bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcome assessments for LBD trials – Should we borrow?
Authors: Boeve Brad F. 
Published: January 2025

AbstractClinical outcome assessments (COAs) are an integral part of clinical trials. A fit‐for‐purpose COA with well‐selected endpoints can help determine the efficacy of a therapeutic intervention in the condition studied. The selection of the appropriate outcome measures depends not only on the condition but also on the disease stage and type of intervention studied.In Alzheimer’s disease (AD) the clinical benefit of anti‐amyloid therapies has been assessed using outcomes that are specifically designed to measure the progression of Alzheimer’s disease during the early stages of the disease.The enthusiasm to develop similar studies in Lewy body dementia (LBD) needs to be tempered with caution as there is no COA LBD that fully captures the progression of LBD, full symptom array, or impact of these upon function. This limitation has been partly met by the reliance on COAs developed for Alzheimer’s or Parkinson’s disease. However, these may not be valid or sensitive to treatment changes in LBD.The impact of LBD on other domains beyond cognition including behavior, movement, and sleep represents one of the major challenges when considering the development of an LBD‐specific scale that encapsulates the severity of the disease as a whole.During this presentation, we will discuss the limitations of the current outcome measures in LBD trials and what those developing a clinical trial focused on LBD in the near future need to be taken into consideration when deciding on a COA for disease‐modifying and symptomatic trials. We will also report on the current efforts to develop the Lewy Body Dementia‐Domain Rating Scale (LBD‐DRS), an LBD‐specific scale to be utilized in disease‐modifying therapy trials.
Objectively measured environmental features and the risk of dementia: a systematic review and meta‐analysis
Authors: Song Suhang , Jia Zimu , Myers Nicholas Gary Lamont , Sun Jin 
Published: January 2025

AbstractBackgroundExisting evidence supports that living in a friendly environment is associated with lower risk of dementia, although the measurements of environmental variables are mixed. However, the type of environmental features reducing dementia risk has not been comprehensively identified and such associations have not been quantified. This systematic review and meta‐analysis aims to summarize the objectively measured environmental features associated with dementia and examine the pooled association between those features and dementia risk in older adults.MethodWe systematically searched PubMed, Web of Science, and EBSCO (Abstracts in Social Gerontology, AgeLine, APA PsycINFO, and CINAHL) databases on December 21, 2023, to identify the empirical studies assessing the role of objectively measured environmental features in the risk of dementia. The search yielded a total of 890 citations. According to the inclusion and exclusion criteria, ten studies were included in the systematic review and meta‐analysis. Among them, four articles included more than one environmental features, resulting in a total of 15 associations between environmental variables and dementia risk.ResultThis study summaries five environmental features that have been reported to be associated with lower dementia risk, including longer distance between residence and major roads (Hazard Ratio [HR] = 0.94, 95% Confidence Interval[CI] = 0.88‐1.00), larger green space (HR = 0.94, 95%CI = 0.88‐1.00), higher level of sidewalk installation (HR = 0.71, 95%CI = 0.52‐0.90), and less exposure to air pollution (i.e., NO2 [HR = 1.05, 95%CI = 0.96‐1.15], PM2.5 [HR = 1.03, 95%CI = 1.02‐1.05], and PM10 [HR = 1.13, 95%CI = 1.05‐1.21]). Pooled analysis showed that living in a friendly environment may reduce 7% of the risk of dementia (HR = 0.93, 95%CI = 0.90‐0.97) and exposure to air pollution may increase 5% of the dementia risk (HR = 1.05, 95%CI = 1.02‐1.08). There was heterogeneity in results across studies.ConclusionEven though a small number of studies included in this systematic review and meta‐analysis have examined the association between objectively measured environmental features and dementia risk, all existing investigations point to statistically significant associations in older adults. Whether those associations vary in different population subgroups and the mechanisms underlying those associations warrant further investigation.
Differential network‐based propagation of cortical thinning in atrophy subtypes in non‐demented individuals
Authors: Lorenzini Luigi , Tranfa Mario , Pieperhoff Leonard , ten Kate Mara , Pontillo Giuseppe , Alves Isadora Lopes , Shekari Mahnaz , Altomare Daniele , den Braber Anouk , Ritchie Craig W , Boada Mercè , Marquié Marta , Vandenberghe Rik , Luckett Emma S. , Hanseeuw Bernard J , Visser Pieter Jelle , Schöll Michael , Frisoni Giovanni B. , Birck Cindy , Mett Anja , Stephens Andrew W. , Gismondi Rossella , Buckley Christopher , Farrar Gill , Jessen Frank , Gispert Juan Domingo , Mutsaerts Henk‐Jan , García David Vállez , Wink Alle Meije , Collij Lyduine E. , Barkhof Frederik 
Published: January 2025

AbstractBackgroundDifferent patterns of atrophy exist in the dementia stage of AD. However, little is known about the heterogeneity of atrophy patterns and the mechanisms that drive subsequent propagation of the disease in the preclinical stages.MethodFrom the AMYPAD‐PNHS cohort, we included a total of 1323 non‐demented individuals, including 1094 amyloid‐negative, and 229 amyloid‐positive participants (Table 1). Gray matter thickness in 100 regions of interest was measured using FreeSurfer. Global cortical amyloid burden was derived from amyloid PET scans in Centiloids (CL).Individuals were assigned to atrophy subtypes based on cortical thickness measures using Non‐Negative Matrix Factorization (Figure 1). Multinomial regression models were used to study differences between subtypes in age, sex, global CL and APOE E4 carriership. Linear regression models were used to investigate the effect of time on atrophy within each subtype. Coordinated deformation models (Figure 1, Shafiei et al. 2023) were used to estimate network‐based thickness changes in each region, by multiplying the effect of time in connected regions by the strengths of their connections. Connectivity strength was based on templates of functional, structural and morphometric similarity networks, and allowed us to evaluate differential mechanisms. Significance was tested using a permutation approach.ResultsThree significant subtypes of regional GM atrophy were identified:‘limbic predominant’, ‘typical AD’, and ‘diffuse cortical’ (Figure 2). Individuals assigned to the limbic predominant subtype were significantly older, while the typical AD subtype had more APOE E4 carriers compared to the others (all p<0.001). Both limbic predominant and typical AD subtypes had higher CL compared to the diffuse cortical atrophy subtype (all p<0.001). Significant longitudinal thickness changes per subtype are shown in Figure 2. In the typical AD subtype, all network architectures constrained longitudinal GM changes (p<0.001), while in the diffuse atrophy subtype, propagation was mostly determined by morphometric similarity (p<0.005). No significant prediction model was found for the limbic predominant subtype.ConclusionWe show that atrophy subtypes can already be detected in non‐demented individuals. Progression of atrophy within subtypes is determined by network‐based mechanisms.
Multilingualism in use and white matter changes amongst healthy middle‐aged and older adults
Authors: Solé‐Padullés Cristina , Cattaneo Gabriele , Cabello‐Toscano María , Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Sánchez Javier Solana , Roca‐Ventura Alba , Alviarez‐Schulze Vanessa , Bargalló Núria , Pascual‐Leone Alvaro , Bartrés‐Faz David 
Published: January 2025

AbstractBackgroundBilingualism can stimulate brain plasticity (Jafari et al. Ann N Y Acad Sci. 2021;1505(1):8‐22) and is also associated with better executive function (Grundy. J Cult Cogn. Sci. 2020;4: 177–199). We investigated whether any feature of multilingualism (age of acquisition (AoA), proficiency or language usage) was related to change in white matter lesions and cognition amongst a cohort of middle‐aged to older adults.MethodHealthy adults (N=267, age range: 45‐69, 53.56% women) from the bilingual Barcelona Brain Health Initiative cohort (BBHI, Cattaneo et al. Front Aging Neurosci. 2018 11;10) were assembled. Participants completed questionnaires of AoA for a third language (L3), level of proficiency in up to five languages and daily use of languages, up to three languages. Shannon Entropy was computed as an index measuring the proportion of languages used daily in different contexts and participants were classified as monolinguals, bilinguals or multilinguals based on this score. T1 and T2‐weighted acquisitions allowed extraction of volumes of white matter hypointensities (WMH) using Freesurfer at baseline and two years later (N=210). Stepwise regression models were conducted cross‐sectionally to investigate associations between the predicted variables (WMH and cognition) and the following predictors: age, sex, education, AoA, proficiency and Entropy levels. Linear mixed models explored changes in WMH, including fixed effects and a random intercept.ResultProficiency (high) and AoA of L3 (after puberty) were retained as factors linked to increased working memory (t=3.49, p=0.001; t=2,88, p=0.004, respectively). High proficiency was also associated with better episodic memory (EM, t=3.19, p=0.002). Multilinguals (high Entropy) presented increased WMH at baseline (t=2.39, p=0.024) and over time (F=4.41, p=0.013). Additionally, there was a slight WMH*Entropy interaction, with a steeper decline in EM amongst monolinguals, regardless of WMH changes, while multilinguals with a medium burden of WMH improved in EM (Figure 1 in green; F=2.39, p=0.065).ConclusionMultilingualism in use was linked to increased white matter change and a slightly better maintenance of EM when the burden of structural damage was low to medium. Language usage may provide the brain with an ability to cope with structural brain changes and may be considered a proxy of CR.
Comprehending Alzheimer’s Patient and Caregiver Needs
Authors: Stümpel Johanne , van Munster Marlena , Dörrhöfer Annika , Schmitz‐Luhn Björn 
Published: January 2025

AbstractBackgroundProjected Alzheimer’s disease (AD) prevalence is expected to fourfold by 2050. With the escalating numbers of individuals affected by neurodegenerative diseases, including Parkinson’s disease (PD) and AD, associated challenges encompass increased burdens on individuals and families, societal and political implications and economic impacts. Integrating patient and caregiver perspectives is essential to creating comprehensive, patient‐centered care models that promote well‐being and resilience in the face of degenerative neurological diseases such as AD. This approach aims to contribute valuable insights into designing patient‐centered care interventions that can address common concerns across diverse neurodegenerative conditions.MethodsTen interviews and co‐design workshops were conducted with PD‐diagnosed individuals and their caregivers to explore future care perspectives. Participants selected cards from three domains (‘Resources,’ ‘Technologies,’ and ‘Interactions’) to envision their care. Most frequently named items were cross‐referenced with existing AD literature. Thematic analysis identified recurring patterns, and rigorous coding ensured a comprehensive exploration of various viewpoints. Synthesizing findings and extracting key themes, we contextualized results through an exploratory literature review. The integration of diverse data sources provided a robust foundation for understanding future neurodegenerative disease care needs.ResultsWe identified needs and challenges throughout the disease trajectory, emphasizing emotional burden and daily life disruption. Recognizing similarities across neurodegenerative diseases, PD experiences may well be transferable to individuals with AD. However, existing AD literature proved inconclusive regarding patients’ and caregivers’ perspectives on future holistic care approaches. Our findings underscored interdependence of patient and caregiver experiences, highlighting the need for holistic support, also in AD. These address providers, administrators, and policy makers and call for tailoring technological advances, resource allocation, and strategies to the unique needs of each stakeholder group.ConclusionThe findings underscore the need for tailored interventions and support services addressing the unique needs of individuals with neurodegenerative diseases and their caregivers. Given the increasing global prevalence of AD, understanding and meeting these needs are critical to improving the quality of life for affected persons. Moving forward, these findings contribute valuable insights for the development of holistic care models, fostering a supportive healthcare environment for those affected by neurodegenerative diseases.
Evaluating the interchangeability of blood‐based biomarkers and amyloid‐PET for identifying patients with Alzheimer’s pathology
Authors: Burnham Samantha C. , Harper Laura , Locascio Tricia , McPherson Holly E , Pontecorvo Michael , Wang Jian 
Published: January 2025

AbstractBackgroundPresence of amyloid pathology is used to identify patients who would benefit from novel amyloid‐targeting therapies for Alzheimer’s disease (AD). Whilst PET tracers are considered the gold standard for establishing the presence of amyloid pathology, they are costly and not widely accessible. Blood‐based biomarkers, if interchangeable with PET, could help negate such an inequitable barrier to treatment. This study assesses the agreement and interchangeability between blood‐based biomarkers and amyloid‐PET.MethodBioHermes participants with MCI or AD‐dementia and available amyloid‐PET evaluations as well as blood‐based biomarker results for PrecivityAD (C2N) and/or P‐tau217 (research use MSD, Lilly) were included. Agreement (PPA, NPA, OPA, PPV, NPV) between amyloid‐PET and blood‐based biomarker stratification as well as the non‐inferiority (Figure 1) of blood‐based biomarkers to amyloid‐PET for patient identification were evaluated. All thresholds and methods for stratification were pre‐specified. Two‐threshold stratification for the blood‐based biomarkers were implemented.Result537 participants with PrecivityAD and amyloid‐PET (mean‐age 73.2 years, 54.0% Female, 85.3% White, 47.3% amyloid‐PET positive) and 531 participants with P‐tau217 and amyloid‐PET (74.0 years, 53.9% Female, 85.3% White, 46.5% amyloid‐PET positive) were included. There was moderate to high agreement between the blood‐based biomarkers and amyloid‐PET visual read, Table 1. Higher agreement with amyloid‐PET visual read was achieved when participants between two‐thresholds were removed (and would require confirmatory CSF or PET evaluations). Generally, the P‐tau217 (MSD, Lilly) blood‐based biomarker demonstrated higher agreement with amyloid‐PET visual read in comparison to the Aβ blood‐based PrecivityAD test. Both blood‐based biomarkers, removing participants between the two‐thresholds, met criteria for non‐inferiority to amyloid‐PET clinical trial criteria for selecting patients with amyloid‐pathology, Table 2.ConclusionA clinically available plasma test (PrecivityAD, C2N) as well as a research use P‐tau‐217 assay (MSD, Lilly) were both able to rule in patients that would also be selected by amyloid PET (PPV 86% and 88%, respectively). New plasma diagnostics that incorporate P‐tau217 or other more sensitive markers may be more accurate than Aβ blood‐based tests for identifying amyloid pathology. Results support the hypothesis that blood‐biomarkers may be interchangeable with amyloid‐PET criteria for selecting patients who are suitable for and would benefit from treatment with amyloid‐targeting therapies.
Plasma pTau217, gender, and synaptic density
Authors: Yang Kao Lee , DiFilippo Alexandra H , Ma Yue , Wilson Rachael E , Thor Yer , Pasquesi Mary‐Elizabeth , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J. , Ashton Nicholas J. , Johnson Sterling C. , Christian Bradley T. , Zetterberg Henrik , Bendlin Barbara B. 
Published: January 2025

AbstractBackgroundSynaptic loss is a key feature of Alzheimer’s disease (AD) dementia. In the entorhinal cortex (ERC) and hippocampus, phosphorylated tau (pTau) colocalizes with synaptosomes, and its presence may play a role in AD‐related synaptic loss. However, the relationship between pTau and synaptic density is not well understood. Plasma pTau represents secreted tau pathology and among the available epitopes, pTau217 has emerged as an accurate biomarker of AD pathology. Here, we tested the relationship between secreted pTau217 and synaptic density.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention (N=38; Table 1). All participants underwent blood sampling for measurement of plasma pTau217 and [C‐11]UCB‐J PET to assess synaptic density in regions of interest (ROIs: hippocampus, ERC, and fusiform gyrus) known to show early AD tau accumulation. Synaptic density was quantified using [C‐11]UCB‐J DVR (LGA, whole cerebellar reference region) and ROIs were identified following FreeSurfer T1w‐MRI parcellation. Plasma pTau217 was determined using the ALZpath pTau217 Simoa assay on the Quanterix HD‐X platform. We utilized multiple regression analysis to examine the extent to which plasma pTau217 and gender predict synaptic density in ROIs controlling for age. All models were fitted in R and considered significant at Bonferroni‐corrected (.05/3) p<.017. During analysis we discovered one outlier; a cognitively‐unimpaired participant with pTau217 concentration >2.5 standard deviations above the mean and high UCB‐J DVR in all ROIs. Results with and without the outlier were considered.ResultPlasma pTau217 (b=‐.07, p=0.01) and gender (b=‐.05, p=0.008) predicted UCB‐J DVR in the hippocampus, but not other ROIs (Table 2). The effect size of plasma pTau217 and gender, as measured by Cohen’s f2, was 0.23 and 0.34, respectively, indicating medium to large effects. Welch’s t‐test showed a significant gender difference in hippocampal UCB‐J DVR (Figure).ConclusionOur results indicate that higher levels of plasma pTau217 associated with lower synaptic density in the hippocampus. However, given the individual with high pTau217 and synaptic density, it is possible other processes unaccounted for in this analysis are impacting this relationship. Further examinations could give insight into early processes that confer neuronal injury in the AD pathological cascade.
Differential association of moderate alcohol use with neurodegeneration, cerebrovascular disease, and cognition by racial, ethnic and sex/gender groups in middle age
Authors: Guzmán Diana S. , Rentería Miguel Arce , Avila Justina F , Turney Indira C. , Johnson Aubrey S. , Smith Anna C. , Okafor Amarachukwu , Houlihan Hannah M. , Heuer Lauren B. , Alshikho Mohamad J. , Morales Clarissa , Mazen Jessica , Gu Yian , Manly Jennifer J. , Brickman Adam M. , Lao Patrick J. 
Published: January 2025

AbstractBackgroundModerate alcohol use may be associated with brain and cognitive benefits compared to heavy alcohol use. However, results have varied. We hypothesized that the relationship between alcohol use and cognition is mediated by neurodegenerative and cerebrovascular measures in a diverse middle‐aged sample of non‐alcohol dependent community‐dwelling adults in Northern Manhattan.MethodParticipants (N=451; age=53±10 years; 36 Black Men (BM), 68 Black Women (BW), 95 Latinx Men (LM), 198 Latinx Women (LW), 17 White Men (WM), 37 White Women (WW)) from the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease underwent structural and vascular MRI (total brain volume (TBV), cortical thickness in AD signature regions, hippocampal volume, white matter hyperintensities (WMH)). Moderate alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C≤9). Mediation models tested whether the association of alcohol use on cognition (SRT total and delayed; Animal and letter fluency; Digit Span Backwards) is mediated by brain measures, stratified in sex/gender by racial and ethnic groups.ResultGreater moderate alcohol use was associated with lower cortical thickness and hippocampal volume LM (cortical thickness: ‐0.005 mm [‐0.008, 0.001], p=0.005; hippocampal volume: ‐25.0 mm3 [‐45.0, ‐4.7], p=0.02), greater vascular burden in BM (temporal WMH: 0.07 cm3 [0.001, 0.121], p=0.05), and lower TBV in WM (‐24.0 cm3 [‐27.5, ‐20.4], p=0.01), but not associated with brain measures in women. Greater moderate alcohol use was associated with lower animal fluency for LM (ADE: ‐0.25 to ‐0.21, p≤0.04), but higher letter fluency for LW (ADE: 0.24 to 0.25, p≤0.04) and BW (ADE: 0.43 to 0.43, p≤0.05), accounting for brain to cognition associations. However, mediation pathways (ACME) were not significant.ConclusionMen had lower cortical thickness and brain volume, greater WMH volume, and lower cognitive measures, while women had higher cognitive measures with greater moderate alcohol use in midlife. Neurodegenerative and vascular associations with moderate alcohol use differed by race and ethnicity in men, while the directionality of associations between moderate alcohol use and fluency differed by sex/gender. Future work should explore alcohol use factors (e.g., context of use, duration of use), and the relationship to brain and cognitive changes over the life course.