bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liraglutide as a potential drug repurposing candidate for Alzheimer’s disease and related dementia: Real World Evidence
Authors: Wang Tiansheng , Buse John B , Pate Virginia , Garden Gwenn A , Stürmer Til 
Published: December 2023

AbstractBackgroundPrevious studies suggested GLP‐1 receptor agonists (GLP1RA) may improve cognitive function and liraglutide’s effect on Alzheimer’s disease is being evaluated by the ELAD (Evaluating Liraglutide in Alzheimer’s Disease) clinical trial.MethodTo examine whether liraglutide decrease Alzheimer’s disease and related dementia (ADRD) risk compared with other antidiabetics, we implemented an active comparator, new user cohort design identifying initiators of liraglutide, DPP‐4 inhibitors (DPP4i), respectively, using a US nationwide 20% random sample of fee‐for‐service Medicare beneficiaries aged 70+ with parts A, B, and D coverage from 2007‐2019. We required patients to have 2nd prescription of the same drug class and be free of ADRD in the 3‐year window (during which requiring 3‐year continuous enrollment of parts A, B) prior to drug initiation. The ADRD outcome was defined as 1) ³1 ADRD claims in 1 year AND 2) ³1 ADRD claims in another year or nursing home stay ³ 6 months in the 3‐year follow‐up period. We estimated propensity scores (PS) to balance confounders across cohorts and estimated adjusted risk difference (RD) and 95% CI using inverse probability treatment and censoring weight.ResultThe initiators of liraglutide (n = 1260) and DPP4i (n = 15952) were followed for a median (IQR) duration of 3.0(2.0 to 3.0) and 3.0 (1.7 to 3.0) years, respectively. During follow‐up, incident cases of ADRD was 196 and 3215 in liraglutide and DPP4i, respectively; and incident rate was 63 and 85 per 1000 person‐years, respectively. Adjusted RD (%) was ‐4.4 (95%CI ‐6.6 to ‐2.39) comparing liraglutide to DPP4i. Results were consistent across sensitivity analyses with varying exclusion criteria, baseline period, and outcome definitions.ConclusionOur active comparator, new user cohort study of older patients showed liraglutide is associated with a decreased ADRD risk compared with alternatives. This study is limited by the relatively short duration of treatments.
Distinct amyloid‐β deposits inversely correlate with glial activation and tangles in Alzheimer’s disease subtypes
Authors: Boon Baayla D.C. , Kouri Naomi , Labuzan Sydney A. , Peng Zhongwei , Tranovich Jessica F. , Frankenhauser Isabelle , Lincoln Sarah J. , Lachner Christian , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R , Dickson Dennis W. , Murray Melissa E. 
Published: December 2023

AbstractBackgroundThe coarse‐grained plaque is a biochemically and morphologically distinct amyloid‐β (Aβ) deposit that was discovered in clinically‐defined atypical Alzheimer’s disease (AD). Unlike other Aβ deposits, this plaque is not observed in cognitively normal people. This study investigates the hypothesis that the coarse‐grained plaque is distinctly associated with AD neuropathologic change and glial activation within the context of AD subtypes.MethodSixty AD cases from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort were assessed. We included 20 hippocampal sparing (HpSp) AD, 20 typical AD, and 20 limbic predominant AD. Immunohistochemistry was performed on the middle frontal, inferior temporal, and inferior parietal cortex for AD neuropathology (Aβ [6F/3D], phospho‐tau [AT8], tau [GT38]) and glial activation (CD68 [KP1] and GFAP). Digital pathology was used to quantify burden. Thioflavin‐S tangle counts were performed at time of neuropathologic diagnosis. Distinct deposit types, including classic cored plaques, coarse‐grained plaques, cerebral amyloid angiopathy (CAA)‐Type 1, and CAA‐Type 2, were semi‐quantitatively scored on Aβ (Fig. 1). Correlations between demographic, clinical, and neuropathologic characteristics were assessed using Spearman rho analysis and reported if p<0.05. An independent cohort of ∼100 HpSp AD cases will be assessed to validate initial findings.ResultIn the frontal cortex of HpSp AD, higher scores of classic cored plaques correlated with older age at onset and death, non‐APOE ε4 carriership, and less CAA‐Type 1 and Type 2 (Fig. 2). On the contrary, the severity of coarse‐grained plaques correlated with a younger age at onset and death, APOE ε4 carriership, higher scores for CAA‐Type 1, CAA‐Type 2, and increased burden of Aβ, GFAP, and CD68. Classic cored plaques correlated negatively with phospho‐tau and tau, whereas coarse‐grained plaques correlated positively with phospho‐tau, tau, and tangles. The two deposit types were negatively correlated with each other. Correlations were weaker but showed similar trends in other AD subtypes (Fig. 2) and regions.ConclusionWithin HpSp AD, classic cored and coarse‐grained plaques show distinct correlations with glial activation, (phospho‐)tau, and tangles. These results suggest opposite directions of association for these deposits on AD neuropathologic change that may impact clinical symptoms. These findings are relevant to therapies targeting overall Aβ pathology.
Longitudinal Changes in Grey Matter Correspond to Changes in Cognition Across the Lifespan: Implications for Theories of Cognition
Authors: Smith Evan T. , Hennessee Joseph P. , Wig Gagan S , Frank Sarah , Gonzalez Hector , Bacci Julia R. , Chan Micaela , Carreno Claudia , Kennedy Kristen M , Rodrigue Karen M , Hertzog Christopher , Park Denise C. 
Published: December 2023

AbstractBackgroundInterpretations of brain and cognitive reserve were tested by assessing the parallel, longitudinal relationship between grey matter atrophy and cognitive decline in an adult lifespan sample.MethodCognitive battery and structural MRI images were assessed in 463 healthy participants of age 20‐89. Participants were assessed up to 3 times over up to 10 years. Change‐over‐time in cortical grey mater, subcortical grey matter, and general cognitive ability were modeled via latent growth curve modeling, and covariance of these latent change scores were assessed via parallel‐process latent change modeling.ResultLatent change in general cognition was found to significantly covary with latent change in both cortical grey matter. Cortical grey matter volume, subcortical grey matter volume, and cognition at baseline were found to significantly relate to longitudinal cognitive decline, such that individuals with higher volume and better cognitive performance experienced less decline over the observation period.ConclusionIndividual differences in cognitive and grey matter decline are demonstrably related. Both cognitive and grey matter resources at baseline reserve to differentiate longitudinal patterns of cognitive decline. Grey matter volume appears to provide a good estimate of what some refer to as “brain reserve” and the latent cognition factor estimated “cognitive reserve.” Overall, these latent measures may be parsimoniously viewed as measures of neoro‐cognitive resource that do not require invoking the construct of “reserve” to explain individual differences in brain structure and cognition.
Type‐I interferon promotes tau pathology by potentiating seeded aggregation
Authors: Sanford Sophie Andrea Izumi , McEwan Will 
Published: December 2023

AbstractBackgroundRecent work has implicated antiviral type‐I interferon (IFN) cytokines in Alzheimer’s disease (AD) and related tauopathies. Signatures of type‐I IFN‐driven gene expression are observed in the post‐mortem AD brain. Whilst the effects of type‐I IFN on β‐amyloid pathology have been previously investigated, its effects on tau pathology remain unclear.MethodWe examined the effects of type‐I IFN signalling on tau pathology ex vivo using primary neural culture models of seeded tau aggregation. In vivo, P301S‐tau transgenic mice were bred as homozygous knockout for the type‐I IFN receptor, Ifnar. Ifnar‐/‐ animals were compared with Ifnar+/+ for the extent of tau pathology by immunostaining.ResultTreatment of neural cultures with polyI:C, a synthetic analogue of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau. Type‐I IFN was the principal driver of this response, as Ifnar‐/‐ cultures were protected from the pro‐aggregant effects of polyI:C or exogenous type‐I IFN treatment. Pharmacological antagonists of IFN signalling prevented the effects of type‐I IFN. These effects of type‐I IFN were independent of microglia, as the phenotype remained when Iba1+ cells were pharmacologically depleted. Tau pathology was significantly reduced in aged Ifnar‐/‐ P301S‐tau mice relative to Ifnar+/+ P301S‐tau mice, consistent with IFN signalling driving tau pathology.ConclusionOur data shows a novel role for type‐I IFNs in the development of tau pathology both in vivo and ex vivo. This implicates the type‐I IFN response as a potential target for therapeutic intervention in AD and tauopathies.
The GSA KAER Toolkit: A Framework to Activate Primary Care in the Early Detection of Alzheimer’s Disease and Related Dementias
Authors: Tracy Karen K 
Published: December 2023

AbstractThe Gerontological Society of America (GSA) developed the KAER Toolkit to support primary care teams in increasing awareness of brain health in older adults, increase detection of cognitive impairment, initiate earlier diagnostic evaluations, and make referrals for supportive services for people with Alzheimer’s disease and related dementias (ADRD.)The GSA KAER model identifies four steps which are essential for improving health‐related outcomes and well‐being for people living with ADRD and their families: Kickstart the Brain Health Conversation, Assess for Cognitive Impairment, Evaluate for Dementia, and Refer to Community Resources. The regularly updated evidence‐based tools and resources showcased in the toolkit were identified by consensus, gathering a diverse range of expert contributors and stakeholders to highlight best practices that research has shown to be most effective. The kit includes practical approaches which primary care teams can use to integrate these tools into their practice workflows.The GSA program director for this initiative, who has shepherded its development and implementation since its inception, will provide insight into the framework’s development; its components, publications, supporting podcasts, and webinars; its wide‐ranging recognition, including by the National Institutes of Health and the National Alzheimer’s Project Act; and will review the projects to support its dissemination which have been funded by the Centers for Disease Control and Prevention. Finally, we will describe successful partnerships which the GSA has built with a number of large organizations, including the Alzheimer’s Association and the Gerontological Advanced Practice Nurses Association, who are now spreading awareness about it and facilitating training based on its principles in health systems across the United States.
Beyond Diagnosis: Compassionate Counseling, Effective Referrals
Authors: Raetz Jaqueline G. 
Published: December 2023

AbstractPatients with Alzheimer’s disease and related dementias (ADRD) who receive an earlier diagnosis receive better care. To achieve system change to facilitate more timely and accurate diagnoses, primary care providers (PCPs) will need knowledge and confidence to compassionately counsel patients and families once a new diagnosis is made. Simply providing PCPs tools to make a diagnosis, without also giving them a clear path forward once they identify a new case, leads to resistance to practice change and poor care.This presentation will outline an intervention built around training and tools for PCPs which meets that need. This intervention was pilot tested with 89 PCPs across the University of Washington’s Primary Care Network of clinics who found the intervention to be highly likely to change their practice (4.4 on 5‐point scale, SD 0.9). They particularly appreciated the guidance for how to provide compassionate counseling to newly diagnosed patients and their care partners.Components of the training were 1) a set of validated serious‐illness communication principles which were adapted for use in ADRD, 2) concise information on how and when to make referrals to community resources and clinical dementia specialists, and 3) a structured checklist for giving guidance on key principles to cover in counseling a newly diagnosed patient.This checklist was embedded in the electronic health record (EHR) and is concise enough to be easily implemented in the EHR of other healthcare systems. Highlights of the checklist include flags which indicate when a more urgent referral to a specialist is needed, a set of activating interventions which PCPs can implement to help patients with ADRD maintain brain health, and high‐quality referrals that PCPs can make to enable more supportive care. Such referrals include those with a national scope, such as Powerful Tools for Caregivers and the Alzheimer’s Association 24‐hour Help Line, and those with a more local focus as well.This innovative, pragmatic intervention provides PCPs with effective knowledge and confidence for counseling newly diagnosed patients, with the understanding that such counseling is an essential component of quality improvement initiatives to facilitate the identification of ADRD in the primary care setting.
Validation of Cerebrospinal Fluid Alpha‐synuclein Assay against Autopsy in Non‐Parkinson’s Disease Neurodegenerative Syndromes
Authors: Samudra Niyatee , Ljubenkov Peter A. , Rojas Julio C. , Staffaroni Adam M. , Wekselman Fattin , Jennifer Lamoureux , Grinberg Lea T. , Boxer Adam L. , VandeVrede Lawren 
Published: December 2023

AbstractBackgroundAlpha‐synuclein (αSyn) is the underlying neuropathology in both Parkinson’s Disease (PD) and non‐PD neurodegenerative syndromes, e.g. dementia with Lewy bodies (DLB). Importantly, αSyn is also a common co‐pathology, especially in Alzheimer’s disease (AD), where autopsy studies reveal comorbid αSyn in >50% of cases. A seeded aggregation amplification (SAA) assay (SynTap) has been shown to be highly sensitive and specific for pathogenic αSyn seeds in patients with PD and DLB, with lower performance in amygdalar‐predominant Lewy Body disease (LBD). Here we evaluated the antemortem CSF performance of SynTap in patients with non‐PD syndromes, with specific attention to performance in brainstem‐predominant αSyn and patients with atypical PD, e.g. progressive supranuclear palsy Richardson’s syndrome (PSP‐RS, N = 6) and corticobasal syndrome (CBS, N = 11).MethodPatients were evaluated through observational studies at the UCSF Alzheimer’s Disease Research Center and neuropathologic evaluation was performed by the Neurodegenerative Disease Brain Bank. Antemortem CSF samples were tested with SynTap. Operators were blinded to diagnosis, and all samples were run as a single batch. Sensitivity and specificity were compared, and clinical correlations were examined across pathological groups and clinical diagnoses, using antemortem clinical records.ResultOverall, in 56 patients, SynTap was 59% sensitive and 96% specific for autopsy‐confirmed αSyn pathology of any type. SynTap had perfect performance for diffuse (4/4) and transitional (5/5) LBD, and correctly identified 3/3 cases where LBD was primary. Consistent with prior reports, sensitivity was low in amygdalar‐predominant LBD (6/14, 43%), and lower in brainstem‐predominant LBD (1/6, 17%). A false positive result was present in 1/27 cases (4%). In the PSP‐RS cohort, SynTap positively identified 1 case caused by diffuse LBD and AD, and was true negative in 5/5. Within CBS, SynTap positively identified 1/1 case with diffuse LBD co‐pathology, 1/2 cases with brainstem‐predominant LBD, but missed 1 case with amygdalar‐predominant LBD.ConclusionSynTap best identifies αSyn pathology in patients with diffuse and transitional LBD, though specificity is high in the entire cohort. The etiology of low sensitivity in amygdalar‐ and brainstem‐predominant LBD co‐pathology requires further elucidation. The test may aid diagnostically in atypical PD syndromes, but results should be carefully considered, given the possibility of co‐pathology.
Progress in imaging by α‐synuclein Positron Emission Tomography
Authors: Bennacef Idriss , Zeng Zhizhen , Miller Patricia J , Riffel Kerry , Purcell Mona L , Haley Hyking D , Meng Xiangjun , Yuchuan Wang , Roecker Anthony J , Shaw Anthony W , Stump Craig A , Mitchell Helen J , Tong Ling V , Fawaz Maria V , Drolet Robert E , Ma Lei M , Marcus Jacob , Li Wenping , Hostetler Eric D. 
Published: December 2023

AbstractBackgroundDeposition of misfolded α‐synuclein (α‐Syn) aggregates in the human brain is one of the major hallmarks of synucleinopathies. Positron Emission Tomography imaging (PET) of α‐synuclein in Parkinson’s disease (PD) patients is highly desirable but remains elusive. An extensive PET radioligand discovery campaign was undertaken. Here, we present the in‐vitro and preclinical in‐vivo characterization of [3H]‐ and [11C]Compound S, representing an example of a promising PET radioligand for α‐Syn.MethodCompetition binding studies and autoradiographic studies were performed in cortexes of PD patients, healthy control, and Alzheimer’s disease (AD) patients brain tissue, and mid‐brain region of the aged A30P mouse using [3H]S. Brain PET experiments using [11C]S were carried out in a healthy non‐human primate (NHP) and the aged homozygote A30P mice.ResultCompound S is a sub‐nanomolar affinity ligand to human and A30P mouse α‐Syn (Kd = 0.15 nM and 0.5 nM resp.). Lower affinity was observed in AD and healthy control brain tissues. [3H]S showed displaceable binding in PD brain cortex and A30P mid‐brain and brainstem, and little binding in AD and healthy control. In the NHP, [11C]S crosses the brain‐blood barrier and the uptake phase of [11C]S is followed by a washout. [11C]S PET studies in A30P mice showed higher uptake in the mid brain and brainstem regions, with standard uptake value ratios in those regions higher than 2.0.ConclusionCompound S is potent for α‐Syn in vitro, and PET imaging in the A30P mice showed an elevated signal in regions known to accumulate α‐Syn. This dataset suggests that the Compound S has promise towards imaging α‐Syn in PD patients.
Basal forebrain nuclei volume is associated with hematoencephalic barrier dysfunction in early Alzheimer’s disease
Authors: Lerch Ondrej , Martinkovic Lukas , Laczó Martina , Nedelska Zuzana , Hanzalová Jitka , Sheardova Katerina , Laczó Jan , Hort Jakub 
Published: December 2023

AbstractBackgroundHematoencephalic barrier (HEB) is a protective layer of cells that separates the circulatory system from the brain. Its dysfunction is one of the possible mechanisms leading to the development of Alzheimer’s disease (AD), a progressive neurodegenerative disease and a leading cause of dementia worldwide. The albumin quotient (QAlb), the ratio between cerebrospinal fluid (CSF) and serum albumin concentrations, is a frequently used measure of HEB breakdown. Elevated levels of QAlb were previously reported in early AD. Here we explored the relationship between QAlb and volumes of the hippocampus and entorhinal cortex (EC) subregions and basal forebrain (BF) nuclei, the brain structures affected early in the course of AD.Method92 participants, including 20 AD biomarker negative cognitively normal (CN), 42 AD biomarker positive with mild cognitive impairment (AD‐MCI) and 30 AD biomarker positive with mild dementia (AD‐DEM), from the Czech Brain Aging Study underwent structural MRI and CSF sampling. CSF levels of amyloid beta 1‐42, total tau, phosphorylated tau 181 and QAlb, as well as volumes of the hippocampal subregions (i.e., head, body and tail), anterolateral and posteromedial EC and BF nuclei were obtained. Associations between regional brain volumes, normalized to total intracranial volume, and QAlb were assessed using MANOVA controlled for gender and age.ResultIn the AD‐MCI group, volumes of the anterior and posterior parts of the nucleus basalis of Meynert (NBM), one of the BF nuclei, were positively associated with QAlb levels (β = 0.317 and 0.345, p = 0.045 and 0.029, respectively). There were no other significant associations of regional brain volumes with QAlb in CN, AD‐MCI or AD‐DEM groups. All measured volumes, except for BF nuclei of medial septum in AD‐DEM (p = 0.058), were smaller in AD‐MCI and AD‐DEM v.s. CN group (p<0.05). There were no differences in volumes between AD‐MCI and AD‐DEM groups. QAlb did not differ between groups.ConclusionOur results show that severity of HEB dysfunction is associated with increased volume of the NBM in individuals with AD‐MCI, suggesting a link between HEB dysfunction and early pathological changes in the BF nuclei.
Patterns and trajectories of multimorbidity prior to dementia: a UK Biobank study
Authors: Patel Raihaan , Mackay Clare , Griffanti Ludovica , Gillis Grace , Anatürk Melis , Suri Sana 
Published: December 2023

AbstractBackgroundThe co‐occurrence of multiple long term conditions (LTCs), termed multimorbidity, is a risk factor for dementia. However, we lack an understanding of how and when specific LTCs accumulate over time to impact dementia risk.Method338,270 individuals from the UK Biobank with linked electronic health records up to January 2022 were studied, excluding those with either a dementia diagnosis or age of latest follow up < 65 years. LTC diagnoses were derived using hospital episode statistics and GP records (age of diagnosis computed using month/year of birth and month/year of diagnosis). We performed an age‐stratified analysis in which we a) cluster individuals based on 43 non‐dementia LTCs diagnosed within age bins (0‐55, 55‐65, 65‐70 years), and b) compute risk of incident dementia using logistic regression with multimorbidity cluster as predictor and incident dementia as outcome. Diagnosis data was submitted to PCA, and the resulting factor scores were kMeans‐clustered. 6 clusters were derived per age bin.ResultWe named clusters based on the most prevalent LTCs within that cluster (Figure 1). Cardiometabolic, arthritis, gastrointestinal, and mixed clusters existed at all ages. Mental health and respiratory clusters were present exclusively in the younger age bin (0‐55) whereas hypertension and eye disorder clusters were exclusive to older ages (55‐65 and 65‐70). Across the lifespan, compared to being disease free, multimorbidity was significantly associated with incident dementia (OR>1). We also observed age‐specific multimorbidity preceding dementia onset. From 0‐55 years, being in the mixed cluster presented the highest dementia risk (OR = 5.13, 95% CI = [4.61, 5.73]). Being in the cardiometabolic cluster was associated with highest risk in 55‐65 (OR = 6.24 [5.48, 7.1]) and 65‐70 (OR = 6.99 [5.91, 8.27]) ranges. The most predictive trajectory of incident dementia involved the mixed cluster at 55, followed by the cardiometabolic clusters from 55‐65 and 65‐70. Table 1 displays the top 10 trajectories associated with dementia. All p‐values are bonferroni‐holmes corrected and < 0.01.ConclusionWe present multimorbidity pathways linked to increased risk of dementia. We describe how and when diseases cluster together prior to dementia diagnosis.