bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloid and tau deposition influences cognitive and functional decline in Down Syndrome
Authors: Grigorova Monika , Mak Elijah , Brown Stephanie S G , Beresford‐Webb Jessica , Hong Young T , Fryer Tim D , Coles Jonathan P , Aigbirhio Franklin I , Tudorascu Dana L. , Cohen Ann D. , Christian Bradley T. , Ances Beau , Handen Benjamin L. , Laymon Charles M , Klunk William E , Clare Isabel , Holland Anthony J , Zaman Shahid 
Published: June 2023

AbstractBackgroundDown Syndrome (DS) is the most common neurodevelopmental disorder caused by the presence of trisomy 21 (1:800 to 1:1000 live births worldwide). The extra copy of chromosome 21 is associated with a 4‐5 fold overexpression of the amyloid precursor protein (APP) gene, increased accumulation of cerebral beta‐amyloid (Aβ) in the brain, subsequent neurofibrillary tangle (NFT) formation and neurodegeneration. This study investigates whether tau has (i) an independent effect from amyloid on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid in the exacerbation of decline in aging DS.Method105 participants with DS underwent baseline PET AV‐1451 and PET PiB scans to quantify tau deposition in Braak regions II‐VI and Striatum and amyloid‐β status respectively. A longitudinal cognitive testing battery was performed consistent with previous research in the same study cohort, with all participants completing at least two timepoints, and 26 completing three timepoints, with an average of 17 months between study visits. Linear Mixed Effects models were implemented to assess how tau and amyloid deposition are related to change over three time points.ResultThree cognitive outcome measures showed a significant effect of time: the Free + Cued Recall (t = ‐6.09, p < 0.01), Cued Intrusions (t = 3.19, p < 0.01) and NTG (z = 5.33, p = 0) variables. Tau SUVR was a significant independent predictor of cognitive and functional change. The three‐way interaction between time, PiB status and tau was significant in the models of episodic memory and visuospatial cognition (Figures 1‐3).ConclusionOur results contribute to an emerging framework in which the elevated risk of developing dementia involves mechanisms associated with both amyloid‐β and tau aggregation. This is supported by our finding that when including the two‐way interactions between amyloid status and time and regional tau and time in the same model, tau seems to be a more significant predictor of cognitive change over time than amyloid status. Our results suggest a synergistic relationship between PiB status and tau as predictors of change in memory and visuospatial cognition.
Sensorimotor responses and emotional perception in empathy for pain: An study in Alzheimer's disease, Parkinson's disease, and healthy older adults
Authors: Martínez‐Pernía David , Troncoso Alejandro , Blanco Kevin , Rivera‐Rei Álvaro , Olivares Daniela , Grandi Fabrissio , Soto Vicente , Forno Gonzalo , Barría Silvia , Villagra Roque , Slachevsky Andrea 
Published: June 2023

AbstractBackgroundMotricity has been proposed to shape our perception and the pre‐reflective knowledge of the other as embodied agents. Through our motor system, we have a meaningful pre‐reflective conception of the experience of the other (empathy). We compared the sensorimotor responses and emotional perception in persons with Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy older adults (HOA) while they watched videos of sportswomen/sportsmen suffering physical accidents and videos of a neutral condition.Method86 participants older than 60 years were recruited (AD = 28, PD = 25, HOA = 33). Subjects with AD were diagnosed following NINCDS‐ADRDA criteria and PD with the United Kingdom Parkinson’s Disease Society Brain Bank. The assessment consisted of two parts. Firstly, a neuropsychological battery that included assessment in global cognition (ACE‐III), executive function (IFS, FAS), memory (FCRST), and social cognition (Minisea). Secondly, participants stood up without moving on a force platform while watching videos (60 seconds long and seven scenes each). One video showed sportswomen/sportsmen having physical accidents practicing extreme sports (pain condition), and the other was a neutral condition (home furnishings). At the end of each video, participants rated valence, intensity, and control (1‐9). Each scene was analyzed through six consecutive windows: three seconds before the fall and three after the fall. The six windows of the neutral condition were selected by taking the central temporal part of each scene. Subsequently, and in each window, the AnteroPosterior amplitude of the Center of Pressure (AP‐CoP) was calculated.ResultsParticipants with AD showed significant impairment in practically all cognitive domains, compared to PD and HOA. An Anova (group*condition*temporal windows) revealed a simple effect on group and condition in AP‐CoP displacement. AD and PD showed higher AP‐CoP in both pain and neutral condition than HOA. PD and HOA showed higher AP‐CoP in pain condition than neutral condition, but not AD. In the ANOVA (group*condition), AD rated (p <0.01) higher the emotional valence in the pain condition (5,93±2,72) than PD (3,52±2,2) and HOA (4,06±2,29).ConclusionSensorimotor responses in AD and PD showed enhanced AP‐CoP when compared to HOA. Moreover, AD patients showed a marked impairment in perceiving empathy towards the pain of others.
Uncovering proteostasis biology causing Alzheimer’s Disease using AMP‐AD transcriptomic data
Authors: Xu Dong 
Published: June 2023

AbstractBackgroundProteostasis biology is the network of various pathways associated with protein homeostasis and malfunction, which is the major cause of developing various neurodegenerative diseases like Alzheimer’s Disease. Recently, Accelerated‐Medicine Partnership – Alzheimer’s Disease consortia has released a huge amount of OMICS data generated by thousands of post‐mortem brains from various cohorts. Such data provides excellent opportunities to gain insight about proteostasis pathway network crosstalk behind Alzheimer’s Disease. As a part of early discovery initiatives using transcriptomic bulk RNA‐seq data derived from post‐mortem brain, AMP‐AD consortia published data‐driven identification of 30 network modules that are supposed to capture disease biology unbiased to any hypothesis. These modules are thousands of genes co‐expressed in the population in various conditions robust to any computational methods, batch effect of cohort‐specific effects.MethodWe explored these AMP‐AD modules from the proteostasis perspective by identifying proteostasis relevant network modules published from AMP‐AD and further integrating additional omics data and network properties to identify candidates associated with Alzheimer’s Disease pathology. We hypothesize that these candidates could be tested for early validation as potential drug targets.ResultOur analysis shows that proteostasis is one of the major underlying mechanisms confounded in most of the network module. However, certain modules are more enriched for proteostasis‐relevant pathways, suggesting their role in disease progression. Furthermore, some of the proposed candidates are known to be involved in the disease, indicating utility of this analysis providing additional candidates for early validation towards AD therapeutics.ConclusionAMP‐AD transcriptomic data analysis provides significant insight on proteostasis biology causing Alzheimer’s Disease.
Sex as a moderator of the association between frailty and mild behavioral impairment
Authors: Guan Dylan X. , Rockwood Kenneth , Smith Eric E. , Ismail Zahinoor 
Published: June 2023

AbstractBackgroundFrailty and mild behavioral impairment (MBI) are associated with dementia and sex differences are recognized in both. Each can facilitate early detection and treatment. This study investigated the association between frailty and MBI and whether this association is moderated by sex.MethodCross‐sectional data from 219 participants (48.9% female; mean and SD of age = 72.2 ± 6.5 years, and education = 15.8 ± 3.5 years) from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study was analyzed. No participants had dementia: 58 (26.5%) were cognitively normal and 161 (73.5%) had mild cognitive impairment. Frailty was measured using the frailty index (FI); higher scores indicate more health deficits/greater frailty. MBI symptoms were derived from Neuropsychiatric Inventory Questionnaire scores using a published algorithm with a cut‐off of >0 indicating MBI symptom presence. As with the FI, greater MBI severity was indicated by higher scores. Multivariable logistic and linear regressions adjusted for age, sex, education, and cognitive diagnosis were used to test the association between FI and MBI symptom presence and severity, respectively, with MBI as the outcome variable. An FI‐by‐sex interaction term was included in the linear regression model to test for sex‐dependent effects.ResultThe FI mean and SD across the entire cohort was 0.14 ± 0.06 (median = 0.14, IQR = 0.09–0.17, range = 0.02–0.38). Approximately half (51.6%) showed MBI symptoms (mean and SD of severity = 1.8 ± 2.7). Higher FI scores were associated with the presence of MBI symptoms both globally and in the domains of decreased motivation, affective dysregulation, and psychosis (Table 1). Higher FI scores were also associated with more severe MBI symptoms in a sex‐dependent manner: both sexes reported similarly low MBI symptom severity at low (‐1 SD) levels of FI but males reported 1.9x higher MBI symptom severity relative to females at high (+1 SD) levels of FI (Figure 1).ConclusionThe FI is associated with both the presence and severity of MBI, especially for males. These findings suggest that patients with frailty should be assessed for MBI and that patients with MBI should be assessed for frailty.
The effects of carotid artery stiffness on cerebral small vessel disease and cognition
Authors: Robert Caroline , Lieng‐Hsi Ling , Tan Eugene , Gyanwali Bibek , Venketasubramanian Narayanaswamy , Lim Shir Lynn , Richards Arthur Mark , Chen Christopher , Hilal Saima 
Published: June 2023

AbstractBackgroundCarotid artery stiffness is associated with cognitive impairment and dementia, however, the underlying mechanism remains unknown. We examined the association of carotid artery stiffness with cerebral small vessel disease (CSVD) markers, cognitive impairment, dementia with its subtypes, as well as cognitive performance.MethodIn this case‐control study, 272 subjects from a memory clinic underwent physical and medical evaluation along with carotid ultrasonography, 3T brain magnetic resonance imaging and detailed neuropsychological assessment. Carotid ultrasonography was conducted to assess arterial compliance (AC), pressure‐strain elastic modulus (Ep), β‐index, augmentation index (AI), and pulse wave velocity‐β (PWV‐β). Brain MRIs were graded for white matter hyperintensities (WMH), lacunes, and cerebral microbleeds (CMBs). Participants were classified as no cognitive impairment, cognitive impairment no dementia, as well as dementia and its subtypes; Alzheimer’s disease (AD) and vascular dementia (VaD). Cognition was assessed using NINDS–Canadian Stroke Network harmonization neuropsychological battery.ResultIncreased carotid β‐index (β = 0.73, P<0.001), Ep (β = 0.86, P<0.001), and PWV‐β (β = 0.83, P<0.001) were independently associated with WMH. Ep (OR = 1.42, 95%CI = 1.05–1.93), and PWV‐β (OR = 1.43, 95%CI = 1.05–1.94) were associated with presence of lacunes. Ep was associated with AD (OR = 1.59, 95%CI = 1.01‐2.73) and VaD (OR = 2.23, 95%CI = 1.04‐5.94). Additionally, PWV‐β was associated with VaD (OR = 2.24, 95%CI = 1.07–5.62). All carotid artery stiffness measurements, except AI, were associated with worse performance in global cognition, visuomotor speed and memory after adjusting for age, sex, education, hypertension, diabetes, hyperlipidaemia, cardiovascular disease, and smoking. These associations became attenuated but remained significant with global cognition after adjusting for CSVD markers (β‐index; β = ‐0.27, P = 0.04), Ep; β = ‐0.30, P = 0.03), and PWV‐β; β = ‐0.32, P = 0.02).ConclusionCarotid artery stiffening is associated with WMH, lacunes, and etiologic subtypes of dementia. Carotid artery stiffening is also associated with global cognition independent of CSVD. Elevated carotid artery stiffness may help identify patients at risk for developing CSVD and dementia.
Methylation age and inflammation in prodromal Alzheimer’s disease
Authors: Behfar Qumars , Andrade Victor , Martin Rafael Campos , Adami Pamela V Martino , Dalmasso Carolina , Kleineidam Luca , Parveen Kayenat , Tripathi Kumar Parijat , Boada Mercè , de Rojas Itziar , García‐González Pablo , Marquié Marta , Puerta Raquel , Brosseron Frederic , Duzel Emrah , Heneka Michael T. , Jessen Frank , Ruiz Agustin , Ramirez Alfredo 
Published: June 2023

AbstractBackgroundThe most relevant risk factor in Alzheimer’s disease (AD) is age. Aging is a complex process involving several biological changes which lead to chronic cellular stress and to a sterile tissue inflammation. During aging cells become senescent which is seen as morphological changes and secretion of immune signaling mediators associated with systemic low‐grade inflammation. Interestingly, during neurodegenerative processes such AD, microglia, astrocytes, and vascular unit cells become senescent. To explore the potential connection between immune signaling mediators, ageing, and biomarkers of AD, we have quantified in CSF several immune related molecules link to AD and analyzed their connection with known biological clocks.MethodBiological age was obtained by deriving the epigenetic clock in DNA derived from peripheral blood. To this end, DNA methylation data was generated using the EPIC array from Illumina in two cohorts including 348 individuals (cognitively normal, subjective cognitive decline and mild cognitive impairment) from DELCODE study and 267 individuals (mild cognitive impairment). Data was prepared and normalized using standard quality controls. Horvath’s and Hannum epiClocks were computed for all individuals in both cohorts. AD biomarkers including Amyloid‐ß, phosphor‐tau and total tau along with a panel of inflammation markers were measured in CSF samples.ResultBoth epiClocks showed a significant strong correlation with chronological age in both cohorts. Methylation age and chronological age showed both a significant association with classical AD biomarkers, as well as a subsets of inflammation markers. The meta‐analysis confirmed the association of the Epiclocks and the chronological age with all AD biomarkers as well as with YKL40, sTREM2, C‐1 and MIF. Based on the difference between the calculated epiClock and the chronological age, we derived an index reporting on increase in biological aging rate (age‐acceleration). This index, however, did not show significant association with any of the AD biomarkers and inflammation markers.ConclusionOur study shows a link between inflammatory markers and methylation age in both healthy aging and pre‐dementia stages of AD. However, biological clocks derived from peripheral tissue seem to be independent of potential AD pathology and inflammation occurring in the aging brain. Thus, these biomarkers are not increasing the odds for methylation age‐acceleration.
Prognosis of patients with subjective cognitive decline in an unselected clinical sample
Authors: Whitfield Tim , Leal Gonzalo , Praharaju Janaki , Radford Darren , Marchant Natalie L , Schott Jonathan M , Oxtoby Neil P , Walker Zuzana 
Published: June 2023

AbstractBackgroundIndividuals with subjective cognitive decline (SCD) perceive that their cognition has worsened, but score normally on standardized cognitive tests. It is increasingly recognized that SCD has variable prognosis with the risk of progression to dementia being twice that of age‐matched controls without SCD. This study aimed to characterize an unselected sample of patients with SCD (n = 433) drawn from a larger memory clinic cohort (n = 2,262) and to compare baseline SCD profiles based on follow‐up diagnosis.MethodThis study used routinely‐recorded data from the Essex Memory Clinic (UK). Baseline data included age, sex, years of education, medical and psychiatric history, and physical examination results. A range of neuropsychological measures were administered, and repeated at 12/24‐month intervals. All included patients had at least one follow‐up visit. A consensus diagnosis was made by three clinicians at each visit and was supported by structural CT/MRI investigations. Group comparisons were made using two‐tailed t‐tests, Chi‐squared or Fisher’s exact tests.ResultThe Table presents the results in full. Of 434 patients with SCD diagnosis at baseline, 189 did not progress (SCD‐stable), 169 progressed to dementia (Alzheimer’s = 113; Lewy body = 31; Vascular = 15; Frontotemporal = 4; Other = 6) and a further 76 to mild cognitive impairment (MCI) during follow‐up (median 2.9 years). At baseline there were significant differences between SCD‐stable patients and those who progressed. Patients who progressed to dementia were older than the other two groups. Patients who progressed to MCI/dementia had worse episodic memory (Logical Memory Test delayed and word list recall) and took longer to complete Trail‐Making Test‐A. The SCD‐stable group had higher baseline anxiety and were more likely to have previous psychiatric history versus patients who declined.ConclusionIn this unselected clinical sample from a non‐academic setting, we have replicated and extended previous findings from research cohorts. Whilst anxiety is a risk factor for dementia, anxiety in the context of SCD is associated with a better prognosis and may be an expression of a subclinical affective disorder rather than prodromal neurodegenerative disease. This project demonstrated clear differences at the group level and the next step is to build data‐driven prognostic models that can be applied to individual patients in a clinical setting.
Artificial intelligence, language and Neuropsychological measures in Alzheimer’s disease
Authors: Battista Petronilla 
Published: June 2023

AbstractBackgroundOne of the current challenges in the field of Alzheimer’s disease (AD) is to identify patients with mild cognitive impairment (MCI) that will convert to AD. Artificial intelligence, in particular machine learning (ML), has established as one of more powerful approach to extract reliable predictors and to automatically classify different AD phenotypes. It is time to accelerate the translation of this knowledge in clinical practice, mainly by using low‐cost features originating from the language and neuropsychological assessment.MethodWe aim at performing a meta‐analytic evaluation of the contribution of ML and language/neuropsychological measures for the automated classification of AD and MCI patients and the prediction of MCIs’ conversion to AD‐type dementia. Specifically, we study, from the results reported by independent studies, whether ML algorithms, trained on a set of language and neuropsychological measures, could be used for the automatic diagnosis of MCI and AD‐type dementia. To tackle the issue of cross‐linguistic sensitivity, this work spans cohorts of speakers from widely different languages. The advantages and issues that should be taken under consideration for translating these approaches into reliable clinical studies are discussed.ResultAlthough a high heterogeneity was observed, this meta‐analysis shows that ML applied to language and neuropsychological measures can lead to a successful automatic classification, being more specific as screening rather than prognosis tool. Relevant categories of language and neuropsychological tests can be extracted by ML that maximize the classification accuracy.ConclusionML applied on language and neuropsychological measures can automatically classify AD patients, even at an early stage of the disease. This brings several advantages, such as the development of more objective and efficient language and neuropsychological batteries for improving the early diagnosis of AD. Future studies should empirically test the combination of methodological features necessary to improve patients’ classification also at the preclinical stages.
Analysis of genetic variants related to oxidative stress in patients with Alzheimer’s disease
Authors: Dorszewska Jolanta , Florczak‐Wyspianska Jolanta , Zasada Aleksandra , Korczowska‐Łącka Izabela , Szymanowicz Oliwia , Kozubski Wojciech 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is one of the common neurodegenerative diseases with an incompletely understood pathomechanism. In AD, generation of oxidative stress is observed as a result of dysfunction of the mitochondrial respiratory chain. The effect of this disturbance is the production of reactive oxygen species (ROS). The SOD2 gene is involved in the elimination of ROS. Glutathione S‐transferases (GST) are a group of enzymes with antioxidant properties that protect cells from ROS damage. GSTP1 gene variants may impair the activity of these enzymes. APOE gene, is also related to the regulation of oxidative stress. In AD patients with APOE E4, higher levels of lipid peroxidation are found. The precise nature of the association between oxidative stress and hallmarks of AD pathology is unknown.The aim of the study was to analyze of genetic variants of SOD2 c.47T>C (exon 2) and GSTP1 c.341C>T (exon 6) genes in AD patients, control subjects related to AD cases (CR), and controls subjects without family history of AD (CU). The APOE E4 allele was included in the studies.MethodThe studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The SOD2 and GSTP1 genetic variants were determined by HRM and sequencing. The apoE concentration was determined by the ELISA method.ResultVariant CC c.47T>C SOD2 was more frequent in CR, while CT in CU. The TT variant of this gene tended to occur more frequently in patients with AD. In AD, the TT variant was more common in the subject without E4 allele (p<0.05). The CC and CT variants of the c.341C>T GSTP1 gene occurred with equal frequency in AD and CR. The TT variant of this gene was not found in the examined subjects. Regardless of the genetic variant of APOE, SOD2, GSTP1, a significantly higher level of apoE was found in CR.ConclusionGenes involved in the regulation of oxidative stress may play an important role in the pathogenesis of AD.