependent and coincided with the formation of huntingtin aggregates. Using co-immunoprecipitation, we demonstrated that huntingtin interacts with Bassoon, and that this interaction is likely mediated by a third linking protein. Three structural proteins involved in neurotransmitter release in the presynaptic active zones of neurons are altered in expression and that the proteins are redistributed from their normal functional site into mutant huntingtin aggregates.
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http://dx.doi.org/10.1186/s40478-020-00949-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268643PMC
June 2020

Spread of pathological tau proteins through communicating neurons in human Alzheimer's disease.

Nat Commun 2020 05 26;11(1):2612. Epub 2020 May 26.

Clinical Memory Research Unit, Lund University, Lund, Sweden.

Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.
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http://dx.doi.org/10.1038/s41467-020-15701-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251068PMC
May 2020
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