bluuebunny/crossref_metadata_2025_split huggingface dataset:
The HOPE4MCI study: AGB101 treatment reduces entorhinal cortex atrophy in patients with amnestic mild cognitive impairment due to Alzheimer's Disease who are ApoE‐4 non‐carriers
Authors: Rani Nisha , Mohs Richard , Gallagher Michela , Bakker Arnold 
Published: January 2025

AbstractBackgroundHippocampal hyperactivity is a hallmark of prodromal Alzheimer’s disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI clinical trial used a 78‐week protocol to assess progression in amyloid‐positive patients with MCI due to AD. Mohs et al. (2024) reported the clinical/cognitive results showing that ApoE‐4 non‐carriers had a more favorable treatment effect of AGB101 over the 78‐week duration of the study. Here we report effects of AGB101 on biomarkers of AD in those patients.MethodsForty‐four participants who completed the 78‐week protocol were ApoE‐4 non‐carriers. Structural MRI scans obtained in the study at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were also analyzed for plasma biomarkers in those participants.ResultsTreatment with AGB101 significantly reduced atrophy in the left entorhinal cortex (p < 0.05) compared to placebo. Reduced atrophy in the entorhinal cortex was significantly correlated with the change in CDR‐SB score (r = ‐0.511) over 78 weeks, as well as with biomarkers of neurodegeneration neurofilament light (NfL; r = ‐0.382) and glial fibrillary acidic protein (GFAP; r = ‐0.398) collected at completion of the protocol.ConclusionAs reported in Mohs et al. (2024), progression on the primary clinical/cognitive endpoint of the Clincial Dementia Rating Scale Sum of Boxes score (CDR‐SB) occurred over the 78‐week protocol in the HOPE4MCI study and non‐carriers of ApoE4 treated with AGB101 showed a substantially more favorable effect than carriers. Here we report that treatment with AGB101, in those participants significantly reduced atrophy of the entorhinal cortex. That reduction in atrophy was significantly coupled with the change in CDR‐SB and with plasma biomarkers of disease. These exploratory analyses would be consistent with a reduction in neurodegeneration in the non‐carriers of ApoE4 treated with AGB101 prior to a clinical diagnosis of dementia.
Hippocampal degeneration is associated with GFAP levels in individuals with vascular dementia independently of amyloidosis
Authors: Oliveira Markley , Bellaver Bruna , Lussier Firoza Z , Ferreira Pamela C.L. , Povala Guilherme , Leffa Douglas Teixeira , Bauer‐Negrini Guilherme , Rodrigues Matheus Scarpatto , Abbas Sarah , Zalzale Hussein , Rohden Francieli , Felix Cynthia , Soares Carolina , Saha Pampa , Ruppert Emma Patrice , Machado Vitor Hugo , da Rocha Andreia Silva , Tudorascu Dana , Benedet Andrea L. , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Hong Chang Hyung , Roh Hyun Woong , Zimmer Eduardo R. , Blennow Kaj , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Son Sang Joon , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundVascular cognitive impairment/dementia (VD) is the second most prevalent cause of dementia following Alzheimer's disease (AD). VD is characterized by the progression of white matter hyperintensity burden (WMH) and associated neurodegeneration. GFAP, a biomarker for reactive astrogliosis, is associated with Aß pathology and mediates tau‐pathology in preclinical AD. However, the association of GFAP levels with the markers associated with VD is poorly understood.MethodWe assessed 796 participants from a research cohort (TRIAD: 355) and a memory clinic cohort (BICWALZ: 441) that were divided into four groups according to their Aß (Aß+/Aß‐) and WMH status (WMH+/WMH‐). WMH values were corrected by intracranial volume, and cutoffs were determined based on the highest WMH value within 50% of the individuals with the lowest WMH rate in the CU Aß‐ group. Biomarker mean level differences between groups were estimated via Ancova Tukey’s test, and linear regressions accounting for age, sex, and cognitive status were used to estimate the association.ResultFor TRIAD, WMH+/Aß+ individuals exhibit higher levels of plasma GFAP when compared to all groups except WMH‐/Aß+, with no differences in NfL levels and hippocampal volume between groups (Fig. 1A). In BICWALZ, only hippocampal volume differs between groups with lower levels observed in both WMH‐/Aß‐ and WMH‐/Aß+ (Fig. 1B’’). The association of GFAP and NfL was observed in all groups (Fig. 2A, 2B’). On the other hand, hippocampal degeneration was associated with higher GFAP levels in individuals with abnormal WMH and absence of Aß burden in both cohorts (Fig. 3A: TRIAD: ß= ‐0.3036; p= 0.0195; Fig. 3B’: BICWALZ: ß= ‐0.1791; p= 0.0125).ConclusionOur findings suggest that astrocyte reactivity, as indicated by plasma GFAP levels, plays a significant role in the hippocampal atrophy observed in patients with vascular disease. These results suggest that therapies targeting astrocyte reactivity could potentially alleviate progressive cognitive deficits commonly found in patients with chronic vasculopathy.
Exploring the effects of using multiple different cerebellar reference regions to improve tau‐PET harmonization ‐ The HEAD Study
Authors: Bauer‐Negrini Guilherme , Povala Guilherme , Bellaver Bruna , Lussier Firoza Z , Tissot Cécile , Tsai Hsin‐Yeh , Amaral Livia , Ferreira Pamela C.L. , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundTau‐PET tracers have been used to diagnose and stage Alzheimer’s disease. However, different tau tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their results. We hypothesize that the choice of a reference region can impact the harmonization of the tau‐PET standardized uptake value ratio (SUVR). In this context, we aimed to explore how different cerebellar reference regions impact the association between [18F]Flortaucipir and [18F]MK‐6240 SUVR values.MethodWe studied 185 individuals across the aging and AD spectrum with head‐to‐head Flortaucipir and MK‐6240 tau PET (HEAD Study). SUVRs were processed to a common 8mm FWHM using 15 different reference regions defined in the spatially unbiased atlas template of the cerebellum (SUIT) (Diedrichsen, 2009). Regression models investigated the association between Flortaucipir and MK‐6240 using multiple combinations of reference regions. R2 statistic was used to estimate goodness‐of‐fitting.Result225 combinations of associations Flortaucipir and MK‐6240 SUVR were tested, where the SUVRs are not necessarily quantified using the same reference region. Figure 1 presents the top 25 strongest and 25 weakest associations, ordered based on the coefficient of determination (R²). Flortaucipir and MK‐6240 exhibited the most robust associations when the inferior cerebellar gray matter or Crus I were employed for SUVR determination (R2 = 0.89, Figure 1‐2). Conversely, combinations incorporating the fastigial region consistently yielded weaker associations between the two tracers (R2<0.70, Figure 1‐2).ConclusionInterestingly, we showed that the inferior cerebellum, when used for both tracers, serves as a robust reference region for determining the most similar SUVRs for Flortaucipir and MK‐6240. Notably, these two regions have been commonly utilized in previous studies involving these tau tracers. Our results imply that the inferior cerebellum could be the optimal reference region for research aimed at harmonizing tau PET tracers using statistical scales.
Unraveling Alzheimer’s Disease Heterogeneity: A Comparative Analysis Using HYDRA and CHIMERA
Authors: An Gordon , Benzinger Tammie L.S. , Sotiras Aristeidis , Gordon Brian A. 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease can present with heterogenous neurodegenerative patterns. In order to optimize clinical trials and personalized medicine, the identification and characterization of diverse pathological brain patterns associated with AD have become paramount. Optimal approaches to identify such heterogeneity are unknown. The present study employed two distinct clustering approaches, namely HYDRA and CHIMERA, to delineate the spatial pattern of brain atrophy attributable to AD. Methods were applied to MRI scans from the Open Access Series of Imaging Studies (OASIS‐4) project.MethodsHYDRA uses a convex polytope formed by multiple linear hyperplanes that correspond to various pathological patterns, capturing disease subtypes. CHIMERA assesses the pathological transition by transforming NC distribution to separate transformations matching the disease distribution. While both identify spatial patterns, the distinction lies in HYDRA’s discriminative analysis of disease subtypes and CHIMERA’s generative nature on disease progression through distribution matching.ResultsBoth approaches identified two patterns, or subtypes (Figure 1) with similar CDR results (Figure 2). All subtypes demonstrate marked atrophy within the medial temporal areas, notably the hippocampus. Disparities are evident when assessing subtypes: Subtype‐2 across both methods shows pronounced variations in regions such as superior frontal, middle temporal, parietal cortex, and precuneus, areas paramount in AD pathology. Conversely, HYDRA’s Subtype‐1 highlights subtle differences in temporal cortex relative to its Subtype‐2. CHIMERA’s Subtype‐1, while mirroring its Subtype‐2 pattern, is less intensified, suggesting an earlier AD stage. Collectively, these patterns concur with recognized AD neuropathological trajectories, pinpointing regions initially impacted in progression. In addition, an in‐depth exploration of subsequent analysis including a longitudinal data evaluation to observe the progression of these patterns over time is slated for later investigation.ConclusionOur findings demonstrate data‐driven approaches to derive clinically meaningful patterns of neurodegeneration. A parallel evaluation of both approaches accentuates the robustness of clustering techniques, revealing consistent and overlapping insights into the intricate pathological landscapes of AD. This convergence in findings bolsters confidence in the reliability of such analytical tools in AD research.
Digital Interventions in Neuro‐Rehabilitation: Gotcha! app‐based therapy for proper name anomia in people with dementia
Authors: Badalova Aygun 
Published: January 2025

AbstractBackgroundProper name anomia is a common experience that can become amplified in patients with a diagnosis of dementia (PWD). The Gotcha! app aims to provide practice‐based therapy for PWD to relearn the names of key people in their lives. It has been developed using the principles of errorless learning and spaced retrieval, which have previously been shown to improve the remembering the familiar people’s names and benefit the relationship between the PWD and their loved ones. (Clare et al, 1999, 2000, 2003).MethodsGotcha! is a digital confrontation naming therapy app which enables patients to train one face per day by using photos of the person whose name is to be trained. We employed a single‐case experimental design with weekly testing of free‐naming in both six‐week blocks (pre therapy and therapy). During the therapy, a novel speech verifier is used to provide real‐time feedback (Barbera et al. 2020). Two analyses method is used to investigate the behavioural data: 1) within‐subject non‐parametric analysis using Tau‐U metric (Parker et al. 2011); 2) a parametric group analysis using an ANOVA.ResultsThe trial is ongoing. Results from the first 20 subjects show: 1) Tau‐U. 80% showed a positive trend with better naming during the training phase with 8/20 reaching statistical significance. 2) ANOVA demonstrated a significant effect at the group level of training>baseline phase, F (1,19) = 13.18, p = 0.01ConclusionApp‐based proper name anomia retraining works for the majority of PWD in our trial thus far. Being able to freely recall and produce the name of a relative or loved one has a big impact on people’s lives.
Multivariate sleep health and cognitive functions in healthy older adults: results from partial least square correlation analysis
Authors: Qin Shuo , Ng Eric Kwun Kei , Soon ChunSiong , Chua XinYu , Zhou Juan Helen , Koh Woon‐Puay , Chee Michael Wei‐Liang 
Published: January 2025

AbstractBackgroundPast studies examining sleep‐cognition relationships mostly employed univariate approaches, which are subject to problems such as multicollinearity and multiple comparisons. Further, results from small sample univariate analyses are difficult to compare, precluding the identification of the aspects of sleep health associated with a particular cognitive domain(s). The current study used a multivariate approach to identify key sleep metrics and cognitive domains that contribute to the maximum sleep‐cognition covariance in healthy older adults. From the reduced list of sleep metrics and cognitive domains, novel associations between different aspects of sleep health and cognitive domains can be uncovered.MethodThe current study is part of the ongoing SG70: Toward Healthy Longevity in Singapore study, which aims to comprehensively assess factors that affect aging health in over 1000 Singaporean older adults. From the SG70 study, 440 healthy older adults wore an Oura Ring (OuraHealth OY) for 14‐30 days. Twenty‐three metrics encompassing 4 major aspects of objective sleep health: duration, timing, regularity, and continuity were extracted (Figure 1). Cognition was assessed using a comprehensive battery that encompassed 7 domains. The overall covariance between sleep and cognition was examined by a partial least square correlation (PLSC) analysis. Sleep metrics and cognitive domains that contributed significantly to significant PLSC components were identified by bootstrapping.ResultPLSC analysis identified a component that explained 68% of covariance between sleep and cognition matrices (r = 0.17, p<0.001). Bootstrapping tests further identified 10 sleep continuity and regularity metrics and 4 corresponding cognitive domains that contributed significantly to the observed covariance (Figure 2). Post‐hoc univariate analyses showed that sleep continuity metrics correlated with speed of processing, while sleep regularity metrics correlated with verbal memory, visual‐spatial ability, executive functions, and speed of processing (Figure 3).ConclusionOur results suggest that sleep continuity and regularity may be more sensitive markers of impairments across multiple cognitive domains in healthy aging compared to sleep duration and timing. In addition, they support the utility of multivariate analyses in uncovering significant association patterns between sleep and cognition.
Setting a Baseline for Normal Cognitive Aging with Lexical Concreteness – A Corpus Linguistic Approach
Authors: Han Kunmei 
Published: January 2025

AbstractBackgroundIdentifying language variation in healthy aging speakers is important for understanding normal cognitive aging. Setting a baseline of normal aging languages in the first place is necessary for the evaluation of language performances of old adults. Lexical concreteness, a well‐studied psycholinguistic parameter, has been used to detect semantic memory‐related deficits. For example, people with semantic dementia were found to display reduced lexical concreteness (Breedin et al., 1994). Healthy old adults, however, are less studied in terms of the concreteness pattern in their speech. This study examines lexical concreteness of free speech samples of normal aging speakers age between 60 – 80 in Singapore.MethodWe collected about 15‐min free speech from 243 English‐speaking, cognitively healthy Singaporeans (133 women, 110 men) age above 60 years old. Demographic variables (age, gender, education, and number of languages spoken) were uncorrelated with each other. Speeches were transcribed by native Singapore English speakers and tagged with part‐of‐speech (PoS) information. We calculated global lexical features including speech rate (in minutes), lexical diversity (Moving‐Average Type‐Token Ratio), and PoS distribution (count per 100 tokens). Then we calculated concreteness (Brysbaert et al., 2014) of major content words for every individual. The relation between age and lexical measures was examined with Spearman’s correlation test.ResultResults of the statistical analysis show that healthy old adults speak slower (𝜌 = ‐0.14, p = .03) with more concrete nouns (𝜌 = 0.14, p = .03) and adjectives (𝜌 = 0.18, p< .05) than younger speakers. PoS distribution and verb concreteness (all p> .05) remain stable in the aging process.ConclusionOur speech sample revealed a general trend of elderly speech – reduced speech rates and increased lexical concreteness. The significant positive association between age and lexical concreteness in free speeches of health old adults was found for the first time, providing corroborative evidence for the link between concreteness and semantic memory. We also found a dissociation between nouns and verbs, consistent with neuropsychological literatures that nouns and verbs are encoded in different areas of the brain (Vigliocco et al., 2011). In sum, measuring lexical concreteness in natural speech data can provide circumstantial evidence for evaluating cognitive aging.
A Brief Digital Neuropsychological Protocol – I: Using Artificial Intelligence Assisted Technology to Assess Process and Errors
Authors: Libon David J. , Swenson Rodney , Tobyne Sean , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro 
Published: January 2025

AbstractBackgroundThere is an urgent need for neuropsychological screening tests that are easily deployed and reliable. We have developed a digital neuropsychological screening protocol that is administered on a tablet, automatically scored using artificial intelligence, and requires approximately 10 minutes to administer. This tablet‐administered protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illnessMethodThe digital protocol was administered to 77 ambulatory care/ memory clinic patients (Table1). The protocol is comprised of a 6‐word version of the Philadelphia (repeatable) Verbal Learning Test [P(r)VLT], three trials of 5 digits backward (BDST), and the ‘animal' fluency test. The protocol provides a panel of six traditional measures as would be obtained using paper/ pencil tests and manual scoring of (P[r]VLT free recall/ recognition hits, backward digit span, ‘animal' fluency output); a variety of outcome measures quantifying errors and the process used to bring tests to fruition; and two separate, norm‐referenced summary scores measuring executive control and memory.ResultCluster analysis using the panel of 6 traditional measures classified participants into normal (nl = 23), amnestic MCI (aMCI = 17), dysexecutive MCI (dMCI = 23), and dementia (dementia = 23) groups. Subsequent analyses of error and process variables operationally defined key features associated with amnesia including rapid forgetting such as (P[r]VLT immediate free recall trial 2 vs. delay free recall (aMCI & dementia < dMCI & nl; p< 0.001), the production of extra‐list intrusion errors (dementia > nl; p< 0.002); profligate responding to recognition foils (aMCI & dementia > dMCI & nl; p< 0.001); key features underlying reduced executive measures (i.e., BDST perseveration/ related errors (dMCI & dementia > aMCI & nl, < 0.050); and the strength of semantic association from successive ‘animal' fluency responses (nl & dMCI > dementia; p< 0.028). The novel executive and memory index scores dissociated all four groups from each other (p< 0.014).ConclusionThis digitally administered and scored protocol yields patterns of impaired performance similar to paper/ pencil tests. The availability of both traditional and error/ process measures suggests that subtle, nuanced indications of early emergent illness may be identified in a fast, efficient, yet comprehensive way.
From glia to cytokine signatures across the Alzheimer's spectrum
Authors: Malpetti Maura , Swann Peter , Chouliaras Leonidas , Jones P Simon , Mak Elijah , Bevan‐Jones W Richard , Su Li , Fryer Tim D , Hong Young T , Aigbirhio Franklin I , O'Brien John T , Rowe James B 
Published: January 2025

AbstractBackgroundEarly neuroinflammation is involved in pathophysiology of Alzheimer’s Disease (AD) and contributes to faster clinical decline. Thus, neuroinflammation has emerged as a promising therapeutic target for dementia. However, a better understanding of the interaction between central and peripheral inflammation in human disease and in vivo biomarkers are required for successful clinical trials. Here we assess inflammatory patterns of serum cytokines and their relationship with central inflammation as quantified by TSPO PET (PK11195) in participants on the aging‐AD spectrum.MethodBlood samples were obtained from 56 participants, including30 controls, 22 patients with MCI and 14 with AD) Serum cytokines were quantified using the MesoScale Discovery V‐Plex‐Human Cytokine panel. We applied a Principal Component Analysis (PCA) across all participants to identify inflammatory profiles, which were compared across groups with ANOVA and post hoc tests. Individual scores of the resulting components were correlated with regional TSPO PET binding potentials, as index of microglial activation, and cognitive impairment (MMSE scores).ResultAnalyses on 30 identified 2 components (explaining 19.4 % and 10.8% of the variance, respectively). Both components were strongly represented by pro‐inflammatory cytokines (Figure 1A). One‐way analyses of variance on the first component could not detected statistically significant differences across the groups (χ2(2)=1.69, p=0.193), while individual scores of Component 2 (χ2(2)=8.46, p<0.001) were statistically higher in patients with AD as compared to patients with MCI and to controls (Figure 1B). Correlation analyses with regional TSPO PET values identified positive widespread associations with individual Component 2 scores in frontal, temporal and parietal regions (r > 0.250, p < 0.05; while associations with Component 1 where limited to the anterior frontal/temporal regions (Figure 1C). Individual scores of Component 2 but not Component 1 were significantly associated with worse cognitive performance (lower MMSE; r = ‐0.315, p = 0.01).ConclusionOur approach identified proinflammatory blood signatures that relate to central inflammation and cognitive impairment across the aging‐AD spectrum. These findings encourage the combination of TSPO imaging and blood‐based markers to clarify the interaction between peripheral and central inflammation in AD, and to identify promising therapeutic targets. "