bluuebunny/crossref_metadata_2025_split huggingface dataset:
Composite SUVR: a new method for boosting Alzheimer’s disease monitoring and diagnostic performance, applied to tau PET
Authors: Saguer Isaac Llorente , Busche Marc A , Oxtoby Neil P 
Published: December 2022

AbstractBackgroundAbnormal brain tau protein accumulation is strongly linked to multiple neurodegenerative disorders. Currently, brain tau pathology is quantified in vivo using tau PET by calculating the Standardized Uptake Value Ratio (SUVR) of target and reference regions of interest (ROIs).Recent work (Schwarz et al., 2021) in Alzheimer’s Disease (AD) explored various target and reference ROIs to report performance of SUVR as a biomarker for diagnosis, disease monitoring, and clinical trial efficacy/eligibility (sample size estimate, SSE). Here we introduce a new method and biomarker: Composite SUVR (CUVR).MethodsWe analyzed longitudinal SUV data from ADNI in the available 103 participants having three or more tau PET scans ([18F]AV‐1451): 58 cognitively normal (CN); 21 mild cognitive impairment; 24 probable AD. In the spirit of SUVR and statistical ROIs (Chen, et al., NeuroImage 2010), we calculate CUVR as the SUV ratio of two composite regions. Our novel method is that the composite regions are determined by a genetic algorithm that searches the possible 3^96 combinations of regions from FreeSurfer’s default atlas. We compare performance of SUVR with CUVR.Performance metrics follow Schwarz et al.: a linear mixed‐effects model quantifies longitudinal group separation by tau accumulation rate (t statistic between fixed effects for CN and AD) and longitudinal precision (model residuals’ standard deviation). CUVR and SUVR values were log‐transformed before model fitting.We calculated SSE for a hypothetical clinical trial designed for 80% power to reduce tau PET accumulation by 20% (vs. placebo) in non‐CN individuals.ResultsOur method identified a CUVR biomarker involving 60 regions. Figure‐1 shows the vast performance improvement of CUVR versus the best‐performing SUVR (inferior‐temporal target; eroded subcortical white matter reference). Group separation improved by 2.9x (t = 9.57 vs 3.32); longitudinal precision by 6.5x (residual std = 0.331% vs 2.14%); and CUVR required a smaller sample size by 3.9x (83 vs 318).ConclusionsOur simple data‐driven approach discovered a new tau PET biomarker called CUVR. Experimental results show state‐of‐the‐art longitudinal group separation, longitudinal precision, and clinical trial enrichment. The remarkable performance improvements provide compelling evidence for using CUVR for both eligibility and efficacy in Alzheimer’s disease clinical trials, particularly of anti‐tau therapies.
Accessible and meaningful engagement for people living with dementia when transitioning arts activities online
Authors: Christensen Justin , MacRitchie Jennifer , Timmers Renee 
Published: December 2022

AbstractBackgroundWith opportunities for self‐expression and enjoyment, creative arts activities can offer many benefits for people living with dementia including improving health and wellbeing. During the COVID‐19 pandemic, arts organizations have had to transition activities previously involving face‐to‐face interactions to remote delivery. Aiming to understand the accommodations that have been made for people living with dementia (PLWD) to access arts activities through technology, we conducted a survey with arts‐workers involved in the remote delivery.MethodA survey using a mixture of qualitative and quantitative questions was distributed online to arts workers delivering activities remotely for PLWD in the UK during the COVID‐19 pandemic. These included what types of activities were employed, how the activities changed due to remote access (including motivations for access), what tools were used, what technological support there was for access, and how this affected the number of people they were able to reach with these activities.ResultsTwenty‐seven arts workers (mean age = 47 SD = 6.4) delivering music (23 respondents), arts (8), crafts (4), dance (6), drama (3), and word‐based activities (1) responded. The main tools used included: Zoom, YouTube Live, Microsoft Teams, and Facebook Live. Several themes emerged from the thematic analysis of open‐ended responses: i) gaining a sense of community, finding structure and purpose, and combatting against physical isolation were perceived to be major motivations for people living with dementia, ii) creating opportunities for choosing, contributing input, and sharing was important, and iii) changes in access resulted from the shift to remote delivery such as difficulty for PLWD to interact through technology, user setup and maintenance needs, and the possibility for geographic expansion of the remote service.ConclusionsThe findings highlight the diverse, individual needs of people living with dementia in group arts participation, while still prioritizing their motivations for participation including sense of community, structure, purpose, and combatting against feelings of isolation during the pandemic. Particularly successful remote activities gave opportunities for meaningful contribution and had a multitude of possibilities for access for PLWD.
Prodromal FTD ‐ what do we know about it and what do we still have to learn?
Authors: Ducharme Simon 
Published: December 2022

AbstractBackgroundFrontotemporal dementia (FTD) is a complex disease that can initially present with subtle symptoms across several domains including behavior, cognitive/language, psychiatric and motor. This heterogenous prodromal phase is preceded by a slowly progressive presymptomatic accumulation of biological changes. With the emergence of new potential therapeutic agents for genetic forms, there is a need for robust clinical characterization and diagnostic definitions of these disease phases.MethodWe performed a systematic literature review on the current state of the science on prodromal FTD and provide expert consensus recommendations on diagnostic definitions.ResultThe preclinical phase should extend from the first signs of protein misfolding to the first FTD symptoms, however we lack molecular biomarkers to characterize this stage, with maybe the exception of C9orf72 expansion cases. In genetic mutation carriers it is uncertain if a ‘no disease’ phase exists, or if there is a neurodevelopmental component. To account for all possible clinical presentations, the definition of the prodromal stage of FTD needs to include the possibility of symptoms emerging with behavioral/psychiatric, cognitive and/or motor features. We subsume these features under the term mild cognitive and/or behavioral and/or motor impairment due to FTD (MCBMI‐FTD). MCBMI‐FTD needs to include psychiatric symptoms outside of typical bvFTD criteria as potential initial prodromal manifestations of FTD in genetic mutation carriers, however this would not be applicable in sporadic cases given the lack of specificity of such symptoms.ConclusionCharacterizing the preclinical and prodromal stages of FTD is crucial for disease detection and patient stratification for future clinical trials. However, several issues remain including the need to develop molecular biomarkers to better characterize the preclinical phase and more accurate models to predict symptom onset.
Effects of optogenetic locus coeurleus stimulation on functional connectivity in a rat model of Alzheimer’s disease
Authors: Kelberman Michael , Anumba Nmachi , Smith Corrie , Pan Wen Ju , Clavijo Perrin G , Marriott Alexia , Kim Ellen , Keilholz Shella , Weinshenker David 
Published: December 2022

AbstractBackgroundActivity of the locus coeruleus (LC) influences behaviors that go awry in prodromal Alzheimer’s disease (AD), and these abnormalities coincide with early accumulation of hyperphosphorylated tau in the LC. LC stimulation changes global functional connectivity, but it is unknown how AD‐like neuropathology affects the LC’s ability to regulate brain state. Therefore, we combined optogenetics and functional magnetic resonance imaging (fMRI) in the TgF344‐AD rats that develop endogenous hyperphosphorylated tau in the LC prior to amyloid or tau pathology in forebrain regions.MethodsAt 2 months of age, TgF344‐AD rats and wild‐type (WT) littermates were infused intra‐LC with a ChR2‐mCherry or an mCherry virus under the noradrenergic‐specific PRSx8 promoter (n=3/group). 2‐4 weeks prior to fMRI, rats were implanted with an optic fiber targeting the LC, and functional stimulation was confirmed using pupillometry. At approximately 6 months, rats underwent fMRI scans with and without 2Hz optogenetic stimulation. During scanning, rats were intubated and subcutaneously given 1.5mg/kg*hr pancuronium while anesthetized with 1.3% isoflurane. fMRI scans were gradient echo EPI (TR=1.25s) and obtained using a 9.4T Bruker Animal MRI scanner. Data were preprocessed using a custom Rodent Whole‐Brain fMRI Data Preprocessing Toolbox. Functional connectivity matrices were generated in MATLAB using Pearson’s linear correlations between parcellated regions of interest (ROI). Histograms were generated in MATLAB by collecting the fisher z‐transformed correlation coefficients across all ROIs for the averages of each group.ResultsPupillometry confirmed optogenetic activation of the LC in ChR2 animals but not mCherry controls. Similar functional connectivity was observed between Tg and WT animals. We next subtracted baseline fisher z‐transformed correlation coefficients from those during 2Hz stimulation within each genotype to determine whether LC stimulation shifted functional connectivity. Across all groups, effects of 2Hz LC stimulation were negligible.ConclusionsTg and WT rats had similar resting‐state functional connectivity at 6 months, and 2Hz LC optogenetic stimulation did not impact functional connectivity. However, functional connectivity deficits progress with age in this strain, and the 2Hz stimulation falls within normal LC pacemaker firing (∼0.5‐2Hz). Therefore, future work will incorporate different stimulation frequency, patterns, and older rats.
Empirical pathological staging and subtyping of TDP‐43 proteinopathies
Authors: Young Alexandra L. , Vogel Jacob W , Robinson John , McMillan Corey T , Ossenkoppele Rik , Wolk David A. , Irwin David J. , Elman Lauren , Grossman Murray , Lee Virginia M‐Y , Lee Eddie B , Trojanowski John Q , Hansson Oskar 
Published: December 2022

AbstractBackgroundPathological aggregation of tar DNA‐binding protein 43 (TDP‐43) in the brain is the primary cause of many cases of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). It is therefore imperative to establish empirical staging systems to characterize and distinguish stereotypical patterns and commonplace deviations of different TDP‐43 proteinopathies.MethodWe use ordinal ratings of TDP‐43 burden from 19 brain regions to perform data‐driven disease progression modeling (SuStaIn) to find the most likely trajectories for FTLD‐TDP (n = 108), ALS (n = 137) and LATE (n = 283) from the CNDR Brain Bank at the University of Pennsylvania. Subtype number was defined using cross‐validated information criterion. Each individual was assigned a subtype and stage. Multivariate OLS models tested differences between subtypes. Stages were compared to age and existing staging schemes. Cross‐validated logistic regression was used for 3‐way classification using SuStaIn information only.ResultSuStaIn provided data‐driven staging of TDP‐43 proteinopathies complementing previously described human‐defined staging schema, further providing additional detail (Fig1A‐C; Fig3A‐C). SuStaIn also identified two distinct subtypes within FTLD‐TDP and a further two within ALS (Fig1D). FTLD‐TDP subtypes differed in TDP‐43 type and Alzheimer’s disease pathology (Table1); ALS subtypes were differentiated by age (Table 2) and by antemortem clinical characteristics. No subtypes were observed for the LATE group. Progression along data‐driven stages was positively associated with age in LATE individuals, but negatively associated with age in individuals with FTLD‐TDP (Fig2). Using only regional TDP‐43 severity, our data driven model could distinguish individuals diagnosed with ALS, FTD or LATE with a cross‐validated balanced precision of 0.93 and balanced recall of 0.92, and these metrics improved to 0.95 and 0.96 when combined with a logistic regression model (Fig3). Very little stage overlap was found between FTLD‐TDP and LATE, but stages that did overlap showed subtly different patterns (Fig4)ConclusionWe provide an empirical pathological staging system for ALS, FTLD‐TDP and LATE, which is sufficient for staging and accurate classification. We demonstrate that there is substantial heterogeneity amongst ALS and FTLD‐TDP progression patterns, whilst LATE exhibits a homogeneous progression pattern.
Do Sex Differences Exist in Cognitive Function in Patients with Atrial Fibrillation?
Authors: Wood Kathryn A. , Han Feier , Ko Yi‐An , Wharton Whitney 
Published: December 2022

AbstractBackgroundAtrial fibrillation (AF) is a risk factor for mild cognitive impairment (MCI) and dementia. To address sex differences in AF‐related MCI, we examined disease prevalence and progression among adults with and without AF in the National Alzheimer’s Coordinating Center (NACC) cohort.MethodData freeze/extraction of NACC data (N = 43,746) took place March 2021. Participants with ≥ 3 annual visits, diagnostic data, and AF status (self‐reported or diagnosed) were included. Diagnostic categories were normal, MCI, and dementia. Multinomial logistic regression and Cox proportional hazard model were used to examine association between AF and baseline cognitive diagnosis and time to progression in cognitive diagnosis, respectively. Covariates included age, sex, race, education, BMI, smoking, depression, hypertension, diabetes, hypercholesterolemia, heart failure, stroke, and sleep apnea. Interactions with sex were examined in all models.Result4,593 participants had AF at baseline (46% female, mean age 78.5 years, 81% White, 8% Black, 11% other ethnicities). AF is associated with higher odds of having MCI (OR 3.43 [1.48, 7.91] in females; OR 1.73 [0.81, 3.71] in males) and dementia (OR 3.00 [1.22, 7.38] in females; OR 2.60 [1.16, 5.81] in males) at baseline. Among the 13,683 subjects included in the survival analysis, 4066 (30%) progressed from normal cognition to MCI and 2895 (21%) developed dementia (2434 [18%] AD) with median follow‐up of 4 years. Women with AF had higher risk of disease progression (HR 1.21 [1.04, 1.40]) compared to women without AF, but the association was not significant in men (HR 0.96 [0.83, 1.11]). AF was significantly associated with faster transition from normal cognition to MCI (HR 1.17 [1.03, 1.33]) and from MCI to vascular dementia (HR 2.51 [1.63, 3.85]) but not MCI to AD.ConclusionThis is the first study to examine sex differences in rate of cognitive change in patients with AF. Women with AF are at higher risk of MCI and dementia with more rapid trajectories to dementia than women without AF or men with or without AF. Identification of those at highest risk of cognitive decline will inform future interventions to prevent or slow AF‐related MCI and AD.
Comparative prevalence of mild cognitive impairment of Alzheimer’s Disease sub‐type in Adult Ugandans living with HIV and demographically matched HIV‐negative controls
Authors: Ezeamama Amara E. , Sikorskii Alla , Boivin Michael , Zalwango Sarah K , Nakasujja Noeline , Rubin Leah H , Giordani Bruno 
Published: December 2022

AbstractBackgroundPrevalence rate of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) in cART treated people living with HIV (PWH) is unknown.Method277 PWH and 189 HIV‐negative Ugandan adults matched by age, sex, and residence were neuropsychologically evaluated i. Impairment in seven domains ‐ including immediate recall, memory and learning (delayed recall, recognition) and others, were defined. Cognitive status – i.e., not impaired, asymptomatic impairment (ANI), minor neurocognitive disorder (MND) or HIV‐associated dementia (i.e., HAD, if HIV+), was defined according to Frascatti criteria. Cognitive dysfunction of the AD subtype was defined per Bondi et al. (2014); MCI included moderate (i.e. ≥1 SD worse in ≥2 tests) or pronounced (i.e. >2.0 SD worse in ≥1 tests) cognitive impairments without functional limitation. AD ‐ i.e., ≥1 pronounced impairment in recognition/delayed recall accompanied with functional limitation. Differences in MCI and AD by HIV status and odds ratios with 95% confidence intervals (CI) were calculated stratified by age (<60 vs. ≥60 years).ResultAmong adults cognitively unimpaired (26.1%) or with ANI (27.8%), amnestic MCI rate was 28.9% (60/204) among PWH and 14.7% (21/133) among HIV‐ controls (OR = 2.18, 95%CI:1.25, 3.84). Similarly, among adults with MND/HAD, prevalent AD was 38.7% (29/75) among PWH and 23% (14/61) among HIV‐ controls (OR = 2.11, 95%CI:0.99, 4.50). Among cognitively unimpaired/ANI affected individuals <60 years old, amnestic MCI prevalence was 16.2% for community controls and 30.3% for PWH (OR = 1.9, 95%CI:1.02, 3.60). Among individuals classified as MND or HAD, prevalent AD was 16.3% for HIV‐ controls vs. 38.6% for PWH (OR = 3.23, 95% CI: 1.23, 8.52) . Among adults 60+ years old with ANI/no impairment, prevalent amnestic MCI was 14.7% for community controls and 41.9% for PWH (OR = 4.04, 95%CI:1.23, 13.40) but the prevalence of AD was identical at 38.9% each for HIV+ and for HIV‐ controls 60+ years old with MND/HAD.ConclusionUgandan PWH are at increased risk for being diagnosed with MCI/AD, and they may be diagnosed at a younger age than HIV‐negative Ugandans. These data highlight the importance of MCI/AD screening in PWH and the need to avail PWH with interventions to mitigate MCI/AD risk.
Examining cerebrovascular burden across the cognitive continuum in older adults with and without evidence of amyloidosis
Authors: Rivera‐Rivera Leonardo A , Cody Karly Alex , Betthauser Tobey J , Koscik Rebecca Langhough , Jonaitis Erin M. , Cadman Robert V. , Hermann Bruce P , Rowley Howard A. , Carlsson Cynthia M. , Chin Nathaniel A. , Eisenmenger Laura , Johnson Sterling C. , Johnson Kevin M 
Published: December 2022

AbstractBackgroundThis work characterized cerebrovascular health in human subjects spanning the cognitive spectrum with and without presence of Aβ using different neuroimaging techniques (Fig1).MethodsSubjects (n=70) were clinically characterized into four groups: cognitively unimpaired (CU), CU‐Declining (at‐risk of progressing to clinical mild MCI based on traditional neuropsychological data), clinical MCI, and clinical dementia (Fig2). MRI:
Vascular imaging: Whole‐brain 4D‐Flow data were acquired to characterize cerebrovascular health. pCASL with three post labeling delays was used to provide transit time corrected CBF maps. Structural imaging: T1‐weighted and T2‐FLAIR images were also collected for quantification of intracranial, hippocampal and white matter hyperintensity volumes. Hemodynamic measurements were extracted from intracranial arteries including the petrous ICAs, BA, MCAs, and veins SSS. Quantified flow parameters included: total cerebral blood flow, trans‐capillary pulse wave delay, and flow pulsatility index (PI). Trans‐capillary pulse wave delay was defined as the time shift between arterial and venous cardiac waveforms. PET: Aβ burden was assessed using 11C‐PiB PET imaging. Amyloid positivity (A‐, A+) was established as mean cortical PiB DVR >1.16. For A+ participants, amyloid time (i.e., estimated duration A+) was estimated using the sampled iterative local approximation algorithm. Differences were assessed using ANOVA followed by post‐hoc analysis (P<0.05 significance).ResultsMicro‐vascular tissue perfusion was statically higher in A+/CU when compared to other A+ groups in the GM, WM, and hippocampus (Fig3 and 4). Trans‐capillary pulse wave delay was statistically longer in A+/CU when compared to A+/CU‐Declining, A+/MCI, and A+/dementia (Fig5A). For A‐ groups trans‐capillary pulse wave delay was similar; yet, flow PI was statistically higher in A‐/CU‐Declining and A‐/MCI when compared to A‐/CU in the ICAs and MCAs (Fig5 C, D). Flow PI in A+/CU was higher than in A‐/CU.ConclusionsDecreased micro‐vascular tissue perfusion and shorter trans‐capillary pulse wave delay in A+ subjects with cognitive alterations (e.g. CU‐Declining, MCI, Dementia) compared to A+/CU indicates decreased metabolism and increased small vessel stiffness may contribute to cognitive decline and/or are induced by amyloidosis. In contrast, for A‐ subjects significant differences in arterial flow pulsatility index between A‐/CU, CU‐Declining, and MCI suggests macro‐vascular arterial stiffness contributes to cognitive decline.
Modeling gene expression on the X chromosome in the brain for transcriptome‐wide association studies
Authors: Zhang Xueyi , Guo Shengru , Naj Adam C. , Below Jennifer , Kunkle Brian W. , Dumitrescu Logan , Martin Eden R. , Bush William S. 
Published: December 2022

AbstractBackgroundAnalysis of sex chromosomes is under‐reported in Alzheimer’s disease (AD) studies. As we gain more knowledge of disease associations and tissue‐specific regulatory effects of autosomal loci, there is a growing interest in building prediction models of gene expression in the brain to model the cumulative functions of non‐coding variants on the sex chromosomes. Transcriptome‐wide Association Studies (TWAS) can identify disease‐associated genes using these prediction models built for specific tissues by integrating genotype, imputed gene expression, and phenotype information. A key challenge of this approach for sex chromosome analysis is how to model copy number differences between males and females: genetic variants on the X chromosome are hemizygous for males, while females are heterozygous or homozygous diploid.MethodWe explore modeling approaches on the X chromosome using WGS and RNA‐seq data in 13 Brain sub‐regions retrieved from the GTEx project, currently restricting analyses to males. We used elastic‐net regression, with a balanced LASSO‐ridge penalty (mixing parameter α=0.5), as recommended by Wheeler et al. 2016. We tuned the penalization parameter λ for each gene in each tissue and assessed the model performance. There are 2392 genes on chromosome X, with only approximately 800 genes expressed in each GTEx brain tissue. SNPs (MAF>0.05) within the gene’s 1M bp flanking window were used to train the model. We used mean squared error to determine the penalization parameter and select the best models.ResultWe built 761 prediction models in 13 Brain sub‐regions on the expression of 503 genes. For example, we fit the prediction model of Gene COL4A6 (ENSG00000197565) in the Cortex, using 89 males. 83 cis‐SNPs were kept in the final model (λ=0.015). The model R2 is 0.20, suggesting that 20% of the variance of expression levels in males can be explained.ConclusionThese models predict the cis‐regulated gene expression on the X chromosome in males. We can then use these estimated gene expression weights to impute male expression levels to identify (putative) causal genes for AD with TWAS.