bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue inhibitor of matrix metalloproteinases 4: a novel marker associated with CAA
Authors: Jäkel Lieke , Stellingwerf Arno , Kort Anna M. , Kusters Benno , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Kuiperij H. Bea , Verbeek Marcel M. 
Published: December 2023

AbstractBackgroundWe have previously shown that matrix metalloproteinase 9 (MMP9) and tissue inhibitor of proteinases 3 (TIMP3) are specifically expressed in the vasculature of patients with cerebral amyloid angiopathy (CAA). Moreover, we have demonstrated increased MMP9 and decreased TIMP3 levels, as well as an altered MMP9:TIMP3 ratio in the vasculature of CAA patients that suffered from intracerebral haemorrhages (CAA‐ICH) compared to CAA patients without ICH (CAA‐nonICH). We now extended our studies to investigate whether TIMP4 may have a similar role in CAA, as this has not been studied before.MethodUsing immunohistochemistry, we studied occipital lobe tissue of 44 controls (mean age 78.4 years; 50% female) and 58 CAA patients (77.5 years; 55% female; 40 CAA‐nonICH and 18 CAA‐ICH). Vascular TIMP4 staining was scored in a semiquantitative manner. Using ELISA, we measured TIMP4 CSF levels of 33 CAA patients (mean age 72.2 years; 47% female) and 35 controls (mean age 71.2 years; 51% female). For a subset of CSF samples (11 CAA samples and 14 controls), the levels of MMP2, MMP9, and MMP14 have been determined previously, and now their ratios to TIMP4 were calculated. Differences between CAA patients and controls were assessed using (ordinal) linear regression analysis.ResultIn brain tissue, CAA cases had increased vascular TIMP4 expression when compared to controls (p = 0.00002, figure 1). TIMP4 expression did not differ between CAA‐nonICH and CAA‐ICH cases. In the absence of vascular TIMP4 staining, we often observed perivascular staining. Decreased levels of perivascular TIMP4 staining were observed in CAA‐ICH cases when compared to CAA‐nonICH cases (p = 0.045) and to controls (p = 0.035). CSF levels of TIMP4 were decreased in CAA patients compared to controls (p = 0.03, figure 2). In addition, the ratios of MMP2 (p = 0.038), MMP9 (p = 0.005), and MMP14 (p = 0.025) to TIMP4 were increased in CAA patients compared to controls.ConclusionWe demonstrated increased TIMP4 expression in vessel walls of CAA patients compared to controls. In contrast, TIMP4 CSF levels were decreased in CAA patients compared to controls, whereas MMP:TIMP4 ratios were increased, indicating a disbalance of MMP/TIMP4 levels in CAA pathophysiology.Funding: BIONIC project (no. 733050822, ZonMW) and CAFÉ project (no. 5R01NS104147‐02, NIH).
Association between blood pressure and Alzheimer’s disease biomarkers in cognitively unimpaired adults
Authors: Osset Mariona , Sánchez‐Benavides Gonzalo , Buongiorno Mariateresa , Sierra Alejandro De La , Shekari Mahnaz , Minguillon Carolina , Kollmorgen Gwendlyn , Carboni Margherita , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo , Grau‐Rivera Oriol ,   for the ALFA study
Published: December 2023

AbstractBackgroundHigh blood pressure is an established risk factor for dementia. However, the underlying mechanisms are not completely understood. We aimed to evaluate the association between blood pressure and Alzheimer’s disease (AD) biomarkers in cognitively unimpaired adults from the ALFA+ study.MethodWe analyzed data from 301 participants with available cross‐sectional blood pressure measures (acquired by trained staff with an oscillometric device after 5 minutes of rest) and cerebrospinal fluid (CSF) AD core biomarkers data (CSF p‐tau and t‐tau were measured with Elecsys® immunoassays and CSF Aβ42 and Aβ40 with the Roche NeuroToolKit, a panel of robust prototype assays, both from Roche Diagnostics International Ltd), and a subset of 278 participants with amyloid PET data, of whom 110 had a second follow‐up PET acquisition (3.4 years after in average). We used separate linear regression models to analyze the association of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP = SBP‐DBP) with CSF and PET biomarkers at a cross‐sectional level, and their association with the annualized rate of change in amyloid PET [(follow‐up centiloids – baseline centiloids) / years between PET scan acquisition]. We adjusted all models by age, sex, APOE status, waist‐to‐hip ratio, dyslipidemia, diabetes, tobacco and alcohol consumption, physical activity, and antihypertensive treatment.ResultHigher baseline SBP (but not DBP or PP) was significantly associated with increased amyloid PET uptake over time (p = 0.043). In cross‐sectional analyses, DBP was negatively associated with Aβ42 (p = 0.013), Aβ40 (p = 0.026), and t‐tau (p = 0.045), and marginally associated with p‐tau (p = 0.069), but not with the Aβ42/40 ratio nor baseline amyloid PET uptake. Associations with Aβ42 and t‐tau were no longer significant after further adjustment by CSF Aβ40 levels. SBP and PP were not associated with CSF biomarkers or baseline amyloid PET uptake.ConclusionHigher SBP is associated with longitudinal brain amyloid accumulation, which reinforces the importance of blood pressure control in AD prevention. DBP is also associated at a cross‐sectional level with AD biomarker concentration in CSF, but the attenuation of this association after adjusting by Aβ40 suggests a non‐specific.
Deep Learning Based Estimation of Synthetic Tau PET from Amyloid PET
Authors: Naseri Maryam , Carmichael Owen T. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common pathological substrate for dementia. Both tau and amyloid positron emission tomography (PET) scans are valuable for evaluating innovative treatments and studying AD progression. However, tau‐PET is extremely expensive and not universally available. Estimating tau‐PET images from amyloid‐PET would mitigate these concerns. In this study, we proposed a novel application of the Conditional Generative Adversarial Network (cGAN) framework to generate high quality tau‐PET (18F‐flortaucipir) scans from the corresponding amyloid‐PET (18F‐florbetapir) scans.MethodA dataset of 475 individuals who underwent both 18F‐florbetapir and 18F‐flortaucipir scans with different clinical diagnosis (Table 1) were used in our study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) online depository. Our cGAN model was trained for 50 epochs using real, corresponding amyloid‐tau PET pairs. The resulting model takes real amyloid‐PET images as input and outputs synthetic tau‐PET images (Figure 1.a). The similarity between synthetic and real tau‐PET images was evaluated via the structural similarity index (SSIM), peak signal to noise ratio (PSNR), and normalized root mean squared error (NRMSE). Furthermore, we extracted regional standard uptake value ratios (SUVRs) and meta‐region of interest (ROI) SUVRs from the real tau‐PET scans and synthetic tau‐PET scans. The utility of the synthetic tau‐PET meta‐ROI SUVR for identifying real tau‐PET scans that are tau positive was evaluated in terms of true positive rate (TPR), false positive rate (FPR), and the area under the receiver operating characteristic (ROC) curve (AUC).ResultOur cGAN model yielded a SSIM of 0.917, a PSNR of 27.04, and a NRSME of 0.18 on the test set. The ROC curve analysis (Figure 2) resulted in an AUC of 0.84%. By applying a cut‐off threshold corresponding to the model optimal operating point, a TPR of 90% and FPR of 28% were achieved. The SUVR analysis yielded a mean absolute percentage error of 8.3% ± 6.5% on the test dataset.ConclusionThe proposed cGAN model generated high quality 18F‐flortaucipir PET images from 18F‐florbetapir PET images (Figure 1.b). This could be highly useful in a screening paradigm to use amyloid‐PET to identify those individuals most likely to be tau positive.
Neurite‐based white matter alterations in MAPT mutation carriers: A multi‐shell diffusion MRI study in the ALLFTD consortium
Authors: Corriveau‐Lecavalier Nick , Tosakulwong Nirubol , Lesnick Timothy G. , Reid Robert I. , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Jones David T. , Vemuri Prashanthi , Rademakers Rosa , Ramos Eliana Marisa , Geschwind Daniel H. , Knopman David S. , Botha Hugo , Savica Rodolfo , Radford Jonathan Graff , Ramanan Vijay K , Graff‐Radford Neill R , Wszolek Zbigniew , Forsberg Leah K. , Petersen Ronald C. , Heuer Hilary W. , Boxer Adam L. , Rosen Howard J. , Boeve Brad F. , Kantarci Kejal 
Published: December 2023

AbstractBackgroundWe aimed to assess axonal integrity in MAPT mutation carriers and early white matter (WM) neurodegeneration in asymptomatic carriers using traditional diffusion tensor imaging (DTI) measurements, i.e., fractional anisotropy (FA) and mean diffusivity (MD), and neurite orientation dispersion and density imaging (NODDI).MethodWe included available multi‐shell diffusion MRI data from 21 MAPT mutation carriers (16 asymptomatic; 5 symptomatic) and 31 non‐carrier family members as controls from the ALLFTD consortium. We used linear mixed‐effect models to assess WM abnormalities measured with FA and MD, neurite density index (NDI) and orientation dispersion index (ODI), combined across hemispheres. Separate models were conducted in all MAPT mutation carriers relative to controls while accounting for relatedness and age, then in symptomatic and asymptomatic carriers relative to controls. ComBat was used to harmonize data across sites.ResultIn models contrasting all MAPT carriers versus controls, WM alterations involved the cingulum bundle (FA, ODI), fronto‐temporal, entorhinal (FA, MD, NDI), and the inferior temporal WM (FA) after correcting for multiple comparisons (Fig. 1). In models contrasting symptomatic and asymptomatic MAPT carriers versus controls, symptomatic carriers had widespread involvement of the fronto‐temporal WM including the cingulum (FA, ODI), entorhinal (MD, FA, NDI), amygdala (MD, NDI) and inferior temporal (FA) areas after correcting for multiple comparisons. Asymptomatic carriers showed higher entorhinal MD and lower inferior temporal and cingulum FA relative to controls, and a more widespread pattern of higher ODI involved the medial temporal, superior temporal and occipital WM as well as long association and projection fibers including the internal capsule, cingulate bundle and fronto‐occipital fasciculi, although they were not statistically significant after correction for multiple comparisons.ConclusionTraditional DTI and novel NODDI measurements revealed some extent of overlap as well as divergences in patterns of WM abnormalities, indicating axonal loss is a feature of neurodegeneration in MAPT mutation carriers. Our results suggest that traditional DTI and novel NODDI measurements may have different sensitivities to WM alterations in MAPT mutation carriers, and that axon‐based metrics, particularly ODI measurements, may be more sensitive to the early WM involvement during the asymptomatic stage of the disease.
Robot‐Administered Serious Brain Games for Older Adults with Mild Cognitive Impairment or early‐stage Alzheimer’s Disease: A Pilot Study
Authors: Mahoor Mohammad , Abdollahi Hojjat , Donis Stephanie Melgar , Chileshe Lombe , Pittman Daniel , Emamian Eshrat 
Published: December 2023

AbstractBackgroundTraditional methods for disease management have shown limited success treating AD/ADRD or mitigating its symptoms. Innovative technology such as Artificial Intelligence and Socially Robots, have begun to alleviate the growing need for novel solutions for AD/ADRD. While Socially Assistive Robots (SAR) are used to interact with patients with dementia or other mental disorders, to our knowledge, no such cooperative social robots have been studied to co‐play serious brain games with older adults with MCI or early‐stage AD/ADRD.MethodThe study involved 20 older adults (average age: 77.7; std: 6.43; 15 female) living in a care facility who were diagnosed with MCI or Early‐Stage ADRD (SLUMS 10‐25). They participated in 12 different games (e.g., Words, Picture Puzzle, Ryan Runs, Flow Control, Birds, Checkers, Solitaire, Birds Count, etc.) with a social companion robot named Ryan, every day for 8‐10 weeks. These games aimed to improve memory, cognitive function, and physical activity. Each participant had a Ryan device in their apartment and were trained on how to use it. The study collected data on usage time, win/loss rate, difficulty level, average score, and average duration per game, as well as depression screening (PHQ‐9) and SLUMS scores before, during, and after the study.ResultParticipants in the study spent 887 hours using Ryan. They spent 254 hours (28.7%) playing games on Ryan. On average they spent 12 minutes (std = 5 minutes) per day playing serious games with Ryan. Checkers, Flow Game, Picture Puzzle, Solitaire, and Word Puzzle, were the most popular games among all. On average, the SLUMS and PHQ‐9 scores improved by 3.3 and 2.43 points, respectively.ConclusionOur study also shows that on average, participants performed better over time in playing the games. For example, the average Win Rate or Scores of the participants in playing the Flow Game, Word Puzzle, improved over the weeks by about 0.5% and 29 scores, every week, respectively. That means participants were more engaged in playing those games and were able to focus and increase their score or win rate over time.
In silico prioritiziation of drug repositioning candidates for Alzheimer’s disease using signature search meta‐analysis
Authors: Bellur Orhan , Kastenmuller Gabi , Requena Francisco , Kaddurah‐Daouk Rima F. , Krumsiek Jan , Arnold Matthias 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with no effective treatment. Due to the genetic, pathological, and clinical heterogeneity among patients with AD, traditional drug development has struggled to target AD‐related pathways. Drug repositioning is a promising alternative to de novo drug development that investigates the potential of existing drugs to be effective in AD. Transcriptome signature matching is one repositioning approach that relies on the signature reversion principle to identify candidate drugs. In this study, we report on several potential candidate drugs for AD obtained by meta‐analyzing transcriptome‐based signature search methods on AMP‐AD nominated target genes for AD that are differentially expressed across seven brain regions.MethodAs search input, we used genes that are nominated as AD targets by the AMP‐AD initiative and significantly differentially expressed in at least one brain region. We compared their expression signatures against the CMAP and LINCS reference databases via four signature search methods (CMAP, LINCS, gCMAP, and correlation‐based methods). Significant candidate drugs were ranked based on their score for each search method and then meta‐analyzed using an ensemble rank aggregation approach employing a modified version of the Dowdall rule. Top‐scoring candidate drugs for AD were annotated using literature search and functional enrichment analysis results.ResultHighest‐scoring drugs in the meta‐analysis included psycholeptics and psychoanaleptics (including acetylcholinesterase inhibitors), antibiotics, antivirals, histone deacetylase (HDAC) inhibitors, and anti‐inflammatory agents. Among those were drugs that are already used for symptomatic treatment of AD or are currently investigated in clinical trials. Novel candidate drugs reported here include antipsychotics, corticosteroids, and calcium channel blockers. Functional enrichment analysis of known targets of these candidate drugs showed shared targeting of biological processes related to dopaminergic synaptic transmission, calcium ion transport regulation, and alkaloid metabolic processConclusionGene expression signature matching is a promising approach for in silico drug repositioning. Our results describe several novel potential candidate drugs for AD obtained through the signature reversion principle, demonstrating the utility of meta‐analyzing data across brain regions and signature search strategies in prioritizing drug repositioning candidates for AD.
Biochemical Evidence for a Pathological Variant of Progressive Supranuclear Palsy
Authors: DeTure Michael , Chalk Jessica L , Murray Melissa E. , Dickson Dennis W. 
Published: December 2023

AbstractBackgroundTau proteins aggregate into spatially and morphologically distinct lesions in primary and secondary tauopathies. These signature lesions result from deposition of tau proteins that are distinctly modified via missense mutation and/or post‐translational modification for each disease strain. Identifying the unique tau protein abnormalities that lead to specific neurodegenerative diseases is beneficial in their early diagnosis and treatment. This is especially true for Progressive Supranuclear Palsy a primary tauopathy with clinical symptoms mirroring Parkinsonian syndromes and frontotemporal dementias.MethodBiochemical analysis of tau aggregates from patients with a pathological diagnosis of Progressive Supranuclear Palsy (n = 60) demonstrate that the tau protein modifications observed in this disease result from tau that is specifically modified and thereby forms the basis of the distinct disease strains observed. Here data collected using the sarkosyl‐insoluble tau fractions from tissue samples of pathologically diagnosed patients with Progressive Supranuclear Palsy without comorbidities allows for the direct observation of the modifications. Most interesting is the variability of the tau proteins that actually accumulate for this disease opening up the possibility that tau strains may exist within any given tauopathy even as the clinical manifestations appear similar. This indicates that early and specific identification and detection of these strains is critical for the development of therapies for these diseases.ResultExtraction and examination of sarkosyl‐insoluble tau proteins from deceased patients pathologically diagnosed with Progressive Supranuclear Palsy indicate that multiple tau strains exist within this primary tauopathy. Western blotting of these extracts from patient tissues demonstrates a unique banding pattern of insoluble tau in a subset of the cases that exhibit extreme hyperphosphorylation as indicated by additional high molecular weight tau banding. These patients also had an earlier age of onset and age of death indicating a more aggressive disease strain. Additional data is presented comparing the structure and seeding capability of this insoluble tau and the distribution and burden of insoluble tau in these Progressive Supranuclear Palsy patients compared to those with typical onset and insoluble tau signature.ConclusionMultiple pathological tau strains exist in Progressive Supranuclear Palsy.
Cognitive functions as predictors of daily functioning among older adults
Authors: Wardana Nido Dipo , Zhang Zhenyu , Lejko Nena , Opmeer Esther , De Deyn Peter Paul , Reesink Fransje E , Spikman Jacoba M , Herrmann Christoph S , Enriquez‐Geppert Stefanie , Aleman André , Ćurčić‐Blake Branislava 
Published: December 2023

AbstractBackgroundCognitive and daily functioning are conceptually critical in distinguishing Mild Cognitive Impairments (MCI) from dementia (Petersen, 2004), but findings on the association between the two have not always been consistent (e.g., Putcha & Tremont, 2016; Teng et al., 2010). We aimed to investigate whether cognitive functions could predict daily functioning among older adults.MethodA total of 182 participants were included in this study, aged between 51 and 92 years. Cognitive functioning was measured using various neuropsychological tests which target different domains (e.g., trail‐making test, WAIS digit span, verbal fluency), while daily functioning was measured using the Functional Activity Questionnaire (FAQ) and the Instrumental Activities of Daily Living (IADL). The Geriatric Depression Scale (DGS) was used to assess depression as a possible moderator. The association between cognitive domains and daily functioning was examined using Partial Least Squares Structural Equation Modelling in R with the “seminr” package.ResultA model with three cognitive predictors and no moderator provided the best fit to the data. However, the model only explained 16.7% of the total variance. Furthermore, only memory was significantly linked to daily functioning (b = ‐0.367, 95% CI [‐0.53 ‐0.18]), while language and attention/executive functions were not. Memory, language, and daily functioning showed good construct validity (all AVE > 0.5 and HTMT < 0.9), but “attention/executive function” construct suffered from poor convergent validity (AVE = 0.43) with only two out of its seven indicators demonstrating loading larger than 0.708. Also unexpectedly, depression was not found to be a significant predictor or a moderator.ConclusionOur preliminary results suggest that cognitive function explains a small portion of the daily functioning variance and memory was found to be the best cognitive predictor. Indeed, in addition to executive function, memory has been rather consistently mentioned as crucial in the maintenance of daily functioning (Pérès et al., 2008; Royall et al., 2007). The lack of evidence for the role of executive function in this study might be due to the poor convergence of the “attention/executive function” construct in our model, suggesting that it may represent different cognitive functions and should be investigated further.
Predicting Transitions from Mild Cognitive Impairment to Dementia within 5‐years
Authors: Amini Samad , Hao Boran , Yang Jingmei , Karjadi Cody , Kolachalama Vijaya B. , Au Rhoda , Paschalidis Ioannis 
Published: December 2023

AbstractBackgroundEarly detection of individuals at high risk of future progression toward dementia is in great need, particularly in the era of emerging treatments for Alzheimer’s disease. Given the easier administration of neuropsychological (NP) tests over invasive and expensive biomarker acquisition, we seek to predict the future cognitive status of an individual based on digital voice recordings of NP exams.MethodWe utilized automatic speech recognition and natural language processing techniques to create an automated tool that predicts if an individual with mild cognitive impairment (MCI) will develop dementia in a fixed follow‐up window (5 years). We characterize the predictive accuracy of this approach using data from the Framingham Heart Study. First, the automated transcription of the digital voice recordings were classified into 8 main NP sub‐tests including memory assessment, naming and language skill, verbal fluency, general questions, etc. Using a large language model, only the participants’ sentences were encoded into quantitative data. These data and the participants’ characteristics, such as age, sex, ApoE4 (+/‐) genotype, and education were employed to train and test a binary classifier, predicting dementia withing 5 years after a positive MCI diagnosis. We also provide a comparison between our approach and alternative models using demographics and ApoE genotype or the Mini‐Mental State Examination (MMSE) score.ResultWe evaluated the performance of the classification task on the data containing 111 stable MCI and 103 progressive MCI subjects. Our method achieved an average accuracy of 75.5% on the held‐out test data while a baseline model using age, sex, education, and ApoE has an average accuracy of 71.8%. The sensitivity and specificity of the proposed method versus the baseline model are 78.2% vs. 81.8% and 72.7% vs. 61.8%, respectively. Our approach also significantly outperforms the model based on the MMSE score by a margin of 14% in accuracy.ConclusionWe have analyzed digital voice recordings of NP exams for participants with MCI to predict their cognitive status in 5 years. The proposed approach offers a fully automated procedure with higher accuracy, providing an opportunity to develop an accessible and easy‐to‐administer screening tool that could be easily adapted to any language.