bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau phosphorylation is more closely associated with amyloid‐β plaques than with tau neurofibrillary tangles
Authors: Vermeiren Marie , Therriault Joseph , Servaes Stijn , Lussier Firoza Z , Tissot Cécile , Pascoal Tharick A , Chamoun Mira , Bezgin Gleb , Benedet Andréa Lessa , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Stevenson Jenna , Rahmouni Nesrine , Kunach Peter , Wang Yi‐Ting , Arias Jaime Fernandez , Massarweh Gassan , Vitali Paolo , Soucy Jean‐Paul , Saha‐Chaudhuri Paramita , Blennow Kaj , Zetterberg Henrik , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundWhile fluid phosphorylated tau (pTau) epitopes are interpreted to be biomarkers of tau pathology according to the A/T/(N) framework, it is unclear to what extent they are preferentially associated with the defining histopathological hallmarks of Alzheimer’s Disease (AD): amyloid‐β plaques and tau neurofibrillary tangles.MethodWe studied 171 individuals, including young adults (n=27), cognitively unimpaired elderly (n=85), individuals with mild cognitive impairment (n=36) and individuals with Alzheimer’s clinical syndrome (n=23), who were evaluated with [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, four tau phosphorylation sites in CSF (pTau181, pTau217, pTau231, pTau235) and two phosphorylation sites in plasma (pTau181, pTau231). To better understand the role of soluble biomarkers in AD diagnostic and research purposes, we evaluated associations between soluble pTau sites and cerebral amyloid‐PET and tau‐PET concentrations. Voxel‐wise linear regressions between fluid and imaging biomarkers were performed. Results for plasma and CSF pTau181 were replicated in an independent sample of 258 individuals included in the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI).ResultWe observed that for all plasma and CSF epitopes, pTau is more closely associated with amyloid‐PET than with tau‐PET. Squared correlation coefficients (Spearman’s R2) between CSF pTau epitopes and neocortical [18F]AZD4694 SUVR range from 0.48 to 0.63, while those for the temporal meta‐ROI [18F]MK6240 SUVR vary between 0.33 and 0.45 (p<0.001 for all phosphorylation sites). Using the R package “Cocor”, for CSF pTau181, pTau217 and pTau231 the difference in correlation coefficients between both measures of imaging biomarkers appear significant (p<0.01). Voxel‐wise linear regression analyses further support these results, in particular showing sizable associations for CSF pTau231 with amyloid‐PET. In addition, soluble pTau is more closely correlated with medial temporal than with neocortical tau. All soluble pTau concentrations rise significantly with increasing amyloid‐β plaque load. In contrast, soluble pTau plateau as tau‐PET concentrations increase, starting at Braak stage III. These findings were replicated using plasma and CSF pTau181 in the ADNI cohort.ConclusionPhosphorylated tau epitopes measured in CSF and plasma better reflect cerebral amyloidosis than neurofibrillary tangles in the brain. The current findings support careful interpretation of fluid pTau concentrations when implementing the A/T/(N) framework.
Examining the level of test burden in NIA’s Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) clinical trials
Authors: Roper Rebecca Anne , Manohar Rhea , Crespo‐Bellido Mayra , Bui Elise , Jarvis‐Gibson Jeanne , Mitchell Alexandra , Massett Holly A , Miscally Memi 
Published: December 2022

AbstractBackgroundThe National Institute on Aging (NIA) is working to increase access of its AD/ADRD clinical trials (CT) into community health care settings. Concerns exist in the field regarding the feasibility of conducting AD/ADRD CTs outside of academic settings given the testing required within CT protocols. We evaluated recently awarded NIA CTs to document their types and frequency of diagnostic tests required. Findings provide NIA the opportunity to understand the potential test burden on sites and consented participants.MethodWe conducted a systematic content analysis of recently funded NIA AD/ADRD CTs involving human subjects to assess the commitment required of participants and the number and type of tests required across protocols (start dates: 2/1/20 – 9/30/2021 (N = 115)). Documented tests included: imaging, biospecimen, genetic, sleep, cognitive, and mental health. Findings were analyzed by the CTs’ standardized Common Alzheimer’s and Related Dementias Research Ontology (CADRO) category.ResultMost CTs (65%) were CADRO C (Translational Research/Clinical Interventions) or E (Dementia Care/Disease Impact; 25%); CADRO E had substantially fewer tests required of participants. Most trials (75%) asked consented participants for less than a year commitment (median = 185 days). Top tests required were cognitive (78% of trials); mental health/well‐being (57%); brain imaging (46%; e.g., MRI, PET, MRS), and blood collection (37%). Fewer CTs required lumbar spinal tap (12%). Initial analyses indicate that potentially 75 unique cognitive tests were documented across the 90 CTs assessing cognition, and that participants were asked to complete a median 8.5 cognitive tests per trial (range: 1 to 71 tests).ConclusionThis review lays the foundation for understanding the complexity of recently funded NIA AD/ADRD clinical trials. Understanding the required tests will inform the discussion with community health practitioners to identify what and how many tests are feasible, and how such input can be incorporated into the design of future trials in a way that can enhance opportunities and research participation by interested communities, particularly those serving traditionally underserved populations.
Non‐Pharmacologic management: Considerations for Family Caregivers
Authors: Fischer Corinne E. , Hakobyan Narek 
Published: December 2022

AbstractBackgroundAgitation is a common symptom of dementia, estimated to occur in upwards of 30% of patients.1 Family caregivers are often the frontline when it comes to management of agitation given that many patients with dementia live at home, and often bear the brunt of caregiver burden. In spite of existing research, which non‐pharmacological interventions should be used when is unclear.MethodThis abstract describes the application of the IPA algorithm to the family‐caregiver setting.ResultThe current IPA algorithm for agitation emphasizes the importance of non‐pharmacological interventions integrated with pharmacological interventions and adapted in an iterative manner dependent on patient response. Data on non‐pharmacological interventions in the family caregiver setting, though sparse, suggest a couple of key themes. Most interventions, including analyses of data from social media platforms, Long Term Care data and clinical trial data emphasize the importance of patient engagement.2 Planning appropriate activities, problem‐solving and teaching communication skills is also paramount. Finally, modification of the environment, reminiscence and engagement with outside support networks is critical. Individualized approaches with multiple components and modified based on follow up are particularly effective. Review of clinical trial data in fact suggests effect sizes comparable to that achieved with medication without the concomitant side effects.2 Finally, interventions that focus on the well‐being of the caregiver and emphasize enhanced self‐efficacy are particularly important, given caregiver burden in family caregivers often exceeds that of professional caregivers. Studies have been limited by lack of standardization, small sample sizes and limited follow‐up.ConclusionFurther rigorous studies are required to establish which approaches are most effective in family caregivers and how they relate to pharmacological interventions, though data to date suggest interventions that work in other setting (such as Long Term Care) may be adaptable to the family setting.1.	Carrarini C, Russo M, Dono F, et al. Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions. Front Neurol 2021; 12: 644317.2.	Brodaty H, Arasaratnam C. Meta‐analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. The American journal of psychiatry 2012; 169(9): 946‐53.
Sex Differences in Mild Cognitive Impairment Risk by APOE Genotype
Authors: Wang Xinran , Edland Steven D. , Sundermann Erin E. , Banks Sarah J. 
Published: December 2022

AbstractBackgroundMale sex is suggested as a risk factor for mild cognitive impairment (MCI), but this association may be influenced by the female verbal memory advantage, and the use of verbal memory tests has been shown to delay MCI diagnosis in women. Moreover, this association may vary by apolipoprotein E (APOE) genotype. The National Alzheimer’s Coordinating Center (NACC) uniform data set (UDS) contains demographic data and annual standardized neuropsychological (with memory being assessed primarily with verbal tests) and clinical diagnostic data obtained by 41 NIA‐funded Alzheimer’s Disease Centers across the U.S. This large database is a rich resource for evaluating sex effects on MCI/Dementia diagnosis by APOE genotype.MethodWe restricted to NACC enrollees above 60 years old, with available APOE genotype, cognitively normal at their initial UDS visit, had at least one follow‐up visit, and without a documented dominantly inherited Alzheimer mutation, leaving 10,461 participants (35.3% men, 77.0% non‐Hispanic White). Cox proportional hazards models of time to incident MCI/dementia controlling for sex, baseline age, years of education, baseline Mini‐Mental Status Exam (MMSE), and interaction terms as indicated were fit separately to APOE E3/E3 homozygotes and E3/E4 heterozygotes. Small sample size precluded analyses of other APOE genotypes. Secondary analyses restricting to non‐Hispanic White participants were also examined.ResultAmong APOE E3/E3 homozygotes, male sex is a risk factor for clinically diagnosed MCI/dementia (Hazard ratio (HR) = 1.27, p < 0.001) independent of age at enrollment. Among APOE E3/E4 heterozygotes, male sex is a risk factor at the lower range of age (age 60–75), while female sex is a risk factor at the higher range (interaction p = 0.006). Similar findings were obtained when restricting to the non‐Hispanic White participants.ConclusionThe higher risk of MCI/dementia in men in the NACC cohort may reflect previously‐reported sex differences in verbal memory performance at early stage AD pathogenesis and the use of verbal memory diagnostic tests more sensitive in men early in the disease.
Assessment of gray matter microstructure and synaptic density in Alzheimer’s Disease: a multimodal imaging study with DWI and SV2A PET
Authors: Salardini Elaheh , Silva‐Rudberg Jason A , O'Dell Ryan S. , Chen Ming‐Kai , Ra Jocelyn , Georgelos Jamie K , Morehouse Mackenzie R , Melino Kaitlyn P , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H , Mecca Adam P 
Published: December 2022

AbstractBackgroundDiffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer’s Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology.MethodThirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses.ResultsAxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group.ConclusionWe found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss.
House dust mite‐induced asthma exacerbates Alzheimer's disease by increasing amyloid beta accumulation and neuroinflammation
Authors: Sahu Bijayani , Nookala Suba , Floden Angela M , Combs Colin K 
Published: December 2022

AbstractBackgroundAlzheimer's disease (AD) is an age‐related neurodegenerative disorder affecting around 35 million individuals worldwide. Besides aging, various comorbid factors increase the risk of AD, including air pollution and asthma. Epidemiological studies have reported a 2.17‐fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma‐associated AD exacerbation is unknown. This study was designed to explore house dust mite‐induced asthma effects on AD‐related brain changes using the App
NL‐G‐F transgenic mouse model.MethodMale and female C57BL/6 wild type and AppNL‐G‐F
mice (8‐9 months old) were exposed to either saline or house dust mite (dose: 833μg/kg in saline) every alternate day for 16 weeks. Mice were sacrificed at the end of the experiment, and broncho‐alveolar lavage fluid (BALF), blood, and brains were collected. BALF was analyzed for immune cell markers, inflammatory mediators and total protein content. Serum was analyzed for cytokine and soluble Aβ1‐40/42 levels. In addition, brain sections were immunostained for Aβ and GFAP. Finally, frozen hippocampi and cortices were used to perform Aβ ELISAs and cytokine arrays, respectively.ResultAs expected, dust mite exposure increased inflammatory cells, cytokine levels, and total protein content in the BALF from both sexes and genotypes, suggesting induction of a severe asthma‐like condition. This correlated with increased levels of serum cytokines in all dust‐mite exposed groups. Serum from the AppNL‐G‐F
dust mite‐induced asthma group also had significantly increased soluble Aβ1‐42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma‐induced male and female AppNL‐G‐F
mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1‐40/42 and insoluble Aβ 1‐40 levels. Dust mite exposure also increased astrogliosis in both sexes of AppNL‐G‐F
mice, as indicated by GFAP immunoreactivity. Finally, dust mite exposure‐induced asthma elevated cortical levels of several cytokines in both sexes and genotypes.ConclusionDust mite exposure was responsible for a severe asthma‐like condition in the lungs that exacerbated Aβ pathology, astrogliosis, and cytokine changes in the brains of male and female App
NL‐G‐F mice. Defining mechanisms of asthma effects on the brain may provide a novel therapeutic approach for both asthma and AD.
Psychotropic polypharmacy in people with neuropsychiatric symptoms referred to an Australian dementia support service
Authors: Atee Mustafa , Andreotta Matthew , Morris Thomas , Alford Marie 
Published: December 2022

AbstractBackgroundDespite limited evidence, psychotropics, such as antipsychotics are commonly used to treat neuropsychiatric symptoms (NPS) in people living with dementia. There are safety concerns on the use of antipsychotics, but co‐prescribing multiple classes of psychotropics (psychotropic polypharmacy) may have a greater and more serious harm to this group. This includes sedation‐induced falls, delirium, hospitalizations, and mortality.In Australia, people with significant NPS, such as agitation and aggression can be referred for free 24/7 support and advise to a national behavior dementia‐specific support service known as Dementia Support Australia (DSA). The aim of this study is to describe the prevalence of psychotropic polypharmacy in DSA referrals.MethodWe used a sample of medication charts from the DSA database to estimate the prevalence of psychotropic polypharmacy in referrals between January and November 2020. A descriptive analysis of psychotropic use was based on the grouping of the World Health Organization Anatomical Therapeutic Classes (ATCs), which included seven classes: antipsychotics, antidepressants, anxiolytics, opioid analgesics, hypnotics, anticonvulsants, and anti‐dementia drugs. Psychotropic polypharmacy was defined as the concomitant use of ≥2 psychotropics overall, whether it is within the same class, subclass, or cross‐class.ResultsOf the 137 referrals [M = 83.6 (SD = 8.5) years of age; 54.0% female], 28 referrals were prescribed medications that could not be nearly categorized into the ATCs (e.g., ibuprofen). For the remaining 109 referrals included in analysis, polypharmacy was common (n = 82, 75.2%; Figure 1A). Polypharmacy was especially common for referrals who were prescribed anxiolytics (n = 25, 100% prescribed additional medication), anticonvulsants (n = 27, 96.4% prescribed additional medication), or anti‐dementia (n = 25, 96.2% prescribed additional medication) medications. Of the 36 different psychotropic medications prescribed to referrals, 23 (63.9%) were prescribed exclusively with additional medications. The most common co‐prescriptions (Figure 1B) were antidepressants+antipsychotics (n = 6, 5.5%), anti‐dementia+opioid analgesic (n = 4, 3.7%), antidepressants+antipsychotics+hypnotics (n = 4, 3.7%), and antipsychotics+hypnotics (n = 4, 3.7%).ConclusionPsychotropic polypharmacy is common in people with dementia related NPS who require external behavioral support. Deprescribing psychotropics should be considered a priority in this group as the risks of these agents outweigh their benefits.
Post synaptic density 95 (PSD95)–Actin interaction: A critical regulator of synaptic strength and plasticity in Alzheimer’s disease pathology
Authors: P A Haseena , Kommaddi Reddy Peera , Ravindranath Vijayalakshmi 
Published: December 2022

AbstractBackgroundPSD95 serves as a scaffolding protein to several neurotransmitter receptors, signal transduction components, and adhesion molecules at the synapse. It is a potential regulator of synaptic strength and plasticity by regulating glutamatergic receptor trafficking, which is impaired in AD. PSD95 interacts directly with NMDA receptors while the interactions with AMPA receptors are through an auxiliary subunit TARPs. Actin cytoskeleton is highly enriched at the synapse. However, the interaction of PSD‐95 – actin and its consequences in synaptic transmission is not understood. Therefore, we investigated the critical role of PSD‐95 association at the synapse with actin and its impact on AMPA and NMDA receptors using AD mice.MethodsSynaptosomes were isolated from adolescent and middle aged wildtype and APP/PS1 mice. Immunoprecipitation was performed using the synaptosomes and F‐actin fractions with anti‐PSD95 antibody followed immunoblotting against glutamatergic receptor subunit antibodies and actin antibody. Statistical comparisons between two groups were performed with the two‐tailed unpaired Mann–Whitney U test.ResultsPSD95 association with actin is detected in synaptosomes isolated from adolescent and middle aged WT and APP/PS1 mouse brain cortex. We found that PSD95‐actin association is significantly decreased in middle aged APP/PS1 mice compared with WT while it remains unaffected in the F‐actin fraction of synaptosomes in APP/PS1 mice. Then, we examined the levels of AMPA and NMDA receptor subunits in APP/PS1 mice. GluA1 and GluA2 subunits of AMPAR are significantly decreased in middle aged but not in adolescent APP/PS1 mice in comparison to age matched WT mice. Protein levels of GluN1 and GluN2B subunits are significantly decreased in both adolescent and middle aged APP/PS1 mice, while GluN2A levels are reduced only in adolescent mice. We detected that PSD95 is physically associated with both AMPAR and NMDAR subunits and this association with GluA1 subunit is affected only in middle aged APP/PS1 mice. Interestingly, interaction of NMDAR subunits (GluN1 and GluN2B) with PSD‐95 is greatly enhanced at adolescent APP/PS1 mice even though these subunit protein levels are significantly diminished.ConclusionOur findings indicate that perturbation of PSD95‐actin association and glutamatergic receptors in AD leads to synaptic dysfunction. It may have critical implications in defective glutamatergic neurotransmission.