bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case Study: New Site Development Program Aimed at Improving Access and Enrollment in Clinical Trials for Traditionally Underrepresented Populations (TUP)
Authors: Rodgers Tamiko MaGee , Zisko Leigh , Dwyer John , Sipchen Julie , Brown Christina M. , Soza Aida L. , Falcon James A. , Falcon Antonio 
Published: December 2022

AbstractBackgroundIncreased awareness and access to clinical trials is essential for recruitment of traditionally Underrepresented Populations (TUPs) into Alzheimer’s disease clinical trials. Identifying trusted physicians in diverse communities and helping build new Alzheimer’s research sites is an effective approach to materially increasing UP participation in clinical research. Global Alzheimer’s Platform (GAP) partnered with two Primary Care Physicians in Rio Grande City, Texas to open a new Alzheimer’s research facility.MethodGAP identified the Rio Grande Valley area to open an Alzheimer’s disease trial site for multiple reasons: high prevalence (∼20%) of Alzheimer’s, significant (98%) Hispanic/Latino population, trusted community physicians with a large geriatric patient population, and lack of access to research opportunities. GAP worked with the physician(s) to develop a project plan to open the clinical trial site. Areas addressed included space, staff, supplies, subjects, and sponsors. Several obstacles to overcome included tracer availability, finances, raters, and training for a clinically sound, but research‐naïve team.ResultAfter 7 months of site development, El Faro Health & Therapeutics (El Faro) opened in November 2021. The site was approved for their first trial in January 2022. The site has completed feasibility or has initiated onboarding for up to 5 additional projects and intends to activate in up to 3 more trials by Q2 2022. In their first three months, the site has completed ∼85 memory screens and reviewed more than 200 charts to begin developing a potential participant database. El Faro successfully leveraged their strong community relationships gaining media attention from over 10 media sources. Additional updates on referrals, prescreens, screens and randomizations will be provided at the conference.ConclusionMembers of the Hispanic/Latino community are 1.5 times more likely to develop Alzheimer’s disease; however, they make up ∼1% of AD clinical trial participants. By establishing an AD research center in Rio Grande City, TX, barriers to participation are being removed, which will result in an increase in trial enrollment of UPs. The success of El Faro will demonstrate that true equity can be achieved in Alzheimer’s research with collaboration from local leaders in diverse communities.
Longitudinal Blood Biomarker Trajectories in Preclinical Alzheimer’s Disease
Authors: Yakoub Yara , Ashton Nicholas J. , Karikari Thomas K , Strikwerda‐Brown Cherie , Montoliu‐Gaya Laia , Meyer Pierre‐François , St‐Onge Frederic , Schöll Michael , Breitner John , Zetterberg Henrik , Blennow Kaj , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: December 2022

AbstractBackgroundBlood‐biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross‐sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood‐biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood‐biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET.MethodWe included a subset of 126 cognitively unimpaired older adults from the Prevent‐AD cohort. Blood was drawn from baseline up to four‐year follow‐up visits. We measured Aβ42/Aβ40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ (18F‐NAV4694) and tau (18F‐flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ‐PET retention (SUVR cut‐off = 1.29), and tau‐PET positivity by entorhinal cortex flortaucipir binding (SUVR cut‐off = 1.23). Using these thresholds, 82 subjects were classified as A‐T‐, 29 as A+T‐, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups.ResultAmyloid‐PET‐positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ42/40 when compared with amyloid‐PET‐negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A‐T‐ group (p = 0.01; Figure 1). Overall, the A+T‐ and A+T+ groups had lower levels of plasma Aβ42/40 compared with the A‐T‐ group (p = 0.05, p = 0.0189; Figure 2), and the A+T‐ group had higher pTau231 compared with A‐T‐ participants (p = 0.0006; Figure 3). Longitudinal rate of change in Aβ42/40 and pTau231 did not differ between the groups.ConclusionWe observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.
Biomarkers and neuropathology in posterior cortical atrophy: an international, multi‐site study
Authors: Chapleau Marianne , La Joie Renaud , Mundada Nidhi S. , Fumagalli Giorgio G , Formaglio Maïté , Grinberg Lea Tenenholz , Hromas Gabrielle , Kasuga Kensaku , Lacombe‐Thibault Mégane , Levin Netta , Lladó Albert , Miklitz Carolin , Perani Daniela , Rodriguez‐Porcel Federico , Seeley William W. , Spina Salvatore , Tousi Babak , Vandenberghe Rik , Walker Jamie M. , Wu Liyong , Yong Keir X X , Pelak Victoria S , Ossenkoppele Rik , Rabinovici Gil D. 
Published: December 2022

AbstractBackgroundPosterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing. The underlying pathology in PCA is most commonly Alzheimer’s disease (AD), but large‐scale biomarker and neuropathological studies are lacking. In this ongoing project we aim to describe demographic, clinical, biomarker and neuropathological correlates of PCA in a large‐scale international cohort.MethodWe contacted 55 research centers conducting PCA research identified in a literature review (n=1353 papers) as well as additional sites recruited through the ISTAART Atypical AD Professional Interest Group (n=7 sites) requesting deidentified, single‐subject data from PCA patients (published and unpublished). Inclusion criteria were: 1. clinical diagnosis of PCA, 2. availability of AD biomarkers (PET or CSF) or 3. availability of autopsy diagnosis. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected.ResultAs of January 2022, we have collected individual patient data from 390 participants evaluated at 14 sites in 10 countries (Table 1). In the preliminary sample, mean age at symptom onset was 63.1 ± 8.8 years, 62.3% of participants were female, and 78.3% presented with a “PCA‐pure” clinical syndrome by Crutch 2017 diagnostic criteria. APOE4 genotype was present in 45.6% (n=125). Preliminary results show that 82.9% (n=270) display predominant MRI atrophy and 91.9% (n=185) predominant FDG hypometabolism in posterior cortical regions. CSF amyloid markers were positive in 80.2% participants (n=187), while CSF phosphorylated tau markers were positive in 61.4% (n=184). Amyloid PET was positive in 85.2% (n=129) while tau PET was only available in 65 patients (positive in all, and all were amyloid positive). At autopsy (n=36, data from 4 centers), high AD neuropathologic changes were found in all but one patient, who had primary frontotemporal lobar degeneration with TDP‐43 type A pathology. Lewy bodies, argyrophilic grains and cerebral amyloid angiopathy were common co‐pathologies (Figure 1).ConclusionIn a large international cohort, PCA is strongly associated with positive AD biomarkers and neuropathology. Data collection is ongoing, and we further aim to identify clinical features associated with non‐AD underlying causes of PCA.
Inhibition of mitochondrial carbonic anhydrases reduces Amyloid β induced cell death in cerebral endothelial cells
Authors: Lemon Nicole L , Ilies Marc A , Fossati Silvia 
Published: December 2022

AbstractBackgroundThe Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS) which has been observed to become dysfunctional in Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA). Cerebrovascular amyloid disrupts the function of brain endothelial cells (ECs). Previous findings from our lab demonstrated that Acetazolamide (ATZ) and methazolamide (MTZ), both pan‐carbonic anhydrase (CA) inhibitors, prevent NVU cell death in models of AD and CAA. Although these FDA‐approved pan‐CA inhibitors are protective, a more specific targeting of the isoforms involved in AD pathology may not only reduce side effects, but also increase the efficacy of pan‐CA inhibition. We have shown that CAIs reduce Aβ‐induced cytochrome C release from the mitochondria, caspase‐9 activation, and mitochondrial H2O2 production in NVU cells. Therefore, we hypothesize that mitochondrial CA‐VA/B are the main isoforms involved in these mechanisms and we anticipate that using inhibitors selective for CA‐VA/B will prevent cerebral EC apoptosis, thereby reducing NVU dysfunction and AD progression.MethodHuman cerebral microvascular EC were treated with the vasculotropic Aβ40‐Q22 Dutch mutant, alone and in combination with a number of CA‐V inhibitors. Cell viability was measured with WST‐1 reagent and apoptosis was measured as the amount of fragmented nucleosomes. To assess mitochondria‐mediated apoptotic pathways, the expression of BAX BCL‐2 and caspase 9 activation were evaluated. The levels of different CA enzymes in cerebral EC was also assessed following Aβ treatment.ResultInhibition of CA‐VA/B significantly increased cerebral EC viability in the presence of Aβ40‐Q22. CA‐VA/B inhibitors also significantly reduced Aβ40‐Q22 induced DNA fragmentation in a dose dependent manner. The inhibition of CA‐VA/B attenuated Aβ40‐Q22 induced caspase‐9 activation as well as the increase in expression of the pro‐apoptotic protein BAX in cerebrovascular ECs. Interestingly, we detected changes in the expression of mitochondrial isoform, CA‐VB, after treating cerebral ECs with Aβ.ConclusionThese results indicate that the targeted inhibition of CA‐V is protective against Aβ‐challenge in cerebral ECs through the inhibition of mitochondria‐mediated cell death and suggest that the efficacy of these new compounds should be explored in animal models of cerebrovascular amyloidosis.
Cerebrospinal Fluid Lactate Levels along the Alzheimer’s Disease Continuum and Associations with Blood‐Brain Barrier Integrity, Age, Cognition and Biomarkers
Authors: Zebhauser Paul Theo , Berthele Achim , Goldhardt Oliver , Diehl‐Schmid Janine , Priller Josef , Ortner Marion , Grimmer Timo 
Published: December 2022

AbstractBackgroundCerebrospinal fluid (CSF) lactate levels have been suggested to be associated with disease severity and progression in several neurological diseases as an indicator of impaired energy metabolism, neuronal death or microglial activation. A small number of studies have examined CSF lactate levels in dementia due to Alzheimer’s disease (AD) and found higher values in AD patients compared to healthy controls (HC). However, these studies were mostly small in size, the inclusion criteria were not always well defined, and the diagnostic value and pathophysiological significance of CSF lactate in AD remains unclear.MethodsWe examined CSF lactate levels and potentially associated factors in a large (n=312), biologically and clinically well‐defined sample of patients with AD at the stage of mild cognitive impairment (MCI‐AD) and dementia (ADD), HC, and patients with frontotemporal lobar degeneration (FTLD).ResultsContrary to previous studies, patients with ADD and HC did not differ in CSF lactate levels. However, we found higher values for patients with MCI‐AD compared to those with ADD and to HC in univariate analysis, as well as for MCI‐AD compared to ADD when controlling for age and blood‐brain barrier integrity. CSF lactate levels were associated with age and blood‐brain barrier integrity but not with clinical severity or CSF biomarkers of AD.ConclusionCSF lactate does not indicate biological or clinical disease severity in AD, nor does it differentiate between patients with AD and healthy controls or patients with FTLD. However, higher CSF lactate levels were found in earlier stages of AD, which might be interpreted in the context of inflammatory processes.
Neuroimaging‐based Biomarkers of Brain Aging in Healthy Older Adults
Authors: Nemati Samaneh , Newman‐Norlund Roger , Newman‐Norlund Sarah , Sayers Sara , Busby Natalie , Bonilha Leonardo , Fridriksson Julius 
Published: December 2022

AbstractBackgroundWith increasing longevity, the incidence of age‐associated functional decline and dementia is on the rise, with Alzheimer’s disease, the third most common type of dementia, projected to affect 13.8 million people by 2050. Previous studies on aging populations have reported that while people chronologically age at the same rate, an individual’s brain maturation/aging trajectory, which can be quantified by measuring the deviation of their brain’s structure and function from normative data, can be predictive of more serious forms of cognitive decline. Software capable of accurately computing this trajectory based on commonly acquired clinical scans, such as BrainAGE R, could provide reliable biomarkers of pre‐clinical disease states thereby enhancing clinicians’ ability to make early diagnosis of cognitive decline. In this study, we evaluate the relationship between resting‐state functional connectivity (rsFC) and BrainAGE measures in healthy older adults.MethodSixty participants (40 Female, 20 Male) aged between 60‐80 (M = 66.78, SD = 6.98) were recruited as part of the Aging Brain Cohort dataset at the University of South Carolina (ABC@UofSC). Participants completed structural T1‐weighted (T1w) and resting‐state fMRI (rsfMRI) scans. Preprocessing of the data was done using default preprocessing steps specified by the CONN toolbox. Following image preprocessing and denoising, ROI‐to‐ROI connectivity matrices in CONN were created for each participant. Individual brain age was estimated using BrainAGE R computer algorithm based on their T1w scans. BrainAGE difference scores were then calculated by computing the difference between each participant’s chronological age and their estimated brain age. Finally, a univariate general linear model analysis was used to identify significant relationships between BrainAGE difference scores and rsFC while controlling for participants’ chronological age.ResultOur analysis revealed a significantly negative association between BrainAGE scores and rsFC of several brain networks. In particular, higher BrainAGE scores were associated with decreased connectivity between 1) default mode and salience networks, 2) default mode and fronto‐parietal networks (bilateral), and 3) visual and salience networks.ConclusionOur results provide novel evidence that accelerated brain maturation/aging, as indexed by BrainAGE scores, is associated with specific patterns of decreased rsFC in healthy older adults.
Artificial Intelligence Tools to Evaluate Language and Speech Patterns in Alzheimer's Disease
Authors: Favaro Anna , Motley Seneca , Samus Quincy M , Butala Ankur , Dehak Najim , Oh Esther S , Moro‐Velazquez Laureano 
Published: December 2022

AbstractBackgroundSpeech and language problems are one of the earliest signs of neurodegenerative diseases including Alzheimer’s disease (AD), but they are often difficult to detect especially in the early stages. Utility of assessing speech and language problems using artificial intelligence (AI) has been examined in the past. However, the accuracy of different methods has been variable, preventing incorporation of these techniques in clinical use. In this study, we present different speech‐based machine learning techniques. We focused on the automatic extraction of a wide array of interpretable features from the speech signals, then compared these features across different neurological disorders.MethodSpoken responses to four different tasks (i.e., Cookie Theft Picture (CTP) and Stroop Task) were recorded from 80 participants, 5 with AD, 28 with Parkinson's disease (PD), 18 normal controls (NCs), and the remaining with other neurological diseases (OTRs). We automatically extracted several acoustic and linguistic features using speech and language technologies. We conducted pairwise Kruskal–Wallis tests to assess how speech and language abilities differed between different neurodegenerative disease vs. control groups. We used SciPy Python library.ResultThe total amount of speech time and pauses as well as the average duration and the variance of the number pauses significantly differed between AD and NC and between PD and NC in almost every task (p <0.05). Prosodic features based on F0 contour and F0 on the first and last voiced segment resulted in significant differences across tasks between AD and NC, AD and PD, AD and OTR (p <0.05). The phonological posterior for the phonological classes of consonantal, voiced, labial, nasal, velar, trill, and close significantly differed in almost every task between AD and NC, AD and PD and AD and OTR (p <0.05). Moreover, from the transcriptions of the CTP task, the number of sentences and noun phrases differed significantly between AD and NC, whereas the number of contrastive connectives and the moving average type‐token ratio were significant between NC and OTR (p <0.05).ConclusionAutomated analysis of speech employing machine learning techniques can provide objective assessment of patients with AD that may be useful in distinguishing AD from other neurological disorders.
Patient Self‐Reported Cognitive Ability and Self‐Reported Confidence in Symptom/Medication Management in People with Dementia Disorders: Twin Pillars of Truth or Illusion for Clinicians?
Authors: Baek Steven , Kaczmarek Olivia , Peraza‐Bonilla Sophia , Bumstead Barbara , Zarif Myassar , Gudesblatt Mark 
Published: December 2022

AbstractBackgroundDementia associated diseases (DAD) refers to clinical conditions characterized by progressive impairment of cognition that interferes with an individual’s ability to function independently due to such cognitive impairment (CI). Clinically, CI can vary in degree and combination across multiple important cognitive domains (CD). Clinician and patient with DAD (PwDAD) self‐awareness/recognition of such varied types/degrees of CI might not only be sub‐optimal or inaccurate, but unable to recognize subtle change or provide quantitative information across multiple CD. Patient self‐reported outcome measures (PRO) are now often incorporated into routine care to gauge cognitive impairment, disability progression and participation in self‐management of symptoms, medications and shared decision making. Clinicians rely on patient provided information/history to treatment decisions. Incorporating PRO measures into routine care has increased and impacts care plans and decision‐making. Both accurate and reliable information is needed by clinicians to improve clinical decision‐making and outcomes as well as to avoid unanticipated/adverse outcomes.MethodRetrospective cross‐sectional analysis of PwDAD who have completed PRO on the same day for both the Self‐Efficacy for PROMIS Managing Symptom s‐SF 8a (MS‐SF) and Neuro‐QOL Cognition Function‐SF (CF‐SF) in the course of routine care. Linear regression analysis of relationship was explored with significance (p<0.05)Results205 PwDaD, 65% female, average age 70 +/‐ 15 years. A significant positive correlation was found between the MS‐SF and CF‐SF reflecting the patient’s perceived cognition abilities and self‐reported self‐confidence in managing their symptoms (r2 = 0.5, p‐value<0.01).ConclusionPwDaD who report higher self‐efficacy/confidence with managing medications on MS‐SF also report higher self‐perception of cognitive functioning on CF‐SF. Low perceived cognitive ability tracks with low confidence in managing symptoms. However, CF‐SF does not track with actual measures of cognitive performance suggesting that clinicians can be misled by relying on patient self‐reported confidence of symptom management. Accurate measurements of both cognitive ability and patient ability to self‐management symptoms are needed in real world care to intervene proactively and improve outcomes.
Epigenome‐wide association study and integrative cross‐omics analyses of cerebral white matter hyperintensities implicate novel gene networks related to Alzheimer’s disease
Authors: Yang Yunju , Yang Qiong , Knol Maria J. , Mishra Aniket , Armstrong Nicola , Adams Hieab H.H. , Smith Jennifer A , Breteler Monique M.B. , Grabe Hans J. , Wardlaw Joanna M , Launer Lenore J. , Longstreth William T , Seshadri Sudha , Debette Stéphanie , Fornage Myriam 
Published: December 2022

AbstractBackgroundCerebral white matter hyperintensities (WMH) on magnetic resonance imaging are markers of cerebral small vessel disease (cSVD), a major risk factor for Alzheimer’s disease and related dementia (ADRD). Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation (DNAm) has received little attention.MethodWe investigated the association of blood DNAm at approximately 450,000 CpG sites with WMH burden in 9,732 middle to late age adults from 14 cohorts. Integrative cross‐omics analyses followed to elucidate the role of identified DNAm in cSVD.ResultWe identified 12 single‐CpG and 46 region‐based DNAm associations with WMH burden. Our top discovery single CpG, cg24202936 (P = 7.6×10−8), was associated with F2 expression in blood (P = 6.4×10−5), and colocalized with FOLH1 expression in brain (posterior probability = 0.75). Some single‐CpG loci (cg17417856 and cg06809326) with suggestive evidence (P<1×10−5) were also identified as differentially methylated regions (DMRs) in PRMT1 and in CCDC144NL‐AS1. Mendelian randomization analyses showed that cg06809326 is causally associated with WMH burden (OR [95% CI]: 1.39 [1.03‐1.87], P = 0.03) and that expression of CCDC144NL‐AS1 mediates this association. DMR analysis, joint epigenetic association analysis, and multi‐omics colocalization analysis consistently identified a role of DNAm near SH3PXD2A, a locus previously identified in genome‐wide association studies of WMH. Gene set enrichment analyses revealed functions of the WMH‐associated DNAm loci in the blood‐brain barrier (BBB) and in the immune response. Integrative cross‐omics analysis identified 19 key regulatory genes in two WMH‐associated networks related to extracellular matrix (ECM) organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated peroxisome proliferator‐activated receptor alpha (PPAR‐α) agonist as a target drug for WMH, which was also proposed as a promising target for ADRD.ConclusionOur epigenome‐wide association study and integrative cross‐omics analyses implicate novel genes influencing WMH burden, which converged on pathways related to the immune response and to a compromised BBB possibly due to disrupted cell‐cell and cell‐ECM interactions. The results also suggest that PPAR‐α may contribute to lowering risk for WMH possibly through protection against BBB disruption, which may potentially modify the ADRD risk.