bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau‐derived Locus coeruleus degeneration as a driver for sleep‐wake alterations and neuropsychiatric symptoms in early and late‐onset Alzheimer’s Disease
Authors: Martínez Neus Falgàs , Muñoz‐Moreno Emma , Guillén Núria , Sarto Jordi , Ramos‐Campoy Oscar , Bosch‐Capdevila Beatriz , Marrero‐González Paula , Bargalló Núria , Balasa Mircea , Fernandez‐Villullas Guadalupe , Walsh Christine M , Neylan Thomas C. , Iranzo Álex , Lladó Albert , Grinberg Lea Tenenholz , Sanchez‐Valle Raquel 
Published: December 2022

AbstractBackgroundEarly‐onset Alzheimer’s Disease presentations (EOAD, under 65) frequently present with atypical phenotypes and a more aggressive disease course with a higher burden of neuropsychiatric symptoms than late‐onset AD (LOAD). Current treatments for sleep and behavioral disturbances are still non‐specific, causing side effects (e.g., sedation, falls). Identifying the underlying changes driving behavioral differences between EOAD and LOAD is crucial to developing tailored treatment avenues. The noradrenergic locus coeruleus (LC), one of the first sites of tau deposition in AD, has been implicated in sleep‐wake patterns and mood regulation. We aim to test the hypothesis that the LC is more affected in EOAD than LOAD by comparing LC volume (neuromelanin‐sensitive MRI) and sleep‐behavioral symptoms in biomarker‐confirmed EOAD and LOAD cohorts.MethodFifty‐four subjects with AD biomarker‐based diagnosis (20 EOAD, 34 LOAD) were recruited at the Hospital Clínic de Barcelona. All participants and informants completed the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Neuropsychiatric Inventory (NPI) questionnaires to assess the severity of sleep‐wake alterations and neuropsychiatric symptoms. In addition, they underwent a 3T turbospin‐echo MRI to measure LC volume. We compared mean values of LC volume, ESS, PSQI, and NPI between EOAD and LOAD. Furthermore, linear regression models controlling by cognitive status (MMSE) were performed.ResultEOAD and LOAD had similar cognition (MMSE 21.3±5 vs. 22.6±4, respectively), functional status (CDR 0.92±0.1 vs. 0.68±0.1), and prevalence of amnestic phenotype (57 vs. 70%). EOAD compared to LOAD, trended towards higher scores for ESS (7.4±1 vs. 5.1±1, respectively), PSQI (7.3±2 vs. 5.6±1), NPI (21.6±8 vs. 14.6±8), and caregiver distress (9.4±3 vs. 4.7±3). LC volume was lower in EOAD according to preliminary MRI data [n=18, 9 EOAD (21.8±3 mm3), 9 LOAD (29.5±3 mm3)]. Linear regression models showed that MMSE did not influence the EOAD/LOAD effect on LC volume (coef. 7.7, p=0.032).ConclusionThe current preliminary study suggests that LC degeneration is greater in EOAD than LOAD. This difference may explain the EOAD‐associated worse sleep‐wake dysfunction and neuropsychiatric symptoms. Deep phenotyping/comparison of EOAD and LOAD can inform tailored treatment strategies for these behavioral symptoms.
Chronic electrophysiology reveals age related loss of coherence between hippocampus and entorhinal cortex in ThyTau22 mice
Authors: Zwang Theodore J , Hyman Brad 
Published: December 2022

AbstractBackgroundRecent studies suggest spatial learning and memory impairment, which is an early clinical sign of Alzheimer’s disease (AD), is caused by dysfunction of neurons that communicate between the hippocampus and entorhinal cortex. Technological limitations have prevented chronic cellular‐level tracking of these interconnected brain regions during the many months or years before onset of age‐related cognitive deficits. This study aims to take advantage of recent progress in chronic electrophysiology probes to explore how cellular and circuit‐level changes progress with aging across these two brain regions in a mouse model of AD.MethodTwo flexible electrophysiology probes were implanted with into a single hemisphere of ThyTau22 or WT mice. One probe was targeted to the hippocampus, and the other to the medial entorhinal cortex. Recordings were made from 32 electrodes from each probe once per week over 6 months while mice were walking along a linear track in virtual reality.ResultLongitudinal electrophysiology in ThyTau22 mice show an aging and tau‐pathology correlated decrease in local field potential (LFP) coherence at multiple frequencies. Decoherence is observed both within and between the hippocampus and entorhinal cortex.ConclusionThese results suggest that tau pathology plays a significant role in the loss of neuronal network integrity with age.
Pain interference, cognition, and depressive symptoms in Alzheimer’s disease
Authors: Dimitrov Theodore , Iversen Wm. Larkin , Anderson Alison R , Monroe Todd B , Failla Michelle D , Wang Jinjiao 
Published: December 2022

AbstractBackgroundUnderrecognized and untreated pain in people with Alzheimer’s disease (AD) is a public health concern1 and is associated with sleep disturbances, loss of appetite, and depressive symptoms2. As cognition worsens, people with AD may be unable to reliably report their pain3; 4. While previous studies have examined self‐reported pain intensity in persons with AD5; 6, there has been limited investigation into how this pain interferes with daily living (i.e. pain interference). Wang et al (2017) reported that cognition has a positive association with pain interference and depression7 in AD. However, the relationship of the specific aspects of pain interference with cognitive function and depression has not been explored. Here we investigate the association of specific pain interference subscores with cognitive function and depressive symptoms in verbally communicative older adults with mild to moderate AD. We hypothesized that (1) AD individuals with better cognitive function will report more pain interference in all categories; and (2) all elements of pain interference will be positively associated with depressive symptoms.MethodFor this secondary analysis, we investigated the relationship between pain interference (Brief Pain Inventory‐ Short Form), cognitive function (Mini‐Mental Status Exam), and depressive symptoms (15‐item Geriatric Depression Scale) in 52 older communicative adults (ages ≥ 65) with AD. Data analyses were conducted in R using Spearman correlation coefficients to assess the univariate associations between study measures.ResultWe found significant positive correlations between cognitive function (median MMSE = 17.00) and pain interference subscores of general activity, mood, walking ability, normal work, sleep, and enjoyment of life (r = .30‐.37, p < 0.05), but not “relations with other people.” Further, the relationship between depressive symptomatology (median GDS‐15 = 2.00) with pain interference was significant in all measures except “general activity” (r = .26 ‐.38, p < 0.05).ConclusionAmong adults with AD, nearly all aspects of pain interference were positively associated with cognitive function and depressive symptoms. Regular assessment of specific pain interference measures and screening for depressive symptomology can be used as another tool to help identify unreported and underrecognized pain. Moreover, distinguishing individual elements of pain interference may allow for more individualized management of pain and depressive symptoms in this vulnerable population.
Daily Stressors, Social Support, and Mental Health Experiences of Dementia Family Caregivers
Authors: Puga Frank , Wang Danny , Rafford Meghan , Pickering Carolyn E 
Published: December 2022

AbstractBackgroundFamily members providing informal care to individuals living with dementia have an increased risk of depression and anxiety. While risk and protective factors of poor mental health outcomes have previously been identified, little is known about the day‐to‐day circumstances in which depression and anxiety‐related symptoms are more likely to appear among dementia caregivers. The purpose of this study was to identify contextual factors associated with daily depression and anxiety symptom experience among dementia family caregivers.MethodA national sample of family caregivers (N = 165) completed daily diary surveys over 21 days (n = 2,841). Mixed‐level models were used to examine relationships between daily behavioral symptoms of dementia (BSDs), emotional and instrumental social support, and depression and anxiety‐related symptoms.ResultDepression and anxiety symptoms were endorsed by 141 (85.45%) and 155 (93.94%) caregivers, respectively. Dementia caregivers were more likely to report depression (OR = 1.15, 95% CI: 1.11‐1.18, p < 0.001) and anxiety (OR = 1.12, 95% CI: 1.09‐1.16, p < 0.001) on a given day when BSDs were present and perceived as more bothersome than usual. Specific BSDs, including restless behaviors and intense emotions, also increased the daily odds of experiencing depression and anxiety symptoms. Further, the daily odds of depression decreased on days when caregivers reported informal instrumental support (OR = 0.67, 95% CI: 0.4‐0.92, p < 0.05), while the daily odds of anxiety increased on days when caregivers reported emotional support (OR = 1.46, 95% CI: 1.07‐1.99, p < 0.05).ConclusionThe risk of experiencing depression and anxiety symptoms varies daily based on the presence of specific contextual factors. The results from this study demonstrate the dynamic nature of mental health in the context of dementia caregiving. These findings support the need for ecologically‐valid interventions to improve the day‐to‐day well‐being of dementia family caregivers.
Subiculum fiber degeneration within the fornix white matter tract in 5xFAD mice
Authors: Bienkowski Michael S , Becerra Marlene , Montagne Axel , Korobkova Laura , Cabeen Ryan P , Khanjani Neda , Sagare Abhay P , Jacobs Russell E. , Zlokovic Berislav V 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease that affects all components of the neurovascular unit. The hallmark pathology of AD, amyloid plaques and tau neurofibrillary tangles, aggregate within gray matter areas and spread across neural networks. Although AD pathology is scarce within white matter brain regions, white matter abnormalities have been observed in AD patients using diffusion tensor imaging (DTI; Sachdev et al 2013) and white matter tracts are putative therapeutic targets for deep brain stimulation (Lam et al 2020). Particularly, the fornix is a white matter tract which connects the hippocampus to brain regions of the classic Papez circuit and Default Mode Network (DMN). A recent whole brain analysis using transgenic 5xFAD/Thy1‐GFP mouse (Zhang et al 2020) found evidence of fornix degeneration and dystrophic axon terminals within the mammillary body (a major SUB target) occurring as early as 2 months of age. However, due to the broad expression of GFP under the Thy1 promotor, it is difficult to determine the origin of axon fibers and further characterize if other SUB pathways are also affected.MethodTo investigate white matter changes in AD and further characterize SUB axon degeneration, we performed triple anterograde tract‐tracing of SUB axon fibers and post‐mortem DTI tractography imaging within the same 8‐9 mo. old 5xFAD mice.ResultDTI imaging revealed a significant decrease in fiber density of the fornix white matter tract in 5xFAD mice. Quantification of tracer‐labeled fluorescent fiber density in the 5xFAD mice vs control mice also revealed significant degeneration of SUB fibers within the fornix white matter as well as downstream SUB targets including mammillary body, retrosplenial cortex, and anterior thalamus. Furthermore, SUB axon terminals in 5xFAD mice appeared dystrophic and terminal field topography was disrupted.ConclusionDTI imaging and anatomical tract tracing approaches reveal white matter degeneration in 5xFAD mice and the fornix/SUB fibers are particularly vulnerable in AD. Diminished SUB input to brain regions of the Papez circuit/DMN likely leads to neural network dysfunction. Whether amyloid pathology, neurovascular dysfunction, or inflammatory response in the 5xFAD mouse contributes to white matter degeneration remains to be determined by future studies.
An Educational Platform about Current and Future Paradigms of Neuroimaging in the Management of Alzheimer’s Disease
Authors: Van Phan Thanh , Praet Jelle , Guarnieri Roberto , Löwenthal Elise , Bettens Laurent , Ribbens Annemie 
Published: December 2022

AbstractBackgroundThe first disease‐modifying treatment (DMT) for Alzheimer’s disease (AD) has been approved by the U.S. Food and Drug Administration (FDA) in 2021, with potentially more DMTs becoming available in the coming years. Neuroimaging was shown to support clinical decision making in the management of AD and will play a crucial role in determining patient eligibility and monitoring treatment efficacy and adverse events [1]. However, while neuroimaging takes center stage, image acquisition and analysis is rapidly becoming more complex. Training and education are critical for successful implementation of new imaging tools by (neuro)radiologists in daily clinical practice [2].MethodsALZimaging.com is a free e‐learning platform about current and future neuroimaging paradigms in AD management, written by three medical experts. It offers six chapters containing a thorough literature review, retaining more than 250 peer‐reviewed papers and guidelines about AD pathophysiology, neuroimaging protocols and tools for early and differential diagnosis, patient monitoring and safety reading. Additionally, all chapters are complemented by a quiz to test the users’ knowledge. Four webinars with Accreditation Council for Continuing Medical Education (ACCME) are also included, presenting expert discussion panels and case studies. We present the qualitative assessment on the general acceptance and feedback about the e‐learning platform, while the educational content was released gradually during the first year.ResultsSince the launch, over 2000 persons have visited the e‐learning platform. The registered participants have read in average 71.5% of the content and the average quiz score is 3.5 out of 5 per chapter. For the Alzheimer’s webinar series, more than 500 participants watched the live versions and completed the courses, resulting in the attainment of ACCME‐accreditation. As feedback, the majority of (neuro)radiologists using the platform expressed their positivity and that knowledge gaps on neuroimaging were filled.ConclusionThe changing healthcare landscape of neuroimaging in dementia results in a strong interest in educational material. Platforms like ALZimaging.com providing curated and interactive educational resources leading to ACCME accreditation can play a crucial role to support the neuroradiology community in improving management of AD in care practice.References:[1] Banerjee, CUREUS (2020)[2] Vavasseur, Insights Imaging (2020)
Native American Ancestry is associated with lower risk of Alzheimer’s Disease: results from the Genetic of Alzheimer’s disease in Peruvian Populations (GAPP) study.
Authors: Custodio Nilton , Soto‐Añari Marcio , Montesinos Rosa , Caipa Maritza Pintado , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Reyes‐Dumeyer Dolly , Tosto Giuseppe 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease Related Dementias (ADRD) is not equally distributed among racial and ethnic groups. The APOE‐ɛ4 allele alone does not explain the different frequency of the disease. In fact, Hispanics (HI) and African Americans e4 non‐carriers still show a two‐to‐four‐fold higher incidence of ADRD, compared with non‐Hispanic Whites. Ancestry is an understudied yet a critical aspect of health disparities, as it may explain observed differences in frequency of ADRD across ethnic groups. We recently launched a genetic study in Peruvians, whose genome is characterized by large Native‐American ancestry proportions (higher than other HI populations such as Caribbean Hispanics or Mexicans), and studied the association between Ancestry, APOE‐e4 and ADRD.MethodWe recruited 264 Peruvians across three main sites in Peru (Lima, Arequipa, Puno). Genotyping was conducted on GSA Illumina platform, and, after QC, global ancestries (Native American [NAT], European [EUR], African [AFR]) were estimated using the Human Genome Diversity Project as reference (Figure 1). Number of APOE‐e4 alleles were entered as predictor along with proportion of global ancestries in regression models, adjusting for age, sex and education. AD status was employed as main outcome; episodic memory scores were used as secondary outcomes in healthy controls.Result51 were diagnosed with AD, 213 were healthy controls (mean age 72 years old). Average ancestry was estimated to be 73.0% NAT, 23.8% EUR, 3.2% AFR. APOE‐e4 was found associated with AD (OR [95%CI] = 4.09 [1.98‐8.47], p<0.001). NAT ancestry proportion was found protective at trend in the whole cohort (OR = 0.73[0.50‐1.06], p = 0.096). When restricted to e4 non‐carriers, NAT ancestry was found significantly associated with lower AD risk (OR = 0.57[0.36‐0.91], p = 0.019). Consistently, higher NAT ancestry was associated with better episodic memory scores in healthy controls (e.g. delayed recall: betastandardized = 0.26, p<0.001).ConclusionTo our knowledge, this is the largest collection of individuals with predominant Native American ancestry showing protective effect towards ADRD. This is particularly evident in those individuals not carrying the APOE‐e4 allele. APOE is confirmed as strong risk factor for ADRD (larger than other HI populations).
Hearing loss and dementia in Peruvian populations
Authors: Custodio Nilton , Failoc‐Rojas Virgilio E , Chambergo‐Michilot Diego , Malaga Diego , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Soto‐Añari Marcio , Reyes‐Dumeyer Dolly , Casavilca‐Zambrano Sandro , Montesinos Rosa , Tosto Giuseppe 
Published: December 2022

AbstractBackgroundHearing loss is prevalent in older adults, affecting a third of this population. Hearing loss is a modifiable and treatable factor. It has been shown that hearing loss can lead to social isolation and later to dementia. In addition, the corresponding cortical area has a close relationship with auditory and cognitive processing. In this study we aimed to evaluate the association between dementia and hearing loss.MethodA multicenter cross‐sectional study was carried out in three locations of different altitude in Peru: Lima, Arequipa and Puno. Participants over 50 years of age with an available informant were recruited in memory clinics. The Hughes Clinical Dementia Rating (CDR) was employed to rate dementia (0 being healthy, 0.5 being questionable dementia, and greater than 1 being dementia). The exposure variable was reported hearing loss, which was defined as current hearing problems for more than six months. A descriptive analysis was performed and to evaluate the association between these variables, multinomial logistic regression with robust variances was used to estimate prevalence ratios (PR) with 95% confidence intervals.ResultsWe evaluated 295 patients. The mean age was 71.9 years. More than a half was female (68.8%). The prevalence of hearing loss was 19.6%. In the crude model, hearing loss were associated with increased prevalence of dementia, with older age and education being associated with higher and lower CDR scores, respectively. After adjusting for confounders and geographic clustering, the association between hearing loss and dementia showed a PR of 3.39 (95% CI: 1.11‐10.39) that in those without dementia.ConclusionIn our cohort of Peruvian participants, we found that hearing loss was associated with dementia in line with previous investigations. Further follow‐up studies are needed to better assess and characterize this association.
Cognitive reserve moderates the relationship between hippocampal volume and cognitive decline – but not gait decline
Authors: Blumen Helena M , Jayakody Shanika Oshadi , Ayers Emmeline , Barzilai Nir , Milman Sofiya , Weiss Erica , Verghese Joe 
Published: December 2022

AbstractBackgroundCognitive reserve (CR) accounts for individual differences in the relationship between brain health and clinical status. Common proxies of CR include education, and physical and social leisure activities. Greater CR allows individuals to cope better with poor brain health, and thereby delay the onset of cognitive impairment and dementia. Yet, whether CR protects against age‐related gait and cognitive decline is not well‐understood. Here, we examined whether CR moderates the relationship between hippocampal volume (a common marker of brain health) and age‐related decline in gait and cognition.MethodData from 101 LonGenity participants without dementia (M Age=79.33±6.09 years; 56% women) who had completed one MRI, and up to 3 years of follow‐up testing (M follow‐up=1.83±0.54 years) was examined. Gait speed was assessed during normal pace walking. Cognition was assessed with 11 neuropsychological tests, and a global cognitive composite. CR proxies (from self‐report), included cognitive (years of education), physical (number of blocks walked per day), and social (volunteering, living with someone) activities. FreeSurfer 6.0 was used to obtain hippocampal volume from structural MRIs. Linear mixed‐effects models adjusted for sex, parental longevity, cognitive impairment, and comorbidities examined the relationship between hippocampal volume and age‐related gait and cognitive decline.ResultEducation moderated the relationship between hippocampal volume and decline in figure copy performance. The number of blocks walked per day moderated the relationship between hippocampal volume and decline in global cognition, Trail Making Test (TMT)‐A, TMT‐interference, digit symbol substitution and phonemic fluency performance. Living with someone moderated the relationship between hippocampal volume and decline in global cognition, TMT‐interference, and logical memory performance. None of the CR proxies moderated the relationship between hippocampal volume and gait speed decline.ConclusionCognitive, physical, and social CR proxies moderated the relationship between hippocampal volume and age‐related cognitive decline – not age‐related gait decline. Follow‐up sensitivity analyses, however, suggested that some CR proxies (e.g. education) moderated the relationship between prefrontal volumes and age‐related gait decline – presumably because prefrontal regions are more consistently associated with gait speed. Future studies are need to confirm whether the relationship between CR and age‐related gait and cognitive decline depends on the brain health marker.