bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trajectory of clinical symptoms accelerates after 10 years of amyloid
Authors: Birdsill Alex C. , Koscik Rebecca L. , Cody Karly Alex , Betthauser Tobey J. , Erickson Claire M. , Chin Nathaniel A. , Christian Bradley T. , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. 
Published: December 2020

AbstractBackgroundUnderstanding the time between amyloid biomarker detection and the onset of cognitive and functional symptoms will be critical in making care planning decisions and determining an optimal time period for potential interventions. Previous studies have suggested that amyloid, as measured with Pittsburg compound B (PiB), can be detected 15‐20 years before symptom onset. However, the designs of these studies do not—on an individual basis—provide an understanding of the duration between amyloid accumulation and symptom onset. Recent research from several groups has suggested that the rate of amyloid accumulation is consistent across individuals, making it possible to estimate the chronicity of amyloid positivity from a single PET scan. In relation to this measure of amyloid chronicity, we examined trajectories of cognitive and functional symptoms, as measured by the Clinical Dementia Rating Scale (CDR).MethodThe sample included 347 study visits from 84 amyloid positive (A+) participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention or the Wisconsin Alzheimer’s Disease Research Center (Table 1). For participant visits that administered the Quick Dementia Rating System (QDRS), the equivalent CDR sum of boxes (CDR‐SB) score was calculated. A mixed effects model with random slope and intercept was used to evaluate the association between chronicity and CDR‐SB (with covariates APOE4 carriage, sex and baseline age). To investigate potential non‐linearity in chronicity’s association with CDR‐SB, a chronicity‐by‐baseline chronicity category (<0, 0‐5, 5‐10, 10‐15, 15‐20 and >20 years) interaction was examined (<0=reference range).ResultSpaghetti plots display the trajectories of CDR‐SB values in relation to amyloid chronicity; shading indicates clinical guidelines for interpreting CDR‐SB (Figure 1). The results of the model indicate that the trajectory of CDR‐SB is significantly greater after 10 years of amyloid chronicity (Table 2 & Figure 2).ConclusionLargely consistent with previous studies, the results indicate that clinical symptoms begin to emerge after 10 years of amyloid positivity. However, symptom severity appeared to vary greatly between 10 – 30 years of amyloid chronicity. Future research will aim to identify other processes that may contribute to decline as well as genetic and modifiable factors that may promote resiliency and delay the onset of clinical symptoms.
Surface‐based amyloid and tau correlates of digital clock drawing performance
Authors: Mayblyum Danielle V. , Sanchez Justin S , Thibault Emma G. , Jacobs Heidi I.L. , Farrell Michelle E. , Rubinstein Zoe B. , Buckley Rachel F. , Sperling Reisa A. , Rentz Dorene M. , Papp Kathryn V. , Johnson Keith A. 
Published: December 2020

AbstractBackgroundUsing a digital pen to record performance on neuropsychological tasks allows for the capture of much more subtle and nuanced aspects of cognitive performance. Previous research showed that lower DCTClock summary score was associated with greater entorhinal tau in clinically‐normal older adults (CN) (Rentz, AAIC 2019). Additionally, spatial reasoning was related to elevated entorhinal tau, inferior temporal tau, and neocortical amyloid. Given the observed cognitive heterogeneity in early stages of AD, we explored the relationship between different aspects of digital clock performance and amyloid and tau pathology across the cortical surface.MethodCN from the Harvard Aging Brain Study completed both a spontaneous (COM) and copy (COP) clock drawing test using a digital pen. We used a summary score (DCTScore) and four main composite scores (drawing efficiency, simple motor, information processing and spatial reasoning) calculated by Digital Cognition Technologies. Participants also underwent [11C]PiB‐PET (n = 112) and [18F]T807‐PET (n = 116) acquisition within one year of cognitive testing. We utilized a vertex‐wise analysis with a cluster‐wise multiple comparison correction (minimum cluster extent=100mm2) and a threshold of ‐log(p)>2 to analyze relationships with clock scores across the vertices, adjusting for age, sex, and education.ResultLower DCTScore strongly correlated with greater amyloid signal in the frontal lobe, with some significant clusters also observed within the lateral temporal and inferior parietal cortices (Figure 1). Lower DCTScore also related to elevated tau signal in the right lateral temporal and inferior parietal lobes. Tau was most strongly associated with COM spatial reasoning score in the right lateral temporal lobe (Figure 2), reflecting known functional associations with this region; this was not reflected with COP spatial reasoning scores.ConclusionIn clinically‐normal older adults, lower scores on clock drawing were associated with greater cortical amyloid and tau. Lower spatial reasoning scores were related to tauopathy, but only in spontaneous clock drawing, supporting the notion that more complex cognitive tasks are compromised earlier in the clinical continuum. More fine‐grained measurements of cognition using digital tasks in relation to neuroimaging markers has the potential to improve our understanding of the pathogenesis of early AD.
Cerebrospinal fluid phosphorylated tau interacts with MMP2 and MMP3: Associations with cognitive performance in older adults
Authors: Meier Shelby E. , Khan Omair A. , Liu Dandan , Bown Corey W. , Moore Elizabeth E. , Pechman Kimberly R. , Acosta Lealani Mae Y. , Bell Susan P. , Blennow Kaj , Zetterberg Henrik , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2020

AbstractBackgroundMatrix metalloproteinases (MMPs) are enzymes that facilitate extracellular matrix remodeling. In Alzheimer’s disease (AD), the MMP system becomes dysregulated and may contribute to disease pathophysiology; however, limited work has examined clinical consequences of MMPs. Thus, we investigated cerebrospinal fluid (CSF) MMP2, MMP3, and MMP9 concentrations in relation to cognitive performance as well as the interaction between MMPs and AD core neuropathology (CSF amyloid beta (Aβ42) and phosphorylated tau (p‐tau)) on cognitive outcomes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia underwent fasting lumbar puncture for CSF acquisition and neuropsychological assessment (n=153, 73±7 years, 67% male). CSF samples were analyzed in batch using commercially available ELISAs. Linear regression models individually related CSF MMP levels to neuropsychological performance, adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham Stroke Risk Profile, and apolipoprotein E (APOE)‐ε4 carrier status. Models were repeated with CSF Aβ42 and p‐tau concentrations as interaction terms.ResultsIncreased CSF MMP9 related to worse language (p‐values<0.03) and episodic memory performances (p=0.03); however, CSF MMP2 and MMP3 main effects were null (p‐values>0.07). CSF Αβ42 did not interact with MMP2, MMP3, or MMP9 concentrations on any neuropsychological outcome (p‐values>0.09). By contrast, CSF p‐tau interacted with CSF MMP2 and MMP3 levels on language performance (p‐values<0.02), and CSF p‐tau interacted with CSF MMP2 levels on episodic memory performance (p=0.01). Increased CSF MMP2 and MMP3 associations with worse language and episodic memory performances were driven by p‐tau negative participants, whereas (unexpectedly) increased CSF MMP2 was associated with better language performance among p‐tau positive participants.ConclusionAmong older adults without clinical dementia or stroke, increased CSF MMP9 related to worse cognitive performance, suggesting extracellular matrix remodeling may be one pathway underlying the development of cognitive impairment. CSF p‐tau, but not Αβ42, interacted with MMP2 and MMP3 concentrations on cognitive performance. P‐tau may interact with MMPs on clinical expression of pathology in complex ways, such that increased CSF levels of MMPs may only be associated with worse cognition in non‐demented older adults in the absence of concomitant neuropathology. Funding: Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373.
Resistance exercise improves cognitive and brain health in overweight older adults
Authors: Furlano Joyla , Nagamatsu Lindsay 
Published: December 2020

AbstractBackgroundApproximately 50% of Canadian older adults over the age of 60 are overweight or obese (based on body mass index; BMI). Individuals with high BMI (≥25) often experience cognitive and brain deficits (e.g., impaired memory, cortical atrophy, reduced neural activation), and are at high risk of dementia. One promising lifestyle intervention that may improve these deficits is exercise. For example, 6 months of aerobic training has been found to improve cognitive and brain function in overweight older adults, however studies examining whether resistance training (RT) can produce comparable results in this population is limited.MethodWe conducted a 6‐month, thrice‐weekly randomized controlled trial of RT in overweight older adults. Twenty‐four participants aged 60‐80 (sedentary; BMI ≥25) were randomized into one of two groups: 1) progressive resistance (weight) training, or 2) balance and tone (BAT; control; stretching exercises). At pre‐ and post‐intervention (0 and 6 months, respectively), we measured associative memory performance during functional MRI, and obtained high resolution T1 weighted structural images from a 3T scanner.ResultSix months of RT showed significant improvements in memory performance (6.38% reduced error rate) compared to BAT. Similarly, structural imaging showed increased hippocampal volume for RT (+0.04%) as well as increased percent signal change (neural activation) in memory‐related brain regions of interest, including the hippocampus, parahippocampal gyrus, lingual gyrus, and medial temporal gyrus, suggesting improved functional brain health overtime.ConclusionOverall, our findings offer a feasible, cost‐efficient lifestyle intervention strategy to improve cognitive and brain health in overweight older adults.
Longitudinal [18F]RO948 PET SUVR is associated with Aβ accumulation and baseline tau pathology
Authors: Leuzy Antoine , Klein Gregory , Ossenkoppele Rik , Mattsson Niklas , Janelidze Shorena , Palmqvist Sebastian , Strandberg Olof , Coloma Preciosa M , Borroni Edilio , Stomrud Erik , Smith Ruben , Hansson Oskar 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is defined by amyloid‐β (Aβ) and tau pathology. Specifically, Aβ and tau are thought to interact, with Aβ mediating the spread of tau. We here aimed to examine the association between cross‐sectional Aβ and tau‐PET with change in tau‐PET SUVR.Methods51 subjects from the ongoing BioFINDER‐2 longitudinal sub‐study were included: 23 cognitively unimpaired (CU; 9 Aβ‐negative,14 Aβ‐positive), 21 with MCI (3 Aβ‐negative,18 Aβ‐positive) and 7 AD with dementia (all Aβ‐positive). Aβ‐status was based on CSF Aβ42/Aβ40. Aβ (CU, MCI only, by design) and tau‐PET (all subjects) were performed using [18F]flutemetamol and [18F]RO948, respectively. Subjects underwent a targeted follow‐up of ∼12‐months (mean=13.2±2.6) with [18F]RO948. FreeSurfer (v.6.0) was used to calculate mean‐SUVR values for tau‐PET across four predefined ROIs reflecting Braak‐stages I‐VI (inferior cerebellar cortex as reference). For Aβ‐PET SUVR, a cortical meta‐ROI was used (composite white‐matter reference region). The association between longitudinal and cross‐sectional findings was assessed using linear regression with subject specific slopes for tau‐PET and tau and Aβ‐PET SUVR at baseline as predictors (adjusted for age, sex, interscan‐interval).ResultsLargest longitudinal change and effect‐sizes followed a group/Braak ROI specific pattern (Figure 1): I‐II (entorhinal cortex) for Aβ‐positive CU (+3.14%, effect‐size 0.72), III‐IV (amygdala, fusiform gyrus, inferior/middle temporal cortex, and parahippocampus) for Aβ‐positive MCI (+3.62%, effect‐size 0.61) and V‐VI (neocortical) for AD dementia (+3.98%, effect‐size 0.58). No significant increases were seen across Aβ‐negative subjects. Regression models in CU and MCI subjects (no AD dementia due absence of Aβ‐PET) showed that increases in tau‐PET SUVR were related to both Aβ‐PET and tau‐PET SUVR at baseline. However, when incorporating both measures as predictors, Aβ‐PET remained significant only in Aβ‐positive CU subjects. Plotting change in tau‐PET as a function of change in Aβ‐PET (Figure 2) revealed a seeming threshold effect whereby tau pathology accelerated around an Aβ‐PET SUVR of 0.65.ConclusionInitial results with longitudinal [18F]RO948 indicate that it is able to capture the progression of early tau pathology in Aβ‐positive CU subjects, as well as cortical increases in subjects with cognitive impairment. A critical burden of Aβ appears to be a prerequisite for increases in tau pathology.
Effect‐modifying role of education and crystalized intelligence on the association of amyloid pathology and cognitive function
Authors: Udeh‐Momoh Chinedu T. , Zheng Bang , Price Geraint J. , Watermeyer Tam J. , de Jager Celeste A. , Robb Catherine , Giannakopoulou Parthenia , Su Bowen , Saad Ziad , Fogle Michael , Ford Jamie , Ritchie Craig W. , Baker David , Novak Gerald P. , Ahmadi‐Abhari Sara , Middleton Lefkos T. 
Published: December 2020

AbstractBackgroundCognitive reserve factors reflecting innate (crystallized intelligence) and derived (educational attainment) cognitive capacity are shown to be associated with preservation of cognitive function and delayed decline. Yet little information is available on how these static measures of reserve themselves are associated with cerebral amyloid burden and influence its effect on neurocognitive performance.MethodsIn the deeply‐phenotyped CHARIOT:PRO substudy, 501 cognitively healthy individuals aged 60‐85 years had available information on ApoE genotype (carrier vs non‐carrier), brain PET‐scan/CSF‐derived amyloid load (positive vs negative), education attainment, premorbid intelligence measured by the National Adult Reading Test (NART), and cognitive performance via the multi‐domain Repeatable Battery Assessment of Neuropsychological Status (RBANS) measured at two time‐points (average 3.5 months apart). Linear mixed models were used to independently examine the effect modifying role of education and intelligence as measures of cognitive reserve on the association of amyloid status and cognitive function.ResultsThere was an effect modification in the association of amyloid status and global cognition (total RBANS score) by both intelligence and Education in mutually adjusted models accounting for age, sex and ApoE. The effect modification was more pronounced for intelligence. RBANS total score was lower in participants who were amyloid positive (vs negative) among those with lower than median intelligence quotient (mean difference in RBANS Z‐score by amyloid status ‐0.2 (95% CI ‐0.35, ‐0.04)). The inverse association between amyloid positivity and global cognition disappeared among those with higher than median intelligence (mean difference in RBANS Z‐score by amyloid status 0.01 (95% CI ‐0.16, 0.18)), P‐value for interaction <0.001. Correspondingly, mean difference in RBANS Z‐score for amyloid positivity (vs negativity) was ‐0.18 (95% CI ‐0.36, 0.00) for participants with below median education, and ‐0.07 (95% CI ‐0.24, 0.09) for participants with above median education attainment, P‐value for interaction 0.19. Further adjustment for body mass index, smoking, physical activity, systolic blood pressure and diabetes did not have a remarkable effect on the findings.ConclusionsOur results support the hypothesis that although education and intelligence are both associated with higher cognitive reserve, crystalized intelligence provides more resilience against the neurodegenerative effect of amyloid pathology on global cognition.
Subjective versus objective cognitive assessment in an ethnically diverse cohort of oldest‐old individuals: The LifeAfter90 Study
Authors: Corrada Maria M.M. , Kawas Claudia H. , DeCarli Charles , Gilsanz Paola , Glymour M. Maria , Mayeda Elizabeth Rose , Mungas Dan M. , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundThe ability to measure cognition accurately in ethnically diverse populations is important. However, information about cognition in the oldest‐old (people aged 90+) comes almost exclusively from cohorts of highly educated Caucasian individuals. We studied the association between self‐rated cognition and objectively measured cognition among the first 610 participants enrolled in an ongoing multi‐ethnic oldest‐old cohort.MethodLifeAfter90 participants are long‐time members of the Kaiser Permanente Northern California Health Care System without a dementia diagnosis in their medical record at recruitment. Evaluations are every six months and include the Everyday Cognition (ECog) and Spanish and English Neuropsychological Assessment Scales (SENAS). The ECog is a self‐rated questionnaire about abilities to perform cognitively relevant functional tasks across multiple domains (on a 4‐point scale from ‘no change’ to ‘much worse’). For analysis, we averaged items within each domain (memory‐2, language‐2, visuospatial abilities‐5, and executive function‐7). The SENAS assesses episodic memory, semantic memory, and executive function domains. We estimated the cross‐sectional associations between self‐rated cognition (ECog) and objectively measured cognition (SENAS) measured at baseline. Using linear regression, we determined in the full cohort which ECog items had the strongest association with each SENAS domain and compared those associations across racial/ethnic groups.ResultAt baseline, participants were on average 92.6 years of age, 62% were women, 45% had a college education, and 68% were racial/ethnic minorities (Table 1). Table 2 shows the associations between ECog items and SENAS domains. ‘Concerned about memory’ was the ECog item most strongly associated with SENAS Verbal Memory, and that association was strongest among Whites and Blacks. The visuospatial ECog items had the strongest association with SENAS Semantic Memory, and that association was present among Whites and Latinos. The executive function ECog items had the strongest association with SENAS Executive Function, and the association was present among Whites and Latinos. No associations between ECog items and SENAS domains were observed among Asians or the multiracial group.ConclusionIn this oldest‐old cohort, we found differences in how racial ethnic/groups report their everyday cognitive function in relation to their measured cognitive abilities. These differences need to be considered when assessing subjective cognitive function in diverse populations.
Piloting a novel screening tool for reducing heterogeneity in clinical trials in Alzheimer’s disease
Authors: Oxtoby Neil P. ,   UCL Centre for Medical Image Computing
Published: December 2020

AbstractBackgroundScreening for clinical trials in Alzheimer’s disease (AD) ideally selects the right people at the right time to efficiently test a putative therapy. Traditional screening instruments have been clinical/cognitive tests scores, including cognitive composites. Moves towards secondary prevention trials necessitated refinement of the screening process using biomarkers. This hasn’t helped, with the number of negative trials continuing to grow. This work takes screening to the next level by proposing and piloting a novel computational tool capable of improving the precision of cognitive‐ and biomarker‐based screening.MethodAn event‐based model of AD progression is a computational model capable of fusing cognitive and/or biomarker data into a fine‐grained staging tool. The tool assigns individuals a numerical severity score that best fits their data. Here the tool was trained on baseline data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and tested, post hoc, on data from AD Cooperative Study’s MCI trial (clinicaltrials.gov: NCT00000173), which recruited individuals with Mild Cognitive Impairment (MCI) and included three arms: Donepezil, Vitamin E, Placebo. Group differences were analysed at follow‐ups using a t‐test, stratified by severity score.ResultFigure 1 shows the event‐based model built on N=803 (of 2040) ADNI participants (229 CN, 182 AD, 392 MCI) having complete data (see Methods). The model estimates a probabilistic, ordered sequence (upper‐left to lower‐right) of cognitive decline from Clinical Dementia Rating, through general cognition/memory, to verbal fluency. Model‐based staging assigned a fine‐grained severity score (SS) to each participant in both the training data and the N=473 (of 769) MCI trial participants having complete data for the trial duration. Histograms of SS in Figure 2 show substantial heterogeneity in both ADNI (left) and, in particular, ADCS‐MCI (right) which shows three clusters: SS<5, SS>10, and 5≤SS<10. Table 1 shows significantly lower mean ADAS‐Cog 13 score under Donepezil treatment in the SS>10 cluster, detectable only with the novel tool.ConclusionThis pilot study proposed a novel screening tool to reduce cohort heterogeneity in clinical trials in Alzheimer’s disease, offering hope for improving efficiency of future trials.