bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of different partial volume correction methods for longitudinal tau PET imaging
Authors: Silva‐Rodríguez Jesús , Moscoso Alexis , Cortés Julia , Aguiar Pablo 
Published: December 2020

AbstractBackgroundPrevious studies have evaluated whole‐brain and region‐specific accumulation rates of tau using longitudinal 18F‐Flortaucipir (18F‐FTP) PET. 18F‐FTP is well known for presenting significant off‐target binding in regions such as the striatum, the white matter and the choroid plexus. However, the use of partial volume correction methods that do not model this off‐target binding is still common in the community, which might hamper optimal longitudinal 18F‐FTP quantification. The aim of the present study is to study the performance of different PVC methods for longitudinal 18F‐FTP PET studies.MethodSerial 18F‐FTP PET and T1 images from 101 cognitively unimpaired (CU) and 77 cognitively impaired (CI) subjects were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). T1 images were segmented using the tools provided by the Computational Anatomical Toolbox (CAT12). Tissue probability maps were binarized to generate GM, WM and CSF masks. The GM was multiplied by the Hammersmith atlas to generate a GM patient‐specific atlas. The CSF was segmented in three different levels based on the maximum uptake in the PET image, so that the choroid plexus was segmented in high/low uptake regions. A traditional region deconvolution PVC, the reblurred Van‐Cittert (RVC) and 2 voxel‐based PVCs, the Region‐based voxel‐wise correction (RBV) and the iterative Yang (iY) were studied (Figure 1). Region‐specific tau accumulation rates were calculated for a medial temporal lobe region of interest, as well as for Braak areas generated by region aggregation. Longitudinal rates of change were estimated for amyloid‐β‐positive CU and CI subjects using linear mixed models and compared with a reference control group of cognitively normal, amyloid‐β‐negative older adults under age 70.ResultVoxel‐based PVCs systematically improved the rate of change across all the studied regions in Aβ‐positive CU and Aβ‐positive CI, compared to deconvolution PVC and no PVC. Among the tested voxel‐based PVCs, the RBV was slightly superior to the IY method. Deconvolution‐based PVC provided similar change estimates as not applying PVC (Figure 2)ConclusionVoxel‐based PVCs that model off‐target binding maximize the annualized rate of change of 18F‐FTP uptake. Our findings suggest that simple deconvolution techniques should be substituted by Voxel‐based PVCs for longitudinal 18F‐FTP imaging.
Association of tau tangle burden with depressive symptoms in community‐dwelling older adults: A longitudinal study
Authors: Gatchel Jennifer R , Marshall Gad A , Locascio Joseph J , Yang Hyun‐Sik , Donovan Nancy J , Buckley Rachel F , Properzi Michael J , Quiroz Yakeel T , Rabin Jennifer S , Vannini Patrizia , Amariglio Rebecca , Chhatwal Jasmeer P , Rentz Dorene M , Blacker Deborah , Sperling Reisa A , Johnson Keith A , Hanseeuw Bernard 
Published: December 2020

AbstractBackgroundDepressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults.Method252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau (18F‐Flortaucipir) and amyloid‐β(11C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time.ResultBaseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11).ConclusionBaseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD.
Peripheral markers of vascular endothelial dysfunction show independent but additive relationships with brain‐based biomarkers in association with functional impairment in Alzheimer’s disease
Authors: Drake Jonathan D. , Chambers Alison , Ott Brian R. , Daiello Lori A. 
Published: December 2020

AbstractBackgroundCurrent epidemiologic evidence suggests that potentially modifiable midlife vascular risk factors specifically influence propensity for later‐life Alzheimer's disease (AD)‐associated cognitive decline. Despite this, a large knowledge gap still exists with respect to characterization of the biological overlap of highly co‐morbid vascular and AD pathologies in clinical AD. Prior studies focusing on contributions of co‐existing imaging‐based white matter disease and amyloid burden have found independent and/or additive rather than interactive associations to risk for cognitive decline, however recent studies utilizing sensitive measures of vascular dysfunction or expanded panels of AD pathology indicate that more nuanced synergistic associations between these pathologies may exist in AD. We hypothesized that elevated plasma cell adhesion molecule (CAM) levels would correlate with severity of diagnosis and functional impairment in AD dementia and be concomitantly lower in mild cognitive impairment (MCI) and normal controls, respectively, and would act synergistically rather than independently with CSF AD biomarkers in this regard.MethodUsing generalized linear regression models, we examined cross‐sectional relationships of plasma vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1 (ICAM‐1), and E‐Selectin to baseline diagnosis and functional impairment staging (clinical dementia rating sum‐of‐boxes, CDR‐SB) in the Alzheimer's Disease Neuroimaging (ADNI) cohort (n=564). We also assessed for modifying effects of AD risk factors including ApoE‐ε4 genotype, and then tested for interactive association by combining CAMs with CSF biomarkers into CDR‐SB models in a subset with available CSF data (n=351).ResultHigher mean VCAM‐1 (p=0.0026) and ICAM‐1 (p=0.0189) levels were found in AD versus MCI groups, however not in MCI versus cognitively normal groups. Only VCAM‐1 was linked with CDR‐SB scores (p=0.0157), and ApoE‐ε4 genotype modified this effect (p < 0.0001). Contrary to our expectation, we observed independent and additive rather than interactive associations of VCAM‐1 and CSF Aβ42, total tau, phosphorylated tau (P‐tau), and P‐tau/Aβ42 (all < p=0.01) in a combined CDR‐SB model (and ICAM‐1 to a lesser extent).ConclusionOur findings indicate independent rather than synergistic associations of plasma‐based biomarkers of vascular endothelial dysfunction and CSF biomarkers of AD pathology and neurodegeneration with AD‐related clinical impairment. Future longitudinal studies will be needed to validate these findings.
Diagnostic rates and amyloid positivity vary by definition of mild cognitive impairment
Authors: Jeffers Sharlene L. , Caldwell Jessica Z.K. , Miller Justin , Cummings Jeffrey L. , Bondi Mark W. , Wong Christina G. 
Published: December 2020

AbstractBackgroundThe concept of mild cognitive impairment (MCI) has evolved, and various approaches are used to classify MCI. Conventional MCI criteria, such as those used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), rely on a single memory test to detect objective cognitive impairment. Actuarial neuropsychological criteria for MCI that incorporate comprehensive neuropsychological performance have been proposed to balance sensitivity and reliability. We applied both actuarial and conventional criteria to a sample of non‐demented older adults. Resulting groups were compared on diagnostic rates and amyloid positivity.Method51 cognitive normal (CN) and 62 MCI participants from the Center for Neurodegeneration and Translational Neuroscience were previously classified by a diagnostic consensus review. Actuarial criteria required impairment (>1 SD below means) on at least 2 tests within a cognitive domain. Conventional criteria were a modified version of ADNI criteria and required Mini Mental State Exam scores ≥ 24 and different cutoffs for Logical Memory based on education. Amyloid positron emission tomography (PET) determined amyloid status.ResultActuarial criteria classified 58 CN and 55 MCI, resulting in 77% agreement with consensus diagnosis. Conventional criteria diagnosed 36 CN and 77 MCI, resulting in 62% agreement with consensus diagnosis. McNemar tests indicated that the proportion of CN and MCI diagnoses were not significantly different between the actuarial and consensus (p=.23) but were significantly different between the conventional and consensus classifications (p=.03), with a 25% false positive rate for the conventional criteria. Chi‐squares demonstrated amyloid positivity was higher in MCI compared to CN for both the actuarial criteria (χ2(1)=31.16, p<.001, Φ=.54) and conventional criteria (χ2(1)=4.71, p=.03, Φ=.21). However, actuarial MCI was twice as likely to be amyloid‐positive than amyloid‐negative (Figure 1), whereas conventional MCI showed similar frequencies of amyloid‐positive and amyloid‐negative status (Figure 2).ConclusionComparisons between MCI diagnostic methods found higher agreement between actuarial criteria and consensus diagnosis versus conventional criteria, which tended to over‐diagnose MCI. A stronger association between amyloid positivity and MCI diagnosis was found using actuarial criteria. Findings support the use of comprehensive neuropsychological criteria to increase the accuracy of identifying individuals with MCI who are at risk for AD dementia.
N‐of‐1‐pathways transcriptomic analysis reveals distinct subtypes of Alzheimer’s disease
Authors: Uyar Asli , Pandey Ravi S. , Preuss Christoph , Kotredes Kevin P. , Oblak Adrian L. , Logsdon Benjamin A. , Rizzo Stacey J. Sukoff , Howell Gareth , Lamb Bruce T. , Sasner Michael , Carter Gregory W. 
Published: December 2020

AbstractBackgroundData from recent studies supports the hypothesis that Alzheimer’s disease (AD) is a heterogenous spectrum disorder characterized by multiple genotypes and phenotypes. Several subtypes of AD can be identified based on genetic makeup together with clinical phenotypes, neuroimaging and molecular signatures at different stages of the disease. N‐of‐1‐pathways approaches have been proposed for single‐subject gene expression analysis enabling disease subtyping at the transcriptome level.MethodWe analyzed existing RNA‐Seq data generated from post‐mortem brain tissue in the Religious Order Study and the Memory and Aging Project (ROSMAP). We calculated Mahalanobis distance based similarity measures between pair‐wise subjects per gene, and also per KEGG pathway. Using these similarity measures, we applied k‐means clustering algorithm to identify distinct subtypes of AD‐relevant transcriptomic signatures. Alignment of the subtypes with eight different mouse models of AD enabled determination of the mouse model(s) best representing each subtype.ResultIn the ROSMAP cohort, 144 and 81 subjects were labeled as AD and Control, respectively, according to predefined thresholds for COGDX, BRAAK and CERAD scores. A total of 186 KEGG pathways were assessed and AD subjects were clustered into four subtypes based on the Mahalanobis distance n‐of‐1‐pathway scores. Neuropathology related pathways, including neurotrophin signaling, axon guidance and long‐term potentiation, were altered in Subtype3 (n = 15). Transcriptomic signatures in the brain of 5XFAD and CR1 mouse models represented similarity with Subtype3. Subtype2 (n = 45) revealed a strong metabolic response with altered lysine and glycan metabolisms similar to ABCA7 and TREM2 mouse models. Immunity related pathways were enriched in Subtype3 (n = 48) mapping to ABCA7 and APOE4 mouse models. Subtype4 (n = 36) did not reveal a significant pathway enrichment.ConclusionAccurate identification of disease subtypes is critical for understanding the distinct molecular mechanisms of AD to provide effective personalized treatment options. To our knowledge, this is the first time that n‐of‐1‐pathways approach has been utilized for subtyping AD based on single‐subject transcriptomic signatures. The AD‐relevant pathways altered in each subtype was associated with specific mouse models suggesting a potential for utilization of the matching “mouse model/AD subtype” pairs for preclinical testing of therapeutic targets.
Introducing the Study of Healthy Aging in African Americans (STAR): Looking back to move forward
Authors: Whitmer Rachel A , Barnes Lisa L , Richards Ashley E , Miles Sunita , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles , Quesenberry Charles P , Gilsanz Paola 
Published: December 2020

AbstractBackgroundRates of dementia and Alzheimer’s disease are 40‐100% higher in African Americans versus non‐Hispanic whites. Yet there’s a lack of information on cognitive aging starting from midlife in African Americans and on lifecourse risk and protective factors. The Study of Healthy Aging in African Americans (STAR; RF1AG050782) is an ongoing cohort study of African‐American men and women ages 50+ aiming to (1) characterize heterogeneity in longitudinal change in cognition; (2) evaluate effects of exposure to vascular risk, psychosocial factors and early life experience over 50 years; and (3) evaluate structural MRI imaging markers of brain status on domain‐specific cognitive function.MethodEnrollment is ongoing and as of Dec 2019, STAR has enrolled 722 individuals of which 333 have completed a second visit. Eligible individuals were non‐demented Kaiser Permanente Northern California (KPNC) members age ≥50 (equal sampling of ages 50‐64 and 65+) who participated in KPNC Multiphasic Health Checkups (MHC) during at least 1 MHC phase (1964‐1973 or 1977‐1985) out of 5. MHC data and KPNC electronic medical record data are linked to lifecourse factors, psychosocial factors, the Spanish and English Neuropsychological Assessment Scales (SENAS), anthropometrics, physical function, and saliva samples from in‐person interviews. In‐person interviews will be repeated every 16 months for a total of 3 follow‐up visits, with a random subsample receiving MRI scans.ResultAmong the first 722 participants enrolled, average baseline age was 68.4. The sample was 68.7% female and a greater proportion of women than men were 50‐64 yrs (46.2% vs 36.3%). 58.4% of men and 36.1% of women were married or living with a partner. 15.1% of the sample had ≤high school education and 18.6% completed graduate school. 30.9% report excellent or very good health and 34.2% were born in a Southern state. 20% of men and 18% of women reported ever being unfairly denied a bank loan. Participants had an average of 2.3 out of 5 MHC phases; almost 15% participated in all 5 phases.ConclusionSTAR is an unprecedented lifecourse study of late‐life cognitive among African Americans with extensive prospectively collected health history.
Higher arterial stiffness but not blood pressure is associated with brain amyloidosis and preclinical AD in healthy adults: Results from the Emory Healthy Brain Study
Authors: Hajjar Ihab , Quyyumi Arshed , Zhao Liping , Hanfelt John , Goldstein Felicia C , Levey Allan I , Lah James J 
Published: December 2020

AbstractBackgroundHypertension increases the risk of Alzheimer’s Disease (AD) but blood pressure (BP) in older adults and cognition associated has been conflicting. We reported that arterial stiffness, which may antedate hypertension, better predicts cognitive decline. We investigated the association between BP and arterial stiffness with cerebrospinal fluid (CSF) levels of Amyloid beta 1‐42 (Ab42), tau, and P‐tau in the Emory Healthy Brain study (EHBS).MethodsEHBS is an ongoing cohort study of cognitively normal adults (50‐75 years) established in 2016. Participants undergo CSF sampling and cognitive, BP and anthropometrics and arterial stiffness (carotid ‐femoral pulse wave velocity [PWV] measured using Sphygmocor device (Atcor Medical, Sydney, Australia) measurements. General Linear Model (GLM) analyses and logistic regression with receiver operator curve (ROC) were used. Preclinical AD was defined in this population at Ab42/tau<5.7 . Covariates included age, gender, race, hypertension diagnosis, and body mass index (BMI).ResultsIn this analysis, 630 participants were included (age= 63 (SD=7), 70% women, 87% White, education mean= 16 (2) years, BMI=25.36 (3.57) kg/m2, MoCA score=26.6 (2.3), mean BP = 143/83 mm Hg, 35% were hypertensive, and PWV=6.3 (1.8) m/sec. Mean Ab42=565.7 (151.3), total tau=52.0 (22.8), P‐tau= 29.4(12.5), and Ab42/tau=12.8 (6.2) and 48 (7.6%) participants fit criterion for preclinical AD. Higher PWV was associated with lower CSF Ab42 (p<0.0001, Ab42 was lower by ‐14.1 pg/dl per each 1 m/s increase in PWV). After adjusting for covariates this decreased to ‐10.6 pg/dl for each unit increase in PWV (p=0.003). Neither SBP (p=0.98) nor DBP (0.45) were associated with Ab42. Higher PWV, but not BP, was also associated with pre‐clinical AD: for each unit increase in PWV, adjusted odds ratio for preclinical AD=1.35, 95%CI (1.18‐1.56), ROC=0.68. This remained true after adjusting for SBP and for all covariates. There was no association between PWV or BP and total tau or P‐tau (p>0.5).ConclusionHigher PWV, reflecting increased arterial stiffness, but not brachial BP is associated with greater brain Ab42 levels and the odds of preclinical AD in cognitively normal adults. PWV may offer a non‐invasive method for identifying healthy individuals with higher likelihood of pre‐clinical AD.
Clinical evaluation of allogeneic mesenchymal stem cells for Alzheimer's disease
Authors: Oliva Anthony A. , Baumel Bernard , Brody Mark , Agronin Marc , Herskowitz Brad , Bookheimer Susan Y , McClain‐Moss Lisa , Hitchinson Ben , Ramdas Kevin , Pena Andrea , Diaz Liliana A. , Green Geoff , Perez Carmen , Fuquay Ana , Castaneda Ricardo , Rodriguez Savannah , Delucca Johanna , Hare Joshua M. 
Published: December 2020

AbstractBackgroundTherapeutic interventions that can broadly target the complex multiple pathological features of Alzheimer’s disease (AD) would be highly desirable approaches for treating these disorders. Mesenchymal stem cells (MSCs) have pleiotropic mechanisms of action that make them highly attractive as therapeutic candidates for AD. These include powerful anti‐inflammatory properties, ability to improve vascular functioning, ability to promote intrinsic regenerative mechanisms, and ability to promote beta‐amyloid clearance. Given these highly desirable properties of MSCs, we set out to clinically evaluate their safety and therapeutic potential for AD, using a proprietary formulation called Longeveron Mesenchymal Stem Cells (LMSCs).MethodCentral to this study is a Phase I clinical trial powered to evaluate the safety of LMSCs for mild AD. Provisional efficacy is also being evaluated. This trial is double‐blinded, randomized, and placebo‐controlled, and registered with ClinicalTrials.gov (NCT02600130). Trial oversight includes FDA, an IRB, and an independent Data Monitoring Safety Board (DSMB). Subjects are enrolled after passing a 3‐step screening process, which sequentially consists of clinical diagnosis of mild AD, a confirmatory MRI, and a confirmatory PET scan using a beta‐amyloid tracer. Enrolled subjects are randomized to receive a single intravenous infusion of a low‐dose of LMSCs (20 million cells), a high‐dose of LMSCs (100 million cells), or placebo. Evaluated for safety and effect are performed over the 1‐year follow‐up.ResultThis multi‐site trial has proceeded ahead of schedule, and was fully enrolled as of September 2019. The trial was designed to enroll 30 patients; ultimately, 33 patients were enrolled. Results support the high safety profile LMSCs for AD: the DSMB has found no safety concerns, and the primary objective of no treatment‐related serious adverse events (SAEs) within 1 month post‐treatment was met. Preliminary data suggest the feasibility of biomarker analyses for evaluating effect changes, and the final lock and unblinding is anticipated in late 2020.ConclusionThe results support the conclusion that LMSCs are safe in AD patients, and that advancing to higher phase clinical studies is warranted. We thank the Alzheimer’s Association for supporting this research through the Part the Cloud Challenge on Neuroinflammation grant awards #PTC C‐16‐422443 and PTC‐CS‐19‐623225.
Neuroinflammation is associated with non‐REM sleep reduction in individuals without dementia
Authors: Tissot Cécile , Blais Hélène , Thompson Cynthia , Benedet Andréa Lessa , Pascoal Tharick A. , Therriault Joseph , Chamoun Mira , Lussier Firoza Z. , Savard Melissa , Rahmouni Nesrine , Stevenson Jenna , Mathotaarachchi Sulantha , Gauthier Serge , Gosselin Nadia , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundSleep disturbances and especially reduction of non‐REM (NREM) sleep are common in aging with accumulating evidence showing it might contribute to cognitive decline as well as increase the risk of developing dementia due to Alzheimer’s disease (AD). Lately, sleep disturbances and AD separately have been linked to increase in systemic inflammation. NREM sleep is thought to allow clearance of extracellular Aβ, which led to studies suggesting NREM could be an early biomarker of AD risk. The main objective of this study was to see the relationship between NREM sleep as assessed with polysomnography and neuroinflammation in vivo.Method25 individuals (18 cognitively unimpaired (CU) and 7 mild cognitive impairment (MCI)) underwent a [11C]PBR28 neuroinflammation‐PET scan, an MRI a full neuropsychological evaluation as well as a polysomnography. [11C]PBR28 standardized uptake value ratios (SUVRs) used the cerebellum grey matter as the reference region and was calculated between 0‐90 min post‐injection. A voxel based regression model evaluated the relationship between neuroinflammation as assessed by PET, and the total minutes of NREM sleep. The model’s covariates were age and diagnosis.ResultWe found a negative correlation between neuroinflammation and the total minutes of non‐REM sleep measured by a polysomnography. The regions showing neuroinflammation were the reticular formation, the arcuate nucleus of the medulla, the frontal cortex and especially the vmPFC as well as the insula and temporal poles. When we corrected for sex and years of education, results were similar.ConclusionThese preliminary results show that less NREM sleep correlates with neuroinflammation, in the brain of CU and MCI individuals. The regions impacted, such as the reticular formation, the vmPFC and the insula are needed for arousal and alertness. The arcuate nucleus of the medulla is required for proper breathing. Finally, temporal poles are part of the first regions affected in AD, and later on in the disease, the medial frontal cortex also starts degrading. Our study adds to previous research showing a link between sleep disturbances and neuroinflammation in vivo and identifies anatomical correlates.