bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower cortical thickness is associated with reduced gray matter cerebral blood flow across the AD continuum
Authors: Sanderlin Ashley H. , Okonmah‐Obazee Stephanie , Craft Suzanne , Bateman James R. , Cleveland MaryJo , Jung Youngkyoo , Rogers Samantha D. , Whitlow Christopher T. , Williams Benjamin J. , Yang Mia , Lockhart Samuel N. 
Published: December 2020

AbstractBackgroundCortical thinning is an early marker of Alzheimer’s disease (AD) neurodegenerative changes. We examined relationships of cortical thickness and cerebral blood flow (CBF) to assess whether structural brain changes in AD‐related regions are associated with functional changes in blood flow dynamics. Previous reports of CBF indicate reduced blood flow progressing along the AD continuum from normal cognition (NC) to mild cognitive impairment (MCI) to AD. We hypothesized that reduced cortical thickness in AD‐specific brain regions would relate to reduced global gray matter (GM) CBF.MethodParticipants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N=373, mean age=70.5 years) underwent neuropsychological assessment, and T1 and pcASL MRI to assess brain structure and CBF. Participants were adjudicated as cognitively unimpaired (NC, N=212) or impaired (MCI or AD, N=161) using NIA‐Alzheimer’s Association criteria. T1 MRI were processed using FreeSurfer v5.3; an “AD‐signature” meta‐ROI cortical thickness value was calculated, which was thresholded to classify participants as neurodegeneration‐negative (N‐, above threshold) or ‐positive (N+, below threshold). PcASL MRI were processed to yield CBF images that were normalized to MNI space (Fig.1). A 2‐tissue partial volume correction was applied to yield voxelwise GM CBF. Mean GM CBF across a set of cortical AAL ROIs was calculated for each participant. A MANCOVA model adjusted for age, sex and education measured differences in GM CBF between N‐ and N+ groups. We additionally assessed cognitive status as a moderator of these associations.ResultWe found a significant difference in GM CBF between N‐ and N+ groups (p=0.010). Participants with lower meta‐ROI cortical thickness had reduced GM CBF compared to participants above the threshold (Fig.2). The interaction of cognitive status and N+/‐ group revealed lower CBF for impaired participants (Fig.3, unadjusted p<0.001), which remained significant after adjustment (p=0.014).ConclusionIn our ADRC cohort, neurodegenerative changes within brain regions vulnerable to AD pathology were associated with global GM CBF reductions. Cognitively unimpaired N+ participants exhibited similar levels of GM CBF as impaired N‐ participants. Future studies will assess whether unimpaired N+ participants with reduced CBF have a higher risk of conversion to MCI or AD.
A high‐throughput drug screen identifies berberine as a potent inducer of tau clearance
Authors: van der Kant Rik , Langness Vanessa , Rissman Robert A. , Goldstein Lawrence S.B. 
Published: December 2020

AbstractBackgroundBerberine is an isoquinoline alkaloid derived from plants of the Berberis genus. Berberine has been clinically evaluated for Type 2 Diabetes and has been shown to reduce blood glucose levels and improve lipid metabolism. Through an unbiased high‐throughput drug screen in human induced pluripotent stem cell‐derived neurons, we recently discovered that berberine also potently reduces Tau pathology in Alzheimer’s disease (AD) neurons.MethodWe used human iPSC‐derived neuronal models and Tau‐transgenic mice to uncover the mode of action by which Berberine reduces Tau pathology.ResultWe show that berberine acts on mitochondrial respiration and induces a switch in neuronal metabolism from oxidative phosphorylation to glycolysis. This switch induced by berberine, and mimicked by other mitochondrial targeting drugs such as metformin, drives activation of the energy sensor AMPK and leads to downstream activation of autophagosomal and proteasomal clearance of Tau. We show that berberine potently reduce Tau levels in a large panel of iPSC‐derived neuron from AD patients, as well as in Tau‐transgenic mice.ConclusionBerberine is a well‐tolerated oral agent that passes the blood‐brain‐barrier. Our data indicate that berberine could be repurposed for the treatment of AD and frontotemporal dementia with Tau pathology (FTD‐Tau).
Heterogeneous distribution of pathology in behavioral variant Alzheimer’s disease
Authors: Singleton Ellen H. , Hansson Oskar , Dijkstra Anke A. , Joie Renaud , Mantyh William G. , Tideman Pontus , Stomrud Erik , Leuzy Antoine , Johansson Maurits , Strandberg Olof , Smith Ruben , van Swieten John C. , Papma Janne M. , Wolters Emma E. , Coomans Emma M. , Golla Sandeep S.V. , Tuncel Hayel , Berendrecht Evi , Blujdea Raluca E. , Van Berckel Bart N.M. , Bouwman Femke , Scheltens Philip , Pijnenburg Yolande A.L. , Rabinovici Gil D. , Ossenkoppele Rik 
Published: December 2020

AbstractBackgroundA distinct subset of patients with Alzheimer’s disease (AD) experience early and predominant behavioral and personality changes, while the neurobiological origins of these symptoms are largely unknown. In this study, we examined the distribution of tau pathology using PET imaging or post‐mortem evaluation in patients with the behavioral variant of AD (bvAD).MethodFor the PET study, seven amyloid‐β positive clinically diagnosed patients with bvAD from the Amsterdam Dementia Cohort (ADC, n=2), University of California San Francisco (UCSF, n=3) and the Swedish BioFINDER study (n=2) underwent [18F]flortaucipir or [18F]RO948 (tau) PET (Table 1). Regional standardized uptake value ratios (SUVR) in entorhinal, temporoparietal, frontal, and insular cortex as well as mean cortical SUVR and frontal‐to‐parietal SUVR ratios were contrasted against patients with typical (memory‐predominant) AD (tAD; n=55, n=60 and n=90, respectively). For the post‐mortem component of the study, the percentages of AT8 (tau)‐positive areas in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between 9 cases with bvAD and 7 with tAD.ResultVisual inspection of subject‐specific tau PET patterns revealed more pronounced frontal involvement in 6/7 bvAD patients compared to patients with tAD (Figure 1). Regional SUVR analyses revealed higher‐than‐average tau uptake in 3/7 bvAD cases in the temporoparietal cortex, 5/7 in the frontal cortex, and 3/7 in the insular cortex compared to patients with tAD (Figure 2). Furthermore, 4/7 cases showed higher‐than‐average mean cortical SUVR and 6/7 cases had higher‐than‐average frontal‐to‐parietal SUVR ratios (Figure 2 & Table 2). Postmortem evaluation revealed that bvAD cases had a lower tau load in the CA1 region of the hippocampus compared to patients with tAD (p<.05); no differences were found, however, in temporal, parietal, frontal or insular regions (all p>.05, Figure 3 & Table 3).ConclusionThis multicenter case series with tau PET and neuropathological examination demonstrates a heterogeneous distribution of tau pathology across patients with bvAD, ranging from pronounced anterior involvement to a more temporoparietal pattern. Further work is needed to explore alternative pathophysiological mechanisms underlying the bvAD phenotype.
Brain transcriptome wide association study (TWAS) implicates 8 genes across 6 loci in Alzheimer’s disease
Authors: Gockley Jake , Montgomery Kelsey S. , Poehlman William L. , Liu Yue , Gerasimov Ekaterina S. , Greenwood Anna K. , Wingo Aliza P. , Wingo Thomas S. , Mangravite Lara M. , Logsdon Benjamin A. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD), an incurable neurodegenerative disease, currently affects 1.75% of the United States population, with projected growth to 3.46% by 2050. Common genetic variation linked transcript expression differences which confer AD‐risk isl necessary to elucidate AD mechanism and develop therapeutic interventions. We modified the FUSION pipeline to ingest expression from multiple neocortical regions, provide a set of 6780 gene weights which is abstracatable across the neocortex, and leverage these to find 8 genes with associated AD risk validated through summary mendelian randomization (SMR) utilizing IGAP summary statistics.MethodAncestry matching based on 1000 genomes supervised clustering utilizing yielded 2003 Northern European (CEU) profiles, 888 of which had matched genotype‐RNASeq profiles. Expression Z‐scaling within‐tissue allowed weights to be trained from multiple Neo‐cortical tissues (TCX = 248, FP = 50, IFG = 41, STG = 34, PHG = 34, DLPFC = 461) after RNA‐Seq profiles were corrected for covariate and AD diagnosis stage within study.ResultCis‐variant architecture alone was informative to train weights for 6780 (49.67%) autosomal genes, the majority of which signficantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). The median correlation to observed gene expression was 0.2176 (IQR = 0.179‐0.277). Validation rate in 621 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (71.08%) in DLPFC and (22.52%) in anterior cingulate cortex (ACC) profiles. After correction for joint conditional probability (JCP) and SMR validation, 8 genes were significantly associated with AD (FDR < 0.05); APOC1 (JCP = 2.22e‐22, SMR = 3.41e‐4), EED (JCP = 3.373e‐5, SMR = 2.50e‐4), CD2AP (JCP = 2.96e‐5, SMR = 2.66e‐4), CEACAM19 (JCP = 3.27e‐5, SMR = 1.00e‐2), CLPTM1 (JCP = 4.04e‐3, SMR = 2.58e‐3), MTCH2 (JCP = 0.011, SMR = 3.32e‐6), TREM2 (JCP = 0.021, SMR = 2.64e‐3), KNOP1(JCP = 0.039, SMR = 2.50e‐4).ConclusionWe provide evidence of cis‐genetic variation confering AD risk through 8 genes across six distinct genomic loci. Moreover, we provide a valuable resource to the community in the form of predictive gene expression weights that are abstractable to multiple neocortical regions and neuronal phenotypes.
Tau therapeutics: Clinical development status and future directions
Authors: Boxer Adam L. 
Published: December 2020

AbstractBackgroundAccumulation of insoluble, misfolded tau protein is a hallmark of AD, chronic traumatic encephalopathy and approximately half of frontotemporal lobar degeneration (FTLD), including progressive supranuclear palsy (PSP) and individuals with autosomal dominant mutations in the tau gene (MAPT), collectively termed tauopathies. While the protein structure and isoform composition differ among diseases, a general principle is that disease severity and clinical phenotype are strongly related to the amount and anatomical distribution of tau protein throughout the brain. In preclinical models generated from human MAPT mutations, strong evidence suggests that disease progression could be explained by transcellular spread of misfolded tau protein, and that reduction of misfolded tau protein levels or prevention of transcellular spread may be viable therapeutic strategies.MethodReview of tau therapeutics currently in clinical development and the tauopathies in which clinical trials may be most feasible at different stages of development.ResultThree classes of tau therapeutics are currently in clinical development: 1) small molecules designed to alter post‐translational modification, aggregation or clearance, 2) immunological therapies (anti‐tau monoclonal antibodies and vaccines) and 3) genetically‐targeted approaches (antisense oligonucleotides, siRNA, AAV‐mediated gene therapies). A few small molecules have completed phase 2 or 3 clinical trials in AD, FTLD or PSP, and two anti‐tau monoclonal antibodies have completed phase 2 studies in PSP. To date, there has been no evidence of clinical efficacy, although a few compounds have demonstrated target engagement.ConclusionThe availability of blood, CSF and PET biomarkers of AD tau pathology suggests that, early stage clinical trials focused on proof of biological concept are likely to be most informative in AD‐spectrum diseases, whereas there are potential advantages to conducting later stage clinical trials focused on clinical efficacy in primary tauopathies such as PSP. Regardless of clinical indication, genetically targeted therapies may have development advantages because of the potential responsiveness of biomarkers to these interventions. Questions to be addressed include: Which diseases are most likely to respond to tau therapeutics given that most were developed in preclinical models that overexpress human MAPT mutations? Do we have adequate biomarkers to demonstrate biological proof of concept and determine appropriate dose?
Potentially inappropriate medication use associated with lower mobility reserve among individuals with preclinical Alzheimer’s disease
Authors: Martinez Ashley I. , Jicha Gregory A. , Lee Kara , Beech Brooke F. , George Rosmy , Hall Megan , Abner Erin L. , Schmitt Frederick A. , Khouli Riham H. El , Eckmann Lynne , Huffmyer Mark , Moga Daniela C. 
Published: December 2020

AbstractBackgroundFalls, a leading cause of disability and mortality in older adults,1 are associated cognitive impairment and inappropriate medication use.2 We propose a novel construct, “mobility reserve” (MR), which describes an individual’s resilience against mobility decline. We hypothesize that augmenting MR may delay fall‐associated morbidity. Here, we investigate the association between MR and inappropriate medication use among participants with and without preclinical Alzheimer’s disease (pAD) enrolled in a randomized medication therapy management trial.3
MethodsNon‐demented older adults who used ≥1 potentially inappropriate medication4 were recruited for the RCT. The Medication Appropriateness Index was calculated for all medications (MAI) and for potentially inappropriate medications (MAI‐PIM). Participants’ gait speed (cm/s) was measured under normal conditions and while challenged with 1.5mg of scopolamine to unmask vulnerability. The difference in gait speeds was calculated as mobility reserve change score (MRCS). PET amyloid total brain relative standardized uptake values > 1.4 was used to define pAD.5Spearman correlation coefficients (rs) assessed the relationship between medication appropriateness and MRCS.Results36 participants were included in this analysis (mean age 75.0 years [SD 6.0]; 78% female); 10 (27.8%) were classified as pAD. The mean (SD) MAI and MAI‐PIM were 10.3 (5.1) and 5.4 (4.0) respectively, not differing by pAD status (p=0.92 and 0.11 for MAI and MAI‐PIM). The mean (SD) MRCS was ‐0.39 cm/s (9.4) (no difference by pAD status; p=0.84). Among those with pAD, MAI and MAI‐PIM were negatively correlated with MRCS (r = ‐0.53 and ‐0.46 respectively), which was not the case among those without pAD (r = 0.37 and 0.34), though a larger sample size is needed to add confidence to these estimates.ConclusionAmong community‐dwelling non‐demented older adults, more inappropriate medication use was associated with lower mobility reserve among those with pAD. These results support the hypothesized relationship between MR and medication appropriateness. Future studies should further operationalize measures of MR to open a novel intervention pathway for reducing fall‐related morbidity in cognitively at‐risk populations. References: 1. Katz R, Shah P. JAMA. 2010;303(3):273‐274. 2. Enderlin C et al. Geriatr Nurs. 2015;36(5):397‐406. 3. Moga DC et al. Trials. 2019;20(1):806. 4. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246. 5.Jack CR et al. Brain. 2015;138(12):3747‐3759.
Accounting for cognitive practice effects results in earlier detection and more accurate diagnosis of MCI: Biomarker confirmation
Authors: Kremen William S. , Sanderson‐Cimino Mark E. , Elman Jeremy A. , Tu Xin M. , Gross Alden L. , Panizzon Matthew S. , Eglit Graham M.L. , Jak Amy J. , Edmonds Emily C. , Thomas Kelsey R. , Eppig Joel S. , Williams McKenna E. , Bondi Mark W. , Lyons Michael J. , Franz Carol E. 
Published: December 2020

AbstractBackgroundPractice effects (PEs) mask true cognitive decline. Even with declines at follow‐up, PEs can still obscure even steeper declines. Accounting for PEs means that impairment cutoffs are reached earlier. Importantly, mild cognitive impairment (MCI) would be detected earlier. If these diagnoses are valid, there should be more biomarker‐positive MCI cases and fewer biomarker‐positive cognitively normal subjects (CNs). We tested this hypothesis using a replacement‐subjects method.MethodWe examined 722 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects who were CN at baseline (mean age=74.9±6.8). MCI at follow‐up was diagnosed by Jak‐Bondi and Petersen criteria. We identified “pseudo‐replacements” whose baseline age was matched to the age of returnees at their 1‐year follow‐up. Education and estimated premorbid IQ were also matched. Difference scores were calculated at Time 2 between returnees on their second testing and the demographically‐matched pseudo‐replacements on their first testing. Attrition effects were estimated by comparing returnee baseline scores with the full baseline sample. PEs = difference scores – attrition effects. PEs are then subtracted from follow‐up scores, with the resultant scores used in diagnosing MCI. CSF Aβ42 and phosphorylated (p)‐tau were measured 6‐12 months prior to retesting.ResultThere were significant PEs on 5 of 6 tests (average Cohen’s d=.27). For Jak‐Bondi diagnoses, accounting for PEs at follow‐up resulted in a 24.8% increase in the proportion of MCI cases (p<.000001). There were increased proportions of Aβ42‐positive (18.8%) and p‐tau‐positive cases (29.8%), and reduced proportions of Aβ42‐positive (5.8%) and p‐tau‐positive (7.9%) CNs (McNemar χ2: Aβ42: p<.0014, p‐tau: p<.028; Figure 1). Results were similar for Petersen diagnoses. Of 26 false negatives (i.e., CNs whose diagnosis changed to MCI after accounting for PEs), 9 (35%) were MCI without PE adjustment at 2‐year follow‐up.ConclusionAccounting for PEs led to earlier detection of MCI at 1‐year follow‐up. Biomarker data support these being more accurate diagnoses because more cases were biomarker‐positive and more CNs were biomarker‐negative. Longer‐term follow‐up indicated that MCI cases may be detected a year or more earlier if performance is adjusted for PEs. Accounting for PEs has meaningful, real‐world implications for early identification, which may, in turn, improve opportunities to slow disease progression.
Healthy dietary patterns are associated with better cognitive performance in older adults: Findings from National Health And Nutrition Examination Survey (NHANES) 2011‐2014
Authors: Gu Yian , Guo Jing , Moshfegh Alanna J 
Published: December 2020

AbstractBackgroundIncreasing evidence from community‐based population cohorts suggests that following healthy dietary patterns is protective against cognitive decline, Alzheimer’s disease, or other dementia in older adults. However, such findings have rarely been confirmed in nationally representative samples.MethodThe current study included 2,864 participants (≥60 years) of the NHANES 2011–2014 who completed both dietary and cognitive assessments. Self‐reported dietary intake was collected by trained interviewers using the USDA’s Automated Multiple‐Pass Method in two nonconsecutive 24‐hour dietary recalls. Intakes of nutrients and food groups were calculated using reference from the USDA 'Food and Nutrient Database for Dietary Studies' and 'Food Patterns Equivalents Database', 2011‐2014, respectively. Mediterranean‐type Diet (MeDi) and Healthy Eating Index 2015 (HEI15) scores were estimated from the mean intakes of the two diet recalls. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer’s disease Word Learning sub‐test (WL), Animal Fluency test (AF), and Digit Symbol Substitution test (DSST). Age, sex, race/ethnicity adjusted z‐score was calculated for each cognitive score, which were then averaged to get a composite cognitive score. Complex samples plan linear regression models were applied to examine the associations of diet and cognition, adjusted for age, sex, education, race (white/black/Hispanic/others), caloric intake, cycles (2011‐2012 /2013‐2014), and annual household income (< or ≥ $45,000).ResultMeDi and HEI2015 were associated with 0.028 (95%CI=0.004‐0.05, p=0.023) and 0.004 (95%CI=0.0002‐0.007, p=0.038) higher mean cognitive z‐score, respectively. Compared to the lowest tertile of MeDi, the highest tertile of MeDi was associated with 0.141 (95%CI=0.029‐0.253, p=0.015; p‐trend=0.016) higher mean cognitive z‐score. Compared to the lowest tertile, the highest MeDi tertile was associated with 1.001 (95%CI=0.161‐1.840, p=0.021; p‐trend=0.021), 1.05 (95%CI=0.227‐1.875, p=0.014; p‐trend=0.015) and 3.02 (95%CI=1.004‐5.027, p=0.005; p‐trend=0.004) higher WL, AF, and DSST, respectively, and the highest HEI15 tertile was associated with 0.827 (95%CI=0.154‐1.499, p=0.018; p‐trend=0.018) higher AF. The effect size of the highest tertile of dietary score was approximately equivalent to 3‐4 less years of aging (b of 1‐year aging=‐0.316, ‐0.229, and ‐0.867 for WL, AF, and DSST, respectively).ConclusionFollowing a healthy diet is associated with better cognitive performance in a nationally representative sample of older adults.
Global networks to address inequities and disparities in dementia: The case of LAC‐CD and GLoDePP
Authors: Parra Mario A , Chan Kit Yee , Ibanez Agustin 
Published: December 2020

AbstractBackgroundNew initiatives are emerging to bridge countries from the global south and global north to identify barriers that have prevented a global approach to the dementia challenge. The Latin American and Caribbean Consortium on Dementia (LAC‐CD) has demonstrated, over 5 years of intense networking activities, that challenges faced by LAC countries are very similar. The Global Dementia Prevention Program (GloDePP), a network that pursues similar aims, has more recently revealed that this also holds for low‐ and middle‐income countries (LMICs) beyond the LAC region. LAC‐CD and GLoDePP are two initiatives that can merge agendas to widen the characterization of the inequities and disparities affecting countries of the global south and propose actions towards harmonization of research and clinical practices.MethodsFrom 2015, LAC‐CD has held five workshops. Here we focus on outcomes from the 2015 (Santiago, Chile, 15 experts) and 2019 workshops (São Paulo, Brazil, 160+ members) which revealed a transition from a state of knowledge to specific actions. From 2018, GLo‐DePP has held five workshops in the UK and China involving experts from Bangladesh, Brazil, China, Ghana, India, Iran, Malaysia, Nigeria and Uruguay. GLo‐DePP workshops focused on the state of epidemic preparedness, research contexts, and readiness to join collaborative strategies focusing on prevention and management of dementia.ResultsThemes emerging from these workshops were: the need for contextually appropriate tools, more public awareness, identify and modify early and mid‐life risk factors, low‐cost methods to gather biomarker evidence across language and cultural groups, longitudinal brain health cohorts, contextually appropriate m‐health, e‐health, and global data science platforms for dementia prevention, detection, and intervention, evidence to inform: policy and health services delivery, investment priorities, national dementia plans and guidelines for equitable access to dementia management that are contextually adaptable across geographies and cultures (Chan et al., 2019; Parra et al., 2018).ConclusionLAC‐CD has recently proposed a knowledge‐to‐action framework which will turn such challenges into unprecedented opportunities. Clear strategies are emerging and paving the way towards harmonized agendas across LAC‐CD and GLoDePP (Parra et al., 2019). Such shared agendas shall provide the building blocks for future Global Dementia Strategies.