bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Drivers of Atypical Alzheimer’s Disease Neuropathologic Change
Authors: Lee Eddie B 
Published: December 2023

AbstractBackgroundQuantitative differences in neurofibrillary tangle density are not well captured by more global measures such as Braak staging. Indeed, amongst cases with high Alzheimer’s disease neuropathologic change (ADNC), quantitative differences in the distribution of neurofibrillary tangle density is associated with atypical, non‐amnestic clinical presentations. We sought here to study the effect of TREM2 and APOE risk genotypes on neuropathologically and clinically defined atypical Alzheimer’s disease.MethodsTREM2 variant versus wild‐type autopsy cases with an intermediate to high level of ADNC were identified from the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Archived clinical records were used to classify cases into typical versus atypical AD. Neuropathologic classification of cases into typical versus atypical AD was based on quantification of neurofibrillary tangle density using PHF1 stained sections from neocortical and hippocampal regions. Morphology from Iba1 stained sections was used to quantify microglial reactivity.Results31 AD cases with TREM2 risk genotypes were compared to wild‐type TREM2 AD cases (n = 119). TREM2 variants were associated with a significantly higher proportion of atypical AD clinical phenotypes including behavioral/dysexecutive variants, primary progressive aphasias, posterior cortical atrophy, and others (19.33% versus 48.39%, Fisher’s exact test p = 0.002). These clinical phenotypes were associated with a significantly higher proportion of TREM2 variant cases with neuropathologically defined atypical AD, namely hippocampal sparing AD (8.7% versus 28.57%, Fisher’s exact test p = 0.046). Moreover, the proportion of microglia with a dystrophic morphology correlated with neurofibrillary tangle density and not amyloid burden. Finally, to get a sense of the magnitude of this TREM2 association relative to other genetic risk factors, we observed a non‐significant trend towards the absence of the APOE E4 risk genotype being associated with hippocampal sparing AD.ConclusionsThis clinicopathologic correlation study suggests that TREM2 risk variants are associated with clinically and neuropathologically defined atypical AD. Given that both TREM2 and APOE affect microglial reactivity to amyloid, the observed tendency towards TREM2 variant cases exhibiting hippocampal sparing AD suggests that altered microglial reactivity to amyloid may change downstream tauopathy patterns leading to atypical AD clinical phenotypes.
Analysis of person recognition deficits in genetic frontotemporal dementia
Authors: Todd Emily G. , Bouzigues Arabella , Foster Phoebe H , Ferry‐Bolder Eve , Peakman Georgia , Bocchetta Martina , Cash David M , Greaves Caroline V , Convery Rhian S , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , Mendonca Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Rohrer Jonathan D. , Russell Lucy L. ,   Genetic FTD Initiative (GENFI)
Published: December 2023

AbstractBackgroundSemantic and socioemotional knowledge, including person recognition, can be altered in frontotemporal dementia (FTD), and is often associated with the right temporal lobe variant. Using data from the Genetic FTD Initiative, we investigated person recognition deficits in genetic FTD.Method901 GENFI participants (279 mutation negative controls, 280 C9orf72 mutation carriers (MCs), 101 MAPTMCs and 241 GRN MCs) were grouped using the Clinical Dementia Rating scale plus National Alzheimer’s Coordinating Centre Frontotemporal Lobar Degeneration (CDR plus NACC FTLD) global score where 0 denotes asymptomatic, 0.5 as prodromal, and 1+ as mild to severe symptoms (C9orf72: 135 = 0, 48 = 0.5, 97 = 1+; GRN: 143 = 0, 35 = 0.5, 63 = 1+; MAPT: 50 = 0, 20 = 0.5, 31 = 1+). Person recognition (PR) was assessed using a single question within a structured clinical questionnaire, scoring the ability to recognise people who should be familiar by face or voice to them, with a value between 0 (absent) to 3 (severe), similar to the CDR scale. The percentage of participants with PR deficits was calculated for each group. Logistic regression with bootstrapping compared the PR score between groups with age, gender, and education as covariates.Result16.1% of C9orf72 MCs (0 = 0.7%, 0.5 = 2.1%, 1+ = 44.3%), 7.5% of GRN (0 = 0.0%, 0.5 = 8.6%, 1+ = 23.8%) and 17.8% of MAPT carriers (0 = 2%, 0.5 = 10%, 1+ = 48.4%) showed PR deficits. Mean (standard deviation) severity in each group was: C9orf72 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.6(0.9); GRN 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.2(0.6); MAPT 0 = 0.0(0.2), 0.5 = 0.1(0.3), 1+ = 0.6(0.8). Each of the symptomatic genetic groups had a significantly greater PR deficit than the control group (p<0.001), with the prodromal MAPT (p = 0.006) and GRN (p<0.001) groups also showing a greater impairment than controls. There was a trend to significance in the C9orf72asymptomatic and prodromal groups compared with controls (p = 0.058 and p = 0.059 respectively). Symptomatic C9orf72 and MAPT carriers showed greater impairment than the symptomatic GRN carriers (both p = 0.005).ConclusionPerson recognition is a key early marker of disease in some individuals with genetic FTD and further imaging analyses will help to reveal the underlying mechanism of this deficit.
Exposure to area disadvantage across the life course and its influence on cognition and neurodegenerative pathology in later life.
Authors: Cartlidge Molly R E , Liu Yiwen , Bakolis Ioannis , Nicholas Jennifer M , Keuss Sarah E , Coath William , Cash David M , Malone Ian B , Sudre Carole H , Schott Jonathan M , Richards Marcus 
Published: December 2023

AbstractBackgroundIn older adults, exposure to area disadvantage is associated with poorer cognitive performance, smaller whole brain and hippocampal volumes and cardiovascular risk. However, there is little research on the timing, accumulation and change in exposure to area disadvantage. This study aimed to investigate whether exposure to area disadvantage across the life course is associated with cognition and neurodegenerative pathology in late adulthood.MethodData from the MRC National Survey of Heath and Development (British 1946 birth cohort; analytical sample: n = 1,762) and a neuroimaging sub‐study (Insight 46; analytical sample: n = 447) were used. Area disadvantage was defined as the percentage of employed individuals in semi‐skilled or unskilled occupations. In the full cohort we assessed the relationship of area disadvantage at 26, 53 and 60‐64 years, cumulative area disadvantage and area disadvantage change score with cognitive performance at 69. In Insight 46 we examined associations between area disadvantage and neuroimaging outcomes (69‐71 years): whole brain, hippocampal, and ventricular volumes, amyloid status, and white matter hyperintensity volume (WMHV). All analyses were adjusted for socio‐economic and lifestyle confounders, with the neuroimaging analyses also adjusted for age at scan and total intracranial volume.ResultNegative associations were found between exposure to area disadvantage at all ages and cognitive performance, with stronger effects at 53 and 60‐64 (Table 1). These effect sizes remained similar when adjusted for sex, father’s social class and childhood emotional symptoms, but were attenuated when further adjusted for educational attainment and childhood cognition. A negative association was found between cumulative exposure to area disadvantage and cognitive performance (Table 1), and no effect was found from change in area disadvantage. WMHV was the only neurological outcome found to be associated with area disadvantage variables (Table 2).ConclusionLiving in a disadvantaged area across the life course is associated with poorer cognitive performance at age 69, most of this affect is accounted for by childhood cognition and educational attainment. Living in a disadvantaged area across the life course is also associated with higher WMHV, suggesting presumed cerebrovascular disease, a dementia risk factor. Further research is required to understand the mechanism driving this association.
Education and amyloid load affect posterior lobe function in subjective memory complainers: an EEG‐fMRI study
Authors: Lopez Susanna , Hampel Harald , Chiesa Patrizia Andrea , Percio Claudio Del , Lizio Roberta , Noce Giuseppe , Teipel Stefan , González‐Escamilla Gabriel , Cavedo Enrica , Lista Simone , Vergallo Andrea , Lemercier Pablo , Spinelli Giuseppe , Grothe Michel J. , Babiloni Claudio 
Published: December 2023

AbstractBackgroundIndicators of
cognitive reserve
(CR) moderate the effect of brain pathophysiology on cognitive deficits in the Alzheimer’s Disease (AD) continuum. In a previous study on individuals with subjective memory complaint (SMCs), a condition at risk for AD, from the INSIGHT‐preAD cohort, we found that CR using educational attainment (Edu) as a proxy altered the association of amyloid load with neurophysiological mechanisms generating posterior electroencephalographic (EEG) alpha rhythms in quiet wakefulness.MethodHere, we tested the hypothesis of an interaction between Edu and cerebral amyloid‐b load by analyzing the association between posterior alpha rhythms and functional magnetic resonance imaging connectivity (fMRI), among cholinergic basal forebrain (BF), thalamus, and cortical regions forming the Visual Network (VN).ResultResults showed a significantly positive association between posterior alpha rhythms and above‐mentioned functional connectivity in the SMC seniors with low brain amyloid accumulation and high education attainment (SMCneg Edu+), characterized by the amplest posterior alpha rhythms. This effect may be related to the neuroprotective effect of CR. On the contrary, SMC seniors with high brain amyloid accumulation and high education attainment (SMCpos Edu+) showed a trend towards the greatest negative association between posterior alpha rhythms and functional connectivity, possibly reflecting the compensatory effect related to high CR and high brain amyloidosis (see Figure).ConclusionThe present results suggest that, in SMC seniors, high CR affects the relation between cortical neural synchronization mechanisms generating posterior rsEEG alpha rhythms and functional connectivity involving the ascending cholinergic system and the VN. Unfortunately, these CR effects may be annulled at earlier stages of Alzheimer’s amyloid pathophysiology.
More than words: Photovoice as an innovative participatory approach to explore perceptions of rare dementia, a pilot study
Authors: Wood Olivia K 
Published: December 2023

AbstractBackgroundThere is limited evidence internationally exploring the everyday experiences of people living with rare dementia (PLWRD)– by which we mean atypical, inherited, and young onset forms of dementia– from their own subjective perspectives. Photovoice (Wang and Burris, 1997) is an inclusive, empowering visual research methodology that facilitates collaboration and supports shared understandings. This pilot study presents findings from the first known study where an inclusive research team, including individuals with different rare dementia diagnoses (e.g. Primary Progressive Aphasia, Posterior Cortical Atrophy, Dementia with Lewy bodies) used Photovoice methodology to visually represent experiences and perspectives of living with these conditions.MethodDrawing on Freire’s empowerment pedagogy, the study aims were consistent with global Photovoice aims: enabling people to visually record critical dialogue about their experiences of dementia through photography. We investigated the benefits and challenges of Photovoice methodology with this population and sought to identify perspectives of rare dementia from eight PLWRD. Data analysis utilised an iterative, participatory approach in which researchers and co‐researchers selected, contextualised, and codified the data. Thematic analyses involved both inductive and realist approaches.ResultThis paper discusses some of the practical challenges associated with using this methodology with PLWRD, as well as issues concerning co‐researcher’s perspectives on the acceptability and utility of Photovoice. We examine the benefits and challenges of using Photovoice and discuss lessons learned relating to the co‐production of topics and outputs, including barriers and facilitators to co‐researcher engagement with the study processes (e.g. use of cameras, photo upload).ConclusionThis pilot study will help inform a larger scale project where Photovoice and other creative participatory approaches (e.g. graphic elicitation) will be applied within a participatory action research framework that will promote group and individual reflection on dementia perspectives. In turn we hope this will lead to social action on a local and national level by co‐researchers with rare forms of dementia. This study contributes to the existing, if limited, international literature on creative participatory approaches with PLWRD.
Re‐estimation of drug‐specific amyloid removal parameters and the rate constant for pathogenic tau turnover brings the Q‐ATN model into better alignment with recent phase 3 data from gantenerumab and lecanemab
Authors: Mazer Norman A , Lott Dominik , Grimm Hans Peter , Machacek Matthias , Boess Frank , Gieschke Ronald , Klein Gregory , Baudler Monika , Doody Rachelle S. 
Published: December 2023

AbstractBackgroundThe Q‐ATN model (Mazer et al., Alzheimer’s & Dementia. 2022; https://doi.org/10.1002/alz/12877) is a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework for simulating the natural history of Alzheimer’s disease and the effects of anti‐amyloid treatment. The recently reported phase 3 trials of gantenerumab (GRADUATE 1&2) and lecanemab (CLARITY) provide additional data to update model parameters and assess the assumptions of the model.MethodThe drug‐specific amyloid removal parameters (αrem) for gantenerumab and lecanemab were re‐estimated from the mean amyloid PET data in GRADUATE 1&2 and CLARITY. Using the new αrem values, Q‐ATN simulations of the Clinical Dementia Rating – Sum of Boxes (CDR‐SB) and tau PET trajectories were made for each study. The rate constant for pathogenic tau turnover (ktau), which was uncertain due to limited data, was re‐estimated using a sensitivity analysis of the CDR‐SB treatment effects. Results from the aducanumab EMERGE and ENGAGE studies were also included in the analysis.ResultThe simulated increase in amyloid PET agreed well with the mean data from the placebo groups. For GRADUATE 1&2, αrem was 34% and 41% lower, respectively, than the prior value (0.0137 Yr−1/(ug/mL)) estimated from the gantenerumab open‐label extension studies. For CLARITY, αrem was 26% lower than the prior value (0.0109 Yr−1/(ug/mL)) estimated from the lecanemab phase 2 study. For GRADUATE 1&2, the simulated CDR‐SB trajectories for the placebo groups were in good agreement with the observed increases from baseline. For CLARITY, the simulation overestimated the observed increase. The re‐estimated value of ktau (0.2 Yr−1), which corresponds to a 3.5 Yr half‐life, yielded treatment effect sizes on CDR‐SB within the 95% confidence intervals for all treatment arms (N = 7). The prior value (0.5 Yr−1) yielded treatment effect sizes that were too large in three cases (see Figure). Tau PET simulations (with ktau = 0.2 Yr−1) were consistent with medial temporal ROI data from lecanemab and aducanumab; tau PET data from gantenerumab are pending.ConclusionThe updated αrem and ktau parameters bring the Q‐ATN model into better alignment with recent phase 3 data. Forthcoming data from the Donanemab TRAILBLAZER‐ALZ 2 study could further help assess the model assumptions.
Relationship between Framingham Risk Score and Cognitive Performance among Rural Indian Participants of SANSCOG study
Authors: Lingegodwa Abhishek Mensegere , Malo Palash Kumar , Stezin Albert , Hameed Shafeeq K Shahul , Mallikarjun Divya N , Partha Ajith , M Amitha C , Narayanasamy Rajitha , R Meghana , Menon Meenakshi , Velavarajan Goutham , Arvind Prathima , HS Sunitha , Singh Sadhana , Kommaddi Reddy Peera , Diwakar Latha , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: December 2023

AbstractBackgroundThe burden of Cardiovascular risk factors is increasing in India and the rural population is more susceptible due to rapidly changing lifestyle. There cardiovascular risk factors are known to occur in clusters and are implicated in poor cognitive performance. The Framingham risk score (FRS) is a simplified and common tool for the assessment of risk of developing Cardiovascular events over 10 years using six risk factors, such as, age, gender, total cholesterol (TC), high density lipoprotein cholesterol (HDL), smoking habits, and systolic blood pressure. Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) is a longitudinal, prospective cohort study in healthy aging individuals in a town located near Bangalore, India, where participants are recruited from the community.MethodOur objective was to examine to effect of FRS on cognitive performance measured by COGNITO among SANSCOG cohort participants. We performed separate multiple linear regression analysis to examine to effect of FRS on various COGNITO domains after adjusting for years of education and Geriatric Depression Scale (GDS) scores.ResultIn a sample of 3929 individuals, 2022 (51.5%) were women. The median (IQR) age of the sample was 58 (50,65), the median (IQR) years of education was 4 (0,9) and the median (IQR) GDS was 2 (1,6). Multiple linear regression analysis was used to see the association of FRS with various cognitive tests after adjusting for years of education and GDS revealed that individuals with higher FRS performed poorly in all cognitive domains as shown in Table 1. When we examined this in men and women separately the results remained the same.ConclusionWe have demonstrated that higher FRS affects cognitive performance among rural elderly Indian individuals of both genders. It is imperative to design and implement strategies for risk‐reduction such as early identification and management of risk factors, a healthy lifestyle, balanced diet and regular physical exercise.
Plasma p‐tau212 is an early biomarker to identify Alzheimer’s Disease pathology in Down Syndrome
Authors: Kac Przemyslaw Radoslaw , Alcolea Daniel , Montoliu‐Gaya Laia , Rodriguez Juan Lantero , Gonzalez‐Ortiz Fernando , Ashton Nicholas J. , Zetterberg Henrik , Karikari Thomas K , Fortea Juan , Blennow Kaj 
Published: December 2023

AbstractBackgroundThe life‐time risk of Alzheimer´s disease (AD) in people with Down Syndrome (DS) is above 95% by the seventh decade of life. Understanding the strong biological relation between those conditions is important to accelerate progress in diagnostics and treatment. Tau phosphorylation at threonine‐212 (p‐tau212) is very sensitive to Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A), which is encoded in chromosome 21. Published results showed that p‐tau212 was significantly increased in AD‐DS male brains. This suggests a possible involvement of p‐tau212 in early progression to AD in individuals with DS. Here, we assessed the potential of these biomarker in DS and sporadic AD.MethodUsing SIMOA technology, we tested in‐house developed p‐tau212 immunoassay (n = 245 for plasma, n = 329 for CSF and n = 115 paired samples) and p‐tau181 (n = 459 for plasma, n = 357 for CSF and n = 245 for p‐tau212 paired plasma samples). A subset of participants had amyloid‐PET data. We used AUC‐ROC to examine diagnostic potential and DeLong test for comparison. Spearman correlations were used to establish associations. Age‐related changes of p‐tau212 and p‐tau181 were examined in relation to amyloid positivity in CSF and Amyloid‐PET.ResultPlasma/CSF p‐tau212 and p‐tau181 showed excellent analytical performances. Plasma p‐tau212 started increasing around 20 years before people were diagnosed as prodromal AD‐DS (pDS) and CSF p‐tau212 approximately 27 years. Paired plasma and CSF p‐tau212 measurements correlated strongly (r = 0.71;p<0.001). Both plasma biomarkers were successful in differentiating asymptomatic DS (aDS) from dementia‐DS (dDS) with an AUC = 91% for p‐tau212 and AUC = 88% for p‐tau181. Plasma p‐tau212 had greater than p‐tau181 magnitude of change in early stages of AD performing 3.4 vs 2‐fold change for pDS and 3 vs 2.1 for vs mild cognitive impairment (MCI‐AD). Pattern remained the same for dDS, AD and CSF measurements. Moreover, plasma p‐tau212 was 2.4‐fold increased in aDS people, when compared to CN. Aside of great discrimination in DS, plasma p‐tau212 had significantly better performance than p‐tau181 for differentiating CN from MCI‐AD (AUC = 84%‐91%;p = 0.026) and CN from MCI‐AD+AD (AUC = 86%‐93%;p = 0.026).ConclusionPlasma p‐tau212 is useful for early DS and AD differentiation. Blood‐based p‐tau212 will be a cost‐effective and simple‐to‐implement alternative to in vivo and autopsy‐based evaluations for AD changes in DS and sporadic cases.