bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating Endocannabinoids and Early Markers of Alzheimer’s Disease: Considering the Role of Sex
Authors: Vered Shiraz , Beiser Alexa S. , Sulimani Liron , Sznitman Sharon , Gonzales Mitzi M. , Aparicio Hugo J , Lewitus Gil M , Meiri David (Dedi) , Seshadri Sudha , Weinstein Galit 
Published: December 2023

AbstractBackgroundEndogenous cannabinoids (i.e. endocannabinoids; eCBs) have an essential role in multiple physiological processes including energy homeostasis, sleep patterns and mood. Moreover, preclinical studies highlight the implication of eCBs in neurodegeneration and Alzheimer’s disease pathogenesis. Yet, observational studies are scarce and limited by small sample sizes and assessment of limited numbers of eCBs. We assessed the relationship of multiple circulating eCBs with cognitive and brain MRI measures and tested for effect‐modification by sex.MethodWe measured serum levels of 44 eCBs and eCB‐like compounds from 237 cognitively healthy participants aged ≥65 years who attended the ninth examination cycle of the Framingham Heart Study Offspring cohort. Linear regressions were used to examine the associations of eCB levels with cognitive and brain MRI, adjusting for age, age2, sex and time between blood draw and cognitive/MRI examination. Bonferroni correction for multiple comparisons was applied, and interactions with sex were assessed by including interaction terms in the models and stratification.ResultMean age was 73.3±6.2 years and 95 (40%) were men. Overall, higher levels of N‐Linolenoyl amide and N‐Linoleoyl amide were associated with poorer performance on Logical Memory (β = ‐1.535±0.442; p = 0.0006; β = ‐0.171±0.045; p = 0.0002, respectively) and Trails‐making A (β = ‐0.127±0.036; p = 0.0005; β = ‐0.014±0.004, p = 0.0003, respectively). Higher levels of Linolenic acid and N‐Oleoyl alanine were associated with poorer performance on Trails‐making B‐A (β = ‐0.001±0.0001; p = 0.0007; β = ‐0.787±0.237; p = 0.001; respectively) (Figure 1). Our results further pointed to a potentially important interaction between sex and eCB signaling with regard to cognitive and brain MRI measures. Specifically, significant interactions between eCBs and sex were observed in relation to all the study outcomes except for total cerebral brain volume. Moreover, most associations that differed by sex were in the opposite directions comparing men to women (Figure 2 and 3). The aforementioned associations between specific eCBs and cognitive performance in the total sample were apparent in women but not men.ConclusionWe identified a wide range of sex‐specific associations between novel eCB compounds and early AD markers among dementia‐free older adults. These findings suggest putative molecular pathways underlying AD pathophysiology, and highlight potential mechanisms behind sex differences in AD susceptibility that need to be further investigated.
Regional Brain Structure Mediates Age‐Related Decline in Eye Movement Control
Authors: Etteldorf Rika , Coors Annabell , Ettinger Ulrich , Breteler Monique M.B. 
Published: December 2023

AbstractBackgroundEye movements (EM) are considered potential biomarkers of neurodegeneration because they are altered in patients with neurodegenerative disease, including Alzheimer’s disease (AD). Alterations in EM control have also been observed in old age, with particularly strong age effects on saccadic latency, inhibitory errors in the antisaccade task, and smooth pursuit accuracy. The goal of our study was to characterize the neural pathways of age‐related changes in these EM outcomes.MethodThe analysis was based on 8,318 participants (aged 30 to 95 years) from the population‐based Rhineland Study. EMs were recorded using video‐based infrared oculography at 1,000 Hz. Volumes and thickness measures of selected brain structures were obtained using FreeSurfer from 3 Tesla T1‐weighted MR images. Relations of brain structure with EM outcomes were quantified using multivariable linear regression models. Brain structure variables were also analyzed as potential mediators in the relation between age and EM outcomes using causal mediation analysis under a counterfactual framework.ResultIn women, higher volume of the right thalamus and right globus pallidus was associated with lower antisaccade latency, whereas higher cortical thickness in the anterior cingulate cortex was associated with higher antisaccade latency. Higher cortical thickness in right supramarginal gyrus and right paracentral lobule and sulcus was associated with fewer antisaccade errors in women. There were no significant associations between regional brain structure and antisaccade performance in men. Higher cortical thickness in the right calcarine sulcus was associated with higher smooth pursuit velocity gain in both men and women. Additionally, individual brain structures mediated up to 11% of the age‐related decline in EM performance.ConclusionOur results support that EMs indeed reflect neurodegenerative processes as changes in brain structure partly account for age‐related decline in oculomotor performance. Relevant brain regions include both brain regions vulnerable to AD pathology and brain regions that are typically spared, suggesting that both “normal” age‐related and pathological mechanisms may be causative for decline in EM control. Our results highlight the importance of taking into account normal age‐related changes when considering EMs as early biomarkers for AD. Further work is needed to better distinguish normal age‐related changes from pathological change.
Perspectives of General Practitioners on signaling and diagnosing dementia
Authors: Visser Fleur C.W. , van Eersel Marlise E.A. , van der Zaag Hester J. , van Munster Barbara C. 
Published: December 2023

AbstractBackgroundAlthough a timely diagnosis of dementia is beneficial for patients, their relatives, and society, people with dementia often remain undiagnosed or receive a diagnosis at a relatively late stage (Lang 2017). General practitioners (GPs) have a prominent role in the detection of dementia, yet GPs experience several barriers in diagnosing dementia in primary care (Koch 2010). This study aims to explore the experiences and perspectives of GPs in diagnosing dementia in primary care.MethodA qualitative study was conducted consisting of semi‐structured interviews with 10 Dutch GPs purposively selected using maximum variation sampling. The study was an initiative of Alzheimer Center Groningen as part of ABOARD (A Personalized Medicine Approach for Alzheimer’s Disease). Overall topics included: experiences in signaling dementia; thoughts about the decision to wait in diagnosing dementia, to perform diagnostics, or to refer to a medical specialist for diagnosing dementia; and the needs of GPs in the diagnostic process of dementia. Interview transcripts were analyzed in multiple rounds by a multidisciplinary research team using thematic analysis with a phenomenological approach.ResultOverarching themes were ‘initiation of the diagnostic trajectory’, ‘timing of diagnosis’, ‘relevance of a formal diagnosis’, ‘division of roles and responsibilities, ‘patient denial’, ‘patient‐physician relationship’, ‘crisis’, and ‘arranging care after diagnosis’. Key findings within the ‘initiation of the diagnostic trajectory’ theme were that observations from people around patients (family, community nurse, practice nurse, pharmacist, or medical specialist) were often signals for GPs to start a conversation about dementia and diagnostic possibilities. The diagnostic trajectory rarely started with a request for help from the patient. Patient denial was described as a major obstacle in diagnosing dementia and arranging appropriate care subsequently. A proactive practice policy to detect and monitor cognitive impairment was a key facilitator to achieve a timely diagnosis and prevent crises in dementia. For example, GPs favored regular home visits by a practice nurse and low‐threshold cognitive examination; a long‐term physician‐patient relationship; and successful interdisciplinary collaboration with local care providers, especially consultation of an elderly care physician.ConclusionPatient denial and surrounding people are important barriers and facilitators, respectively, to the diagnostic process of dementia.
Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort
Authors: Grazia Alice , Dyrba Martin , Nunzio Pomara , Teipel Stefan 
Published: December 2023

AbstractBackgroundImaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.MethodWe analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.ResultWe found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.ConclusionOur findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.
Exploring the relationship between cognitive frailty and cognitive reserve in SCD and MCI
Authors: Facal David , Lojo‐Seoane Cristina , Campos‐Magdaleno Maria , Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Stern Yaakov , Pereiro Arturo X 
Published: December 2023

AbstractBackgroundCognitive frailty (CF) has been defined as the simultaneous presence of physical frailty (PF) and subjective or objective cognitive impairment, with current definitions differentiating, respectively, between reversible and potentially reversible CF. The former is indicated by subjective cognitive decline (SCD) and the latter by Mild Cognitive Impairment (MCI). Although CF is an emerging topic in the study of cognitive ageing, its relationship with cognitive reserve (CR) proxies have not been established.MethodThe prevalence of CF and the characterization of the sample in terms of its level of CR was studied in the second cohort of the Compostela Ageing Study (CompAS). 150 participants of the second follow‐up of this cohort who completed the PF assessment were studied. The frailty phenotype was used to operationalize the level of PF of the participants. Weakness was measured by 3 measurements of the grip strength (GS) in the dominant hand. Slow gait speed was measured through a timed‐up and go (TUG) task. Low physical activity was measured with the Spanish version of the Minnesota Physical Activity Questionnaire (VREM). MCI and SCD were diagnosed using the current criteria. The level of CR was established using the scores of the Cognitive Reserve Index questionnaire (CRIq). Bivariate correlations were made between CRIq subscales scores and the results in GS, TUG and VREM.ResultsA higher percentage of high CR was observed in participants without frailty, and a higher percentage of participants with medium level of CR showed pre‐frailty (c2 = 27,96 p<.05). Significant moderate correlations were obtained between GS and CRI‐q working activity (r = .47), and between TUG and CRI‐q leisure time (r = ‐.35).ConclusionAs expected for a risk factor for dementia, there were significant relationships between CF and several domains of CR. Future longitudinal analysis should analyze the capacity of the CR to attenuate or delay the onset of cognitive frailty.
Deterioration of true resting state electroencephalographic alpha rhythms in patients with mild cognitive impairment due to Alzheimer’s disease at a 6‐Month follow‐Up
Authors: Jakhar Dharmendra , Noce Giuseppe , Tucci Federico , Lopez Susanna , Lizio Roberta , Percio Claudio Del , Soricelli Andrea , Ferri Raffaele , Arnaldi Dario , Güntekin Bahar , Yener Görsev , Stocchi Fabrizio , Marizzoni Moira , Frisoni Giovanni B , Babiloni Claudio 
Published: December 2023

AbstractBackgroundPrevious studies have shown that patients with Mild Cognitive Impairment due to Alzheimer’s disease (ADMCI) were characterized by reduced posterior rsEEG alpha rhythms after a 12‐month follow‐up (Babiloni et al., 2013). However, none of them have found an alpha deterioration considering a shorter follow‐up.A promising neurophysiological biomarker of the quiet vigilance alteration is the measurement of the posterior rsEEG alpha rhythms reduction in amplitude (reactivity) in the transition from the eyes‐closed to the eyes‐open condition (Babiloni et al., 2022).Here we tested the exploratory hypothesis that ADMCI reactive patients may display a deterioration of rsEEG alpha rhythms at a 6‐month follow‐up as a sign of disease progression (a relevant feature for intervention clinical trials).MethodClinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 matched healthy elderly (Healthy) seniors were available from an international archive (www.pdwaves.eu). The rsEEG frequency bands were individual delta, theta, and alpha (defined based on its posterior topography and “reactivity” to the eyes‐open condition) or background frequency (BGF), as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz). Cortical source estimation was performed by eLORETA freeware.ResultA substantial (> ‐10%) reduction in the posterior alpha source activities during the eyes‐open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI participants (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes‐closed condition predicted the global cognitive status at 6‐month follow‐up. In all younger ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes‐closed condition reduced in magnitude at that follow‐up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD.ConclusionThese results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation.
CSF proteome profiling identifies novel biomarkers for Frontotemporal Dementia and its pathological subtypes
Authors: Hok‐A‐Hin Yanaika S. , Vermunt Lisa , Peeters Carel F.W. , van der Ende Emma L. , de Boer Sterre C.M. , Meeter Lieke H. , van Swieten John C. , Hu William T. , Lleó Alberto , Alcolea Daniel , Engelborghs Sebastiaan , Sieben Anne , Chen‐Plotkin Alice , Irwin David J. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , del Campo Marta 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD) and the most common forms are characterized by either tau (FTLD‐Tau) or TDP43 (FTLD‐TDP) brain aggregates. However, FTD‐specific fluid biomarkers are lacking. Furthermore, the pathological subtypes are not distinct in their presentation, hampering accurate subtyping at clinical diagnosis. Therefore, there is a strong need to identify fluid biomarkers that could aid in FTD diagnosis and to discriminate the pathological subtypes.MethodWe employed an antibody‐based proteomic technology to analyze >600 proteins in a large multicenter cohort including cerebrospinal fluid (CSF) samples from FTD (n = 189), AD (n = 235) and cognitively unimpaired individuals (n = 196). For a subset of cases the underlying neuropathology was known or could be predicted (FTLD‐Tau = 85 and FTLD‐TDP = 57). Differences in protein expression profiles were analyzed by nested linear models. Penalized generalized linear modeling was used to identify classification protein panels. Protein panels were then validated in independent clinical cohorts (cohort 1: n = 157; cohort 2: n = 165) and a neuropathology cohort (n = 100) using customized assays.ResultWe observed 65 differentially regulated proteins in FTD versus controls and AD patients, associated with axonogenesis, synapse assembly, or locomotory behavior pathways. We identified panels of 14 and 13 proteins that could discriminate FTD from controls (AUC = 0.96, 95%CI:0.91‐0.99) and AD patients (AUC = 0.91, 95%CI:0.85‐0.96), respectively. Most of these proteins (21 out of 27) were translated into customized panels, which discriminated between groups with high accuracy for all three cohorts (FTDvsCon: AUCs > 0.96, FTDvsAD: AUCs > 0.88). When comparing the FTLD‐Tau and FTLD‐TDP subtypes, we observed that 86 proteins were increased in FTLD‐Tau, and associated with developmental and cellular processes and locomotion pathways. A panel of 8 proteins could discriminate between the pathological subtypes (AUC = 0.82, 95%CI:0.66‐0.95), which was however not stable during cross‐validation.ConclusionWe identified and validated CSF panels to discriminate FTD from controls and AD with high accuracy. The identification of a biomarker panel to discriminate between the FTLD pathological subtypes likely requires larger and more homogeneous groups. The panels developed within this study might be useful for diagnosis and trial inclusion of FTD patients.
Effect of neuroinflammation markers on the relation between A, T and N: sex‐specific resilience or vulnerability?
Authors: Akinci Muge , Vila‐Castelar Clara , Palpatzis Eleni , Argiris Georgette , Kollmorgen Gwendlyn , Carboni Margherita , Blennow Kaj , Zetterberg Henrik , Falcon Carles , Gispert Juan Domingo , Suarez‐Calvet Marc , Arenaza‐Urquijo Eider M 
Published: December 2023

AbstractBackgroundSex‐specific vulnerability and resilience along the amyloid cascade may be partly explained by neuroinflammatory processes. Microglial activation may play a more important role in the development of Alzheimer’s disease (AD) in women than in men. We investigated the effect of sex and biomarkers of microglia and astrocytic activation on amyloid (A) and tau (T) burden, and neurodegeneration (N) in cognitively unimpaired (CU) older adults at increased AD risk.MethodWe included 397 CU participants (49‐73 years, 61.5% women) with the following available CSF biomarker data: Aβ42/40, p‐tau181, sTREM2, GFAP, and YKL40 measured with Roche NeuroToolKit or Elecsys® immunoassays. A subsample (n = 299) also had MRI‐based hippocampal volume data (ASHS segmentation). The outcomes of interest were A: Aβ42/40, T: p‐tau181, and N: hippocampal volume. Predictors included demographics and neuroinflammation markers. First, we tested the effect of sex and neuroinflammation markers on A, T, and N in the whole sample. Then, we tested the neuroinflammation*Aβ42/40 and neuroinflammation*p‐tau interactions on p‐tau and hippocampal volume, respectively. Finally, we looked at sex‐stratified models.ResultMen were older, more often APOE‐ε4 carriers and showed higher GFAP levels (men>women). In the whole sample, neither sex nor neuroinflammation markers were associated with Aβ42/40. However, sex (women>men), higher sTREM2 and higher YKL40 were associated with higher p‐tau181 levels, and sex (women<men), lower sTREM2, and higher YKL40 were associated with lower hippocampal volume. Models including interaction terms showed a sex‐independent interaction of GFAP with Aβ42/40 and p‐tau181 on p‐tau181 and hippocampal volume, respectively, suggesting a role of astrocytic activation along the ATN pathway. Sex‐stratified analyses showed (1) in women only, a YKL40*Aβ42/40 interaction on p‐tau181 and an association of higher sTREM2 levels with greater hippocampal volume (p = .030), suggesting a protective effect, and (2) in men only, a p‐tau181*sTREM2 and p‐tau181*YKL40 interaction on hippocampal volume. Statistics are provided in Table 1.ConclusionPending replication with longitudinal measurements, our results suggest that microglial and astrocytic activation may play a sex‐specific role in downstream amyloid. While astrocytic activation moderates the associations between A, T and N in men and women, microglial activation might provide resilience to neurodegeneration only in women (Figure 1).