bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anticholinergic effect on cognition (AEC) scale: Associations with mortality, hospitalisation and cognitive decline following dementia diagnosis
Authors: Bishara Delia , Perera Gayan , Harwood Daniel , Taylor David , Sauer Justin , Stewart Robert , Mueller Christoph 
Published: December 2020

AbstractObjectivesTo investigate associations between central anticholinergic burden (using the AEC scale), and mortality, hospitalisation and cognitive decline in patients with dementia.MethodsThe South London and Maudsley NHS Foundation Trust (SLaM) Clinical Records Interactive Search (CRIS) application was used to identify patients 65 years or older at their first recorded diagnosis of dementia. Data were linked to national mortality and hospitalisation sources, and serially recorded Mini‐Mental State Examination (MMSE) scores were used to investigate cognitive decline over the 36 months after diagnosis in mixed models.ResultsPatients for whom a review of their medication was indicated (AEC score ≥ 2 for any individual drug or total AEC score ≥ 3) had an increased risk of mortality (hazard ratio 1.07; 95% CI 1.01‐1.15) and emergency hospitalisation (1.10; 95% CI 1.04‐1.17), but there were no associations with duration of hospitalisation. Cognitive trajectory analyses showed that this exposure group had lower MMSE scores at diagnosis and a sharper increase in MMSE scores over the subsequent 6 months, but similar slopes for the 6‐36 months period to the remainder of the sample.ConclusionsPatients with dementia receiving medication with high central anticholinergic activity (as measured on the AEC scale), appear to have worse prognosis in terms of mortality and hospitalisation risk, but have primarily acutely impaired cognitive function, rather than longer term differences in cognitive decline.
Aberrant protein O‐GlcNAcylation drives AD‐like neurodegeneration in DS mice
Authors: Domenico Fabio Di , Zuliani Ilaria , Perluigi Marzia , Lanzillotta Chiara , Barone Eugenio , Tramutola Antonella 
Published: December 2020

AbstractBackgroundDown syndrome (DS) is related with an increased incidence of Alzheimer’s disease (AD) neuropathology. Among the putative mechanisms leading neurodegeneration, the reduction of cerebral glucose metabolism may trigger brain damage by impacting the hexosamine biosynthetic pathway (HBP). As reported in AD, defective HBP is responsible for flawed protein O‐GlcNAcylation coupled by a mutual inverse increase of protein phosphorylation on Ser/Thr residues, which gives to O‐GlcNAcylation the ability to modulate various pathways involved in AD progression. Previous studies have shown the aberrant O‐GlcNAcylation/phosphorylation ratio of tau and APP in AD brain, confirming dysfunctional O‐GlcNAcylation as a key contributor in the pathogenesis of the disease. Our work aims to unravel, for the first time, the role of protein O‐GlcNAcylation in DS neuropathology along with its possible pharmacological modulation to prevent DS cognitive decline.MethodsWe performed western blot analysis of global O‐GlcNAc levels and total protein Ser/Thr phosphorylation in the hippocampus of 6‐months‐old Ts2Cje, mouse model of DS, compared to age‐matched controls. Furthermore, we measured the activity of enzymes involved in O‐GlcNAcylation cycling (OGT and OGA), as well as the functionality of GFAT1, the rate limiting enzyme of the HBP. Additionally, we determined by immunoprecitation the O‐GlcNAcylation/phosphorylation ratio of AD‐related markers (tau and APP). Finally, we tested the efficacy of an intranasal short‐term treatment with an O‐GlcNAc‐modulating compound.ResultsWe observed an early reduction of total O‐GlcNAcylation levels in young Ts2Cje mice and established its correlation with an increase in total protein phosphorylation. We measured the alteration in OGT and OGA functionality, unrelated with a dysfunctional activity of GFAT1. Moreover, we demonstrated that the reduction of O‐GlcNAcylation/phosphorylation levels affects both tau and APP, actively contributing to DS neuropathology. Lastly, our novel therapeutic strategy was able to increase O‐GlcNAc levels in Ts2Cje mice and restore AD‐related markers, possibly slowing disease progression.ConclusionOur research highlights the pathological role of the altered protein O‐GlcNAcylation profile in DS neurodegeneration and investigates the neuroprotective effects of an O‐GlcNAc‐modulating compound.
Neuron‐selective induction of granulovacuolar degeneration bodies: A lysosomal stress response to tau aggregation?
Authors: Wiersma Vera I. , van Ziel Marieke , Vazquez‐Sanchez Sonia , Nölle Anna , Berenjeno‐Correa Ernesto , Bonaterra‐Pastra Anna , Clavaguera Florence , van Weering Jan , Verhage Matthijs , Hoozemans Jeroen J.M. , Scheper Wiep 
Published: December 2020

AbstractBackgroundGranulovacuolar degeneration bodies (GVBs) are membrane‐bound vacuolar structures harboring a dense core that accumulate in the brains of patients with neurodegenerative disorders, including Alzheimer’s disease and other tauopathies. Insight into the origin of GVBs and their connection to tau pathology has been limited by the lack of suitable experimental models for GVB formation.MethodWe used confocal, automated, super‐resolution and electron microscopy in different models for seeded tau aggregation.ResultWe demonstrate that the seeding of tau pathology triggers the formation of GVBs in mouse models in vivo and in primary mouse neurons in vitro. Seed‐induced intracellular tau aggregation, but not seed exposure alone, causes GVB formation in cultured neurons but not astrocytes. The extent of tau pathology strongly correlates with the GVB load. The in vitro tau‐induced GVBs are immunoreactive for the established GVB markers CK1δ, CK1ɛ, CHMP2B, pPERK, peIF2α and pIRE1α. GVBs contain a LAMP1‐ and LIMP2‐positive single membrane that surrounds the dense core and vacuole. The proteolysis reporter DQ‐BSA is detected in the majority of GVBs, demonstrating that GVBs contain degraded endocytic cargo. GFP‐tagged CK1δ accumulates in the GVB core, whereas GFP‐tagged tau or GFP alone do not, indicating selective targeting of cytosolic cargo to GVBs. In addition, GVB positive neurons have increased levels of stress related proteins.ConclusionWe established the first in vitro model for GVB formation by seeding tau pathology in primary neurons. The tau‐induced GVBs have the marker signature and morphological characteristics of GVBs in the human brain. We show that GVBs are lysosomal structures that are distinguished by the accumulation of a characteristic subset of proteins in a dense core. Our data indicate that GVB containing neurons are in a state of enhanced cellular stress.
Exploring the effect of type 2 diabetes on brain structure and cerebral perfusion in patients with early Alzheimer’s disease
Authors: Dake Manmohi D , De Marco Matteo , Wilkinson Iain , Teh Kevin , Mitolo Micaela , Remes Anne , Liu Yawu , Pikkarainen Maria , Soininen Hilkka , Venneri Annalena 
Published: December 2020

AbstractBackgroundPast research has shown that Alzheimer’s Disease (AD) can have a significant detrimental effect on the cerebrovascular system. Previous work has also indicated that type 2 diabetes mellitus (T2DM), along with being a risk factor for AD, shares certain similarities with AD in terms of the mechanisms affecting the cerebrovascular system. Hence, comorbid T2DM in AD could cause additional cardiovascular burden that may cause further damage to brain structure and function than that seen in AD.MethodThe current study compares 54 patients across the AD spectrum with and without T2DM (with 27 patients in each group). Voxel based morphometry was used to determine volumetric differences in grey matter using T1‐weighted magnetic resonance images. To assess whether these volumetric differences were associated with a reduction in cerebral blood flow, arterial spin labelling (ASL) was used to measure cerebral perfusion.ResultsPatients with T2DM had smaller grey matter volume compared to patients without T2DM in the anterior caudate nucleus and posterior cerebellum in the right hemisphere. Perfusion deficits mirrored the regional volumetric abnormalities, along with additional hypoperfusion observed in the right parahippocampal gyrus. These differences were also associated with deficits in cognitive function.ConclusionsMicrovascular and macrovascular complications seen in the AD patients with comorbid T2DM could therefore contribute toward the negative effects exerted on cerebral perfusion that could potentially contribute toward the structural deficits observed. Furthermore, the right lateralised effects seen in the present study could arise due to the characteristic trajectory of the arteries supplying the brain. With the increasing prevalence of cardiovascular risk factors such as T2DM combined with the rise in numbers of people living with AD, the additional cardiovascular burden caused by such risk factors may be a crucial tipping point toward conversion to AD dementia from prodromal stages. This is one of the first studies to show that the additional cerebrovascular burden resulting from comorbid T2DM in AD can result in worse structural and perfusion deficits using multi‐modal neuroimaging and that these deficits can be associated with clinical presentations.
Assessing and improving primary care physician confidence in the recognition of young‐onset and atypical dementia: A pilot intervention
Authors: Chiew Hui Jin , Choong Tanya‐Marie Yuen Oi , Chua Esther Vanessa , Mei Nyu Mei , Lim Linda Lay Hoon , Ng Kok Pin , Ng Adeline Su Lyn , Ting Simon Kang Seng , Hameed Shahul , Kandiah Nagaendran 
Published: December 2020

AbstractBackgroundYoung‐onset dementia (YOD) is defined as dementia with symptom onset below 65 years. The heterogeneous symptomatology of YOD can lead to delayed recognition and referral by primary care physicians (PCPs). Data from our tertiary referral centre in Singapore show that atypical presentations of YOD are more likely be referred and diagnosed at a later stage of disease than typical amnestic Alzheimer disease (AD) dementia.MethodWe piloted a structured, multimodal training programme to assess and increase the confidence of PCPs in the recognition of YOD and atypical dementia. The programme combined lectures, case studies and interactive workshops in 4 half‐day modules conducted between September 2019‐January 2020 (Module 1: clinical approach to cognitive impairment, overview of cognitive disorders and AD; Module 2: YOD, atypical and reversible causes of dementia; Module 3: cognitive assessment tools; Module 4: management of dementia, with a focus on YOD). Faculty included 6 cognitive neurologists and 4 dementia care nurses. 28 PCPs involved in dementia care in primary care memory clinics from all regions of Singapore were enrolled by invitation in mid‐2019. Prior to module 1, PCPs completed an anonymized questionnaire with 15 questions assessing their confidence in the recognition, diagnosis and management of YOD on a 5‐point Likert scale. An identical follow‐up questionnaire was administered upon completion of the programme.Results20 baseline and 20 follow‐up questionnaire responses were obtained. The PCPs had a mean of 1.93 (SD 2.10) years of dementia care experience. At baseline, they were significantly more confident in recognizing symptoms of typical elder‐onset AD (70% confident, 10% very confident) compared to YOD (30% confident) or atypical/non‐AD dementia (15% confident), (p<0.001). Upon programme completion, PCPs reported significantly increased confidence in recognition of YOD (70% confident, 15% very confident; p<0.001) and atypical/non‐AD dementia (75% confident, 10% very confident; p<0.001). These findings persisted even when stratified by years of dementia care experience.ConclusionA structured, multimodal training programme was effective in improving PCP confidence in the recognition of YOD and atypical dementia. Follow‐up assessment of PCP knowledge and longitudinal monitoring of referral trends will help to determine its long‐term efficacy.
Functional enrichment analysis of differentially expressed genes leads to dysregulation in biological processes networks in Alzheimer’s disease continuum
Authors: Ferreira Pamela C.L. , De Bastiani Marco Antônio , Bellaver Bruna , Povala Guilherme , Brum Wagner Scheeren , Ramos Vanessa G. , Bieger Andrei , Froehlich Pedro E , Zimmer Eduardo R. 
Published: December 2020

AbstractBackgroundReliable blood‐based biomarkers are of urgent need in Alzheimer’s disease (AD). In this context, whether changes in blood cells are present in AD remains unresolved. An interesting strategy to identify dysregulated biological pathways is the use of omics technologies, bioinformatic tools and, biological networks. Applying these contemporary techniques to blood samples of individuals in the Alzheimer's continuum may aid in understanding the periphery‐brain interface, providing the field with new pathophysiological insights and novel biomarkers. Here, we aim to investigate biological processes altered in peripheral blood cells across the Alzheimer's continuum. We hypothesized that blood transcriptomic profiles of mild cognitive impairment (MCI) and AD individuals will reflect changes in the brain.MethodWhole blood transcriptomic profiles from 99 cognitively unimpaired (CU), 169 MCI and 48 AD individuals were obtained from the ADNI database. Afterward, we computed differential expression analyses between CU‐MCI and CU‐AD. Finally, differentially expressed genes (DEGs) (p‐value < 0.05) from each comparison were submitted to functional enrichment analysis (FEA) of Gene Ontology (GO) biological processes and pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.ResultPeripheral blood cells transcriptome analysis identified a total of 1232 DEGs for MCI and 1985 DEGs for AD patients. For MCI, FEA showed GO terms associated with energetic metabolism, lipid metabolism, and purines pathway (Figure 1A). For AD, GO terms are related to immune and inflammatory response and amino acid metabolism (Figure 1B). Curiously, DEGs are mainly downregulated in MCI but upregulated in AD patients.ConclusionHere, we demonstrate a prominent difference between blood transcriptomic profiles of MCI and AD individuals using FEA. Interestingly, the transcriptomic profile of MCI individuals presented changes in energetic metabolism, which is in line with the well‐established early cerebral glucose metabolism changes observed in the MCI stage. In AD individuals, more pronounced changes in immune and inflammatory processes were found, which also fits with the known late neuroinflammation peak verified in the AD stage. In summary, our findings indicate that blood transcriptomics may reflect aspects of pathophysiological brain events, offering a great opportunity for identifying new peripheral biomarkers and disease stage‐specific treatments.
Regulation of insulin transport across the blood‐brain barrier by CNS insulin receptor signaling
Authors: Rhea Elizabeth , Banks William A. 
Published: December 2020

AbstractBackgroundImpairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer’s disease (AD), age‐related cognitive decline, and mild cognitive impairment (MCI). Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood‐brain barrier (BBB). CNS insulin is derived from the blood and crosses the BBB by a saturable transport system. Therefore, the insulin resistance observed in the CNS and at the neurovascular unit in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Much focus has been placed on the peripheral mediators of insulin transport, with the direct role of the CNS often ignored. Therefore, the goal of this study was to investigate the communication of the neurovascular unit (NVU) in mediating CNS insulin levels in AD.MethodWe utilized the multiple‐time regression analysis technique to measure 125I‐insulin pharmacokinetics at the BBB. We were able to define the transport rate for 125I‐insulin and amount of vascular binding due to changes in CNS insulin receptor signaling. First, we inhibited CNS insulin receptor signaling by administering 1 μg S961 by intracerebroventricular (icv) injection. Second, we evaluated 125I‐insulin transport in mice lacking the insulin receptor in astrocytes.ResultAcute, broad inhibition of the CNS insulin receptor following icv delivery of S961, a selective antagonist, led to decreased 125I‐insulin transport across the BBB that was sex specific in CD‐1 mice. Follow‐up studies revealed the astrocytic insulin receptor may be responsible for this decreased transport as mice lacking the insulin receptor in astrocytes, GFAP insulin receptor knock‐out (GIRKO) mice, also have decreased 125I‐insulin BBB transport.ConclusionThese studies suggest the insulin receptor present on specific cell types within the CNS have a regulatory role in mediating insulin uptake by the brain.
Loss of biliverdin reductase‐a (BVR‐A) impairs beneficial effects of CNS insulin on brain energy metabolism favoring the development of Alzheimer's disease (AD) neuropathology
Authors: Lanzillotta Chiara , Tramutola Antonella , Di Domenico Fabio , Vasavda Chirag , Paul Bindu D. , Snyder Solomon , Butterfield D. Allan , Perluigi Marzia , Duarte Joao M.N. , Barone Eugenio 
Published: December 2020

AbstractBackgroundAlterations of brain insulin signalling are a common pathophysiological mechanism leading to dementia in AD and Type 2‐Diabetes Mellitus (T2DM). These alterations are often associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration. Studies from our group identified impairment of BVR‐A – a regulator of insulin signalling – as an early event leading to insulin resistance in the brain. Here, we tested the hypothesis that reduced BVR‐A levels link failure of insulin signalling with mitochondrial stress resulting in AD neuropathology.MethodAlterations of insulin signalling pathways, autophagic flux, total oxidative stress levels and AD neuropathology were analyzed in the hippocampus of 6‐month old wild‐type and the goto‐kakizaki (GK) model of T2DM rats. Hippocampal mitochondrial function was evaluated by measuring oxygen consumption rate (OCR), mitochondrial complexes, mitochondrial unfolded protein response (UPRmt) and oxidative stress levels. These data were correlated with peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tasks (spatial memory). To confirm the role of BVR‐A, similar analyses were performed in the hippocampus of 2‐ and 6‐month old BVR‐A knock‐out mice. Additional mechanistic insights were gained by evaluating the response to insulin in Sh‐Sy5y cells lacking BVR‐A.ResultsGK rats displayed a diabetic phenotype and impaired spatial memory. Reduced BVR‐A levels along with IRS1 hyper‐activation and loss of Akt‐mediated inhibition of GSK3β were observed in the hippocampus, consistent with a regulatory role for BVR‐A. As result, hyperactive GSK3β accumulated in hippocampal mitochondria fostering their impairment characterized by reduced OCR and activation of UPRmt. Notwithstanding, reduced oxidative stress and pTau levels were observed in GK rats. BVR‐A KO mice displayed alterations of insulin signaling and mitochondrial function resembling those of GK rats with increased oxidative stress and pTau levels the adult mice. Loss of BVR‐A promoted an early protective response (UPRmt‐mediated) followed by a later general impairment (GSK3b‐mediated mitochondrial dysfunction, increased oxidative stress and pTau levels) in Sh‐Sy5y cells treated with insulin.ConclusionThese results suggest that early BVR‐A loss impairs brain insulin signalling favoring mitochondrial stress mediated by hyper‐active GSK3β. These alterations lead to impaired energy metabolism and development of AD neuropathology.
Modeling the early accumulation of amyloid using differential equations in WRAP and BLSA
Authors: Vernhet Paul , Bilgel Murat , Durrleman Stanley , Resnick Susan M. , Johnson Sterling C. , Jedynak Bruno Michel 
Published: December 2020

AbstractBackgroundAccumulation of beta‐amyloid plaques, an early hallmark neuropathology of Alzheimer’s disease (AD), begin more than a decade prior to the onset of clinical symptoms. Understanding the temporal progression of early amyloid accumulation is important for predicting who will become amyloid‐positive and when. Based on observations from several longitudinal amyloid positron emission tomography (PET) studies that the rate of overall amyloid burden is closely associated with baseline level of amyloid, we develop a formal mathematical model capturing this phenomenon and use it to (i) align temporal trajectories of amyloid accumulation across individuals, (ii) create a fine‐grained timeline of amyloid accumulation, and (iii) estimate the age at onset of amyloid positivity per individual.MethodWe used (PiB) PET scans from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Baltimore Longitudinal Study of Aging (BLSA) to assess global amyloid burden cDVR, see Figure 1. A first‐order autonomous model for the slope of cDVR as a function of cDVR was fit to the data. We used Bayesian modeling with a Gaussian process (GP) prior and independent homoscedastic noise.ResultThe best fit was obtained with a quadratic GP kernel (Figure 2). Since the system is autonomous, the trajectories are parallel and thus can be registered by translation. The progression of the Amyloid burden is thus visualized as a function of the time (in years) from PIB positivity in Figure 3. The estimated age when the PIB cDVR becomes positive is estimated. This age depends on APOE status, with a significant difference between the APOE groups [3,3] and [3,4]. p‐value=.008 in WRAP, p‐value=.054 In BLSA.ConclusionLarge studies on aging allow studying the time‐progression of the amyloid burden. We found that an autonomous ordinary differential equation allows for a good explanatory model of the PIB‐DVR data in the WRAP as well as in the BLSA studies. Still, a few participants do not fit the data closely. It remains to understand if this is due to noisy measurements or to specific conditions. Also, alternative dynamical systems, including Hamiltonian, still need to be investigated and compared.