bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronicling the diagnostic journey, symptom experiences, and disease impact in frontotemporal degeneration
Authors: Barker Megan S , Joyce Jillian L. , Dodge Shana G. , Niehoff Debra , Denny Sharon S. , Dacks Penny A. , Dickinson Susan , Cosentino Stephanie , Wheaton Dianna K.H. 
Published: December 2022

AbstractBackgroundFrontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive decline or changes in cognition, language, behavior, and personality. The FTD Insights Survey was created with the aim of gathering information on the lived experience of FTD. Here we present a subset of survey data chronicling the diagnostic journey, symptoms experienced, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease course.MethodIn total, 1,796 individuals completed the survey. Persons reported as severe to profoundly impaired due to FTD, as well as past caregivers, were excluded for this analysis. The resulting cohort included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses (n = 395 behavioral variant frontotemporal dementia or Pick’s disease; n = 155 primary progressive aphasia; n = 61 progressive supranuclear palsy or corticobasal syndrome; n = 13 FTD with amyotrophic lateral sclerosis; n = 32 unknown).ResultAround half of survey respondents saw three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses, including primary psychiatric disorders, Parkinson’s disease, or Alzheimer’s disease, were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was highly endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick’s disease. Participating independently in activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the significant disruption to daily living even at the mild and moderate stages of disease.ConclusionOverall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop new therapies that improve quality of life
Validation of a continuous model of amyloid‐β CSF/PET discordance across cohorts and PET tracers
Authors: Sala Arianna , Gispert Juan Domingo , Salvadó Gemma , Shekari Mahnaz , Bucci Marco , Collij Lyduine E. , García David Vállez , Garibotto Valentina , Barkhof Frederik , Nordberg Agneta K , Rodriguez‐Vieitez Elena ,   Alzheimer's Disease Neuroimaging Initiative, on behalf of the AMYPAD project
Published: December 2022

AbstractBackgroundRecently, we provided evidence that discordance in CSF vs. PET amyloid‐β biomarkers represents a natural phase in the progression of amyloid‐β pathology, with either CSF or PET biomarkers becoming abnormal first, based on well‐validated cut‐offs. We found that CSF‐/PET+ individuals had lower prevalence of APOE‐ε4 genotype and slower rate of amyloid‐β PET accumulation compared with CSF+/PET‐ individuals [1]. Given the methodological limitations of binary cut‐offs, here we aimed to validate a continuous model of imbalance in CSF vs. PET amyloid‐β biomarkers across cohorts and tracers, and to investigate biological factors underlying discordance in CSF and PET results.MethodThe study included n=944 participants from two independent cohorts: ADNI and AMYPAD. We selected n=822 individuals (73.0±7.4 yr‐old, 53% female, 45% APOE‐ε4 carriers, 16.3±2.6 yr‐education) from ADNI, ranging from cognitively‐normal to demented, with global cortical 18F‐florbetapir‐PET and CSF‐Aβ42 measurements available within 3‐months; all participants also had CSF‐Aβ38 and CSF‐Aβ40 available. We also selected n=112 individuals (65.6±7.0 years, 59.8% female, 30.6% APOE‐ε4 carriers, 15±3.5 yr‐education) ranging from cognitively‐normal to MCI from the AMYPAD Prospective and Natural History Study (PNHS) cohort with CSF‐Aβ42 and global cortical 18F‐flutemetamol (n=75) or 18F‐florbetaben (n=37) PET available within one‐year, expressed in Centiloids. In each cohort, we iteratively fitted the CSF/PET cross‐sectional data to a hyperbolic regression model with three parameters, by minimizing the Euclidean distance of the experimental points to the fitted line (Fig. 1). For each individual, we derived a measure of imbalance based on standardized residuals, with zimbalance>0 reflecting PET‐over‐CSF imbalance (zimbalance<0 reflecting CSF‐over‐PET imbalance).ResultsThe hyperbolic model adequately fitted the CSF/PET data across cohorts and tracers (pseudo‐R2>0.90, Fig. 1). In ADNI, greater zimbalance (PET‐over‐CSF imbalance) was associated with lower APOE‐e4 prevalence, and higher levels of CSF‐Aβ42, CSF‐Aβ40 and CSF‐Aβ38, corrected for demographics and disease stage. Studies in the AMYPAD cohort are ongoing.ConclusionWe tested a continuous model of amyloid‐β CSF vs. PET imbalance across cohorts and PET tracers. Imbalance in CSF vs. PET amyloid‐β values carries meaningful biological and genetic information, which allows to identify heterogeneous pathological trajectories in the AD continuum, with implications for clinical trials.[1] Sala et al. (2021) Mol. Psychiatry 26(10):5864‐5874
INPP5D inhibition attenuates amyloid pathology through the regulation of microglial functions.
Authors: Lin Peter Bor‐Chian , Tsai Andy Po‐Yi , Soni Disha , Lee‐Goseelin Audrey , Nho Kwangsik , Lamb Bruce T , Oblak Adrian L 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome‐wide association studies recently highlighted a prominent role for microglia in late‐onset AD (LOAD). Specifically, inositol polyphosphate‐5‐phosphatase (INPP5D) is selectively expressed in brain microglia and one of its common intronic variants (rs35349669; OR=1.08, 95%CI=1.06‐1.11) has been reported to be associated with increased risk of LOAD. INPP5D is linked to the triggering receptor expressed on myeloid cells 2 (TREM2) signaling, but little is known about the function of INPP5D in microglia and how INPP5D regulates TREM2‐related AD pathogenesis. Therefore, we aim to understand the role of INPP5D in microglia and AD pathology.MethodWe performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density using transcriptomic data from the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD) cohort. We also performed quantitative real‐time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression and microglial markers in the 5xFAD amyloid mouse model with INPP5D deficiency. Behavioral deficits were assessed by the Y‐maze assay in all animal cohorts at 4‐ and 6‐month of age. The primary microglial culture was used the evaluate the amyloid uptake ability of microglia.Result
INPP5D gene expression was upregulated in LOAD and positively correlated with amyloid plaque density. Inpp5d expression increased as the disease progressed in the 5xFAD mice, and selectively in plaque‐associated microglia. Inpp5d deficiency mitigated the plaque burdens and neuropathology in the 5xFAD mice and further protected against behavioral deficits induced by amyloid pathology. Inpp5d deficiency modulates the microglial signaling, including Trem2 expression and Syk phosphorylation, and further upregulates the expression of the post‐synaptic marker. In the primary microglial culture, Inpp5d inhibition increased the uptake of fibril amyloid beta‐peptide.ConclusionOur findings show that INPP5D expression increases throughout the AD progression and is predominantly in plaque‐associated microglia. Importantly, INPP5D deficiency reduces Abeta pathology through the regulation of microglial functions, highlighting INPP5D as a potential therapeutic target.
A Population‐Based Meta‐Analysis of Plasma Glial Fibrillary Acidic Protein for Cognitive Decline and Incident Dementia
Authors: Gonzales Mitzi M , Wiedner Crystal , Wang Chen‐Pin , Bis Josh C , Li Zhiguang , Himali Jayandra J , Parent Danielle , Kautz Tiffany F , Pase Matthew P , Aparicio Hugo J , Beiser Alexa S , Launer Lenore J. , Fornage Myriam , Tracy Russell P. , Seshadri Sudha , Satizabal Claudia L 
Published: December 2022

AbstractBackgroundExpression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, co‐localizes with neuropathology in the brain. Blood‐derived levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability and assess the biomarker’s potential efficacy in community settings.MethodPlasma GFAP levels were assayed using a Simoa HD‐1 analyzer in 4,338 adults without prevalent dementia from four longitudinal cohort studies, the Framingham Heart Study (FHS), the Cardiovascular Health Study (CHS), the Age, Gene/Environment Susceptibility – Reykjavik Study (AGES), and the Coronary Artery Risk Development in Young Adults Study (CARDIA). The associations between plasma GFAP levels with a general cognition score derived from multiple cognitive tests, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer’s disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random effects models with inverse variance weighting. The Sidik‐Jonkman estimator was used to report overall associations across studies.ResultMeta‐analysis indicated that higher plasma GFAP associated with lower general cognition (ß=‐0.09, [95% confidence interval [CI]: ‐0.15 to ‐0.03], p=0.005), but not with total brain or hippocampal volume (p>0.05 for all). However, higher GFAP was significantly associated with a 2.5‐fold higher risk of incident all‐cause (Hazard Ratio [HR]: 2.47 (95% CI: 1.52‐4.01)) and Alzheimer’s disease dementia (HR: 2.54 (95% CI: 1.42‐4.53) per standard deviation increase over up to 15‐years of follow‐up.ConclusionThe findings suggest that elevations in plasma GFAP may be detectable several years prior to a clinical diagnosis, highlighting the potential value of the biomarker for aiding dementia risk prediction at a population‐based level
Novel AD biomarker based on platelets tau: Expanding to plasma detection
Authors: González Andrea , Guzmán‐Martinez Leonardo , Maccioni Ricardo Benjamin 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly. One of the major drawbacks of this disease is the lack of molecular biomarkers that could provide of an early detection, as the ones currently available are invasive (CSF biomarkers), not cost‐efficient (neuroimaging, PET scan) and do not provide an early detection. In this work we propose the novel biomarker Alz‐tau®, based on platelet tau, as a non‐invasive and cost‐efficient way for early detection of pathological events that may lead Alzheimer’s disease.MethodsPlasma samples were obtained by centrifugation. Platelets were obtained from blood samples of AD patients and controls, lysed to obtain protein extracts and further processed for a western blot analysis. The immuno‐ detection was performed with a novel monoclonal antibody tau51, which detects two variants of tau protein: a high molecular weight variant (HMW) and a low molecular weight variant (LMW). The results obtained were subjected to a densitometric analysis with ImageJ and the algorithm HWM/LMW was obtained.ResultsWe demonstrated that in platelets the algorithm HWM/LMW was statistically higher in AD patients when compared to controls. Similar results were obtained in plasma. Likewise, the platelet biomarker has a proven sensitivity of 71.43% and a specificity of 69.23%, while a sensibility of 80% and specificity of 66.5% was found in plasma samples.ConclusionsHere, we demonstrate the efficiency and functionality of of a novel, non‐invasive, and cost‐efficient biomarker for early detection of AD, based on 4 clinical trials. The most relevant feature of this biomarker is that it is able to detect alterations before the patient presents any symptoms, thus it would be highly beneficial for prevention of AD.
The Gut Microbiota in Mild Cognitive Impairment in Community‐Dwelling Older Adults in Taiwan
Authors: Chuang Yi‐Fang 
Published: December 2022

AbstractBackgroundRecent microbial studies of Alzheimer’s disease and mild cognitive impairment (MCI) have focused on the alterations of gut microbiota in cognitively impaired patients. However, related research remains limited and varies with analytical pipelines. This study aims to examine biodiversity and the differential abundance of gut flora in MCI.MethodThe study sample of 96 older adults was derived from a community‐based prospective cohort study, the Epidemiology of Mild Cognitive Impairment in Taiwan (EMCIT). Among them, 31 were ascertained as MCIs, matched with 65 cognitively normal individuals on age, gender and community. Fecal samples were analyzed by Illumina sequencing of the V3‐V4 regions of the 16S rRNA gene. The divisive amplicon denoising algorithm 2 (DADA2) pipeline was applied to the production of the amplicon sequence variant (ASV) table, and the SILVA database 138.1 was used to assign taxonomies.ResultThere is no significant difference in alpha‐ and beta‐ diversity between MCI and cognitively normal adults after adjusting for age, gender, community, education and hypertension. (Fig. 1). However, the results of linear discriminant analysis (LDA) effect size (LEfSe) showed a differential abundance of ASVs between two groups. Increased abundance of several genera within Firmicutes phylum and reduced abundance of Ruminococcus, Butyricimonas, Oxalobacter are associated with MCI. A ROC curve using these microbial genera of interest can distinguish MCI patients from controls with AUC = 84%. (Fig. 2)ConclusionCompared with cognitively normal older adults, the gut microbiota of older adults with MCI identified from the community was significantly altered, particularly manifesting in enriched genera from the Firmicutes phylum and decreased abundance of genera Ruminococcus, Butyricimonas, Oxalobacter.
Language Fluency and Premature Brain Aging
Authors: Busby Natalie , Newman‐Norlund Sarah , Sayers Sara , Newman‐Norlund Roger , Nemati Samaneh , Bonilha Leonardo , Fridriksson Julius 
Published: December 2022

AbstractBackgroundAge‐related changes in the brain are often associated with general cognitive decline. Cognitive aging affects the ability to produce spoken language, with older adults experiencing increased difficulties in word‐finding1 and verbal fluency2,3. Neurodegenerative diseases such as Alzheimer’s disease are often attributed to an acceleration of typical aging processes (i.e., premature aging). Accelerated age‐related atrophy is present in mild cognitive impairment4,5 and premature brain aging may contribute to declining cognitive skills6,7. A recent study demonstrated that the disparity between chronological age and brain age (based on measures of cortical integrity) is a good predictor of early cognitive impairment8. Our aim was to extend these findings by investigating the role of brain age in overall cognition as well as language in particular.MethodParticipants included 216 healthy controls (age range 20–79) from the Aging Brain Cohort at the University of South Carolina9. Structural T1‐weighted MRI scans were collected, and participants completed the Montreal Cognitive Assessment (MoCA10). Brain age was calculated based on T1‐weighted structural data using the BrainAgeR analysis pipeline (github.com/james‐cole/brainageR). A brain age gap estimate (BrainAGE)11 was calculated as the difference between brain age and chronological age. This was used as the primary measure of advanced/delayed brain health, where positive values represent premature brain aging.ResultEstimated brain age differences ranged from 22 years younger to 14 years older than chronological age. Pearson correlations revealed a negative correlation between MoCA total score and chronological age (r(209) = ‐0.41, p<0.001), but not in partial correlations using BrainAGE, accounting for chronological age (r(207) = ‐0.003, p = 0.48.). Regarding our language measure (words generated during the MoCA fluency task), we observed a negative correlation with BrainAGE, corrected for chronological age (r(208) = ‐0.133, p = 0.03), but no correlation with chronological age (r(210) = ‐0.04, p = 0.58).ConclusionOur data support the hypothesis that differences between chronological and brain age are related to cognition and language, and highlight the utility/importance of brain age in understanding cognitive impairment. Interestingly, findings suggest that there may be a particularly strong relationship between the brain age gap estimation and MRI‐based measure of brain aging and language in particular.
Feasibility Study for Detection of Retinal Amyloid in Clinical Trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Trial
Authors: Ngolab Jennifer , Korouri Shaina , Rissman Robert A. 
Published: December 2022

AbstractBackgroundAlterations to the retina manifest in patients diagnosed with neurodegenerative diseases such as Alzheimer’s disease (AD). Retinal imaging techniques open the possibility for non‐invasive evaluation of AD pathology. Clinically AD diagnosed patients exhibit retinal amyloid deposits. Few studies monitoring preclinical individuals exist, limiting the assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection.MethodWe compared retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline.ResultParticipants from the A4 trial exhibited a greater number of retinal spots compared to those from the LEARN study. We report a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr).ConclusionThe results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.
Support for Dementia Care Partners using Telehealth: Tele‐STELLA Phase 1
Authors: Lindauer Allison , Gothard Sarah , Boardman Charles , Smith Samantha , Mattek Nora , McDaniel Delaney , Bernard Hannah , Tran Leslie , Tadesse Ruth 
Published: December 2022

AbstractBackgroundEffective interventions that reduce dementia Care Partner stress and burden are available. but access to them is impeded by barriers such as distance, cost, behavioral symptoms of dementia, stigma and social anxiety.Tele‐STELLA is a multi‐component, videoconference‐based intervention designed to provide easily‐accessible education and support for Care Partners.The goal of this intervention is to diminish the frequency of behavioral symptoms that persons with dementia experience, and Care Partner reactivity to these symptoms. Here we report on the findings of Phase 1 of Tele‐STELLA.MethodIn Tele‐STELLA interventionists meet with Care Partners, via videoconferencing, to identify specific behavioral symptoms of dementia that are distressing for them. The interventionists and Care Partners meet, first individually and then in groups, to address these symptoms using an analytic approach. Care Partners are encouraged to contact each other for support.Prior to, during, and after the 8‐week intervention we collect data on behavioral symptoms (frequency and Care Partner reactivity to the symptoms), depression, and burden using electronically‐administered surveys.ResultOf the 26 Care Partners who completed 8 weeks of the intervention 19 (70%) were female, average age of 67; 25 (96%) identified as white; 14% lived in a rural area. Burden, as assessed on the Revised Memory and Behavior Problem Checklist, did not change significantly over the 8‐week intervention, nor did scores on depression, grief or quality of life measures. There was no change in behavior frequency, but we did appreciate a significant improvement in Care Partner reactivity to the two personalized target problems they identified (p<0.01 and p=0.025, respectively).ConclusionSignificant improvement was seen in Care Partner reactivity to the specific behavioral problems chosen by the Care Partners. This suggests the intervention is effective when Care Partners work on the personalized problems they identified. The lack of significant improvement on the (depersonalized) surveys may be due to unbiased reporting by Care Partners using electronically‐administered surveys, small sample size, or stabilization of affective symptoms. Phase 1 will inform revisions for the remainder of the study (total n goal=150).