bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double‐blind, placebo‐controlled study of the effect of a TNFα inhibitor, Etanercept, on microglial activation in amyloid PET‐positive patients with mild cognitive impairment due to AD‐intermediate likelihood
Authors: Gerhard Alexander , Jacobs Andreas H. , Goerttler Tsepo , Sharples Richard , Beardmore Rebecca C. , McDonald Katy R. , Visi Eszter , Hinz Rainer , Turkheimer Federico , Herholz Karl , Holmes Clive 
Published: December 2020

AbstractBackgroundPrevious studies have shown that systemic TNFα is associated with increased disease progression in AD and that this may be modulated by the anti‐TNFα agent Etanercept. The effect of Etanercept on microglial activation in patients with MCI due to AD is unknown.MethodA total of 13 patients (from a planned 46 patients) with a clinical diagnosis of MCI due to AD were randomised to receive either placebo or 50 mg of Etanercept (weekly s.c injection) over one year. Aß deposition was established by AmyvidTM ([18F]Florbetapir‐PET) scan. Clinical assessments, [11C]‐(R)‐PK‐11195 PET (a marker of microglial activation) and [18F]Florbetapir‐PET were performed at baseline and after 1 year.Result10 out 13 enrolled participants completed the whole study. 6 on Etanercept and 4 on placebo. The region of interest analysis of the [11C]‐(R)‐PK‐11195 binding potential (BP) at baseline showed a widespread increase in MCI patients as compared to age‐matched controls with the cingulate gyrus being targeted. When comparing the change of regional and global PK11195 BP for these 10 patients between baseline and follow‐up after one year, there were no significant differences in the placebo or in the active drug group. Likewise, we found no major changes in measurement of memory function or other cognitive tasks in those subjects taking Etanercept compared with placebo. However, study power was severely compromised.ConclusionMCI patients show increased microglial activation as compared to healthy controls. In our relatively small treatment group Etanercept does not seem to modify microglial activation as measured with [11C]‐(R)‐PK‐11195 PET.
Plasma amyloid‐beta42/40 ratio as biomarker of cerebral amyloidosis in cognitively unimpaired APOE‐e4 homozygotes, heterozygotes and non‐carriers
Authors: Jansen Willemijn J. , Ghisays Valentina , DeMarco Kathryn L. , Boker Connie A. , Chen Kewei , Chen Yinghua , Luo Ji , Protas Hillary D. , West Tim , Meyer Matthew , Kirmess Kris , Verghese Philip B. , Hu Helen , Yarasheski Kevin E. , Su Yi , Reiman Eric M. 
Published: December 2020

AbstractBackgroundPlasma amyloid‐β (Aβ) blood tests have great promise in research and care. C2N Diagnostics has developed a mass spectrometry‐based plasma Aβ42/40 assay (APTUSTM‐ pAβ42/40), which has previously demonstrated approximately 88% accuracy (81% sensitivity and 83% specificity; CTAD 2019) to distinguish between individuals with Aβ‐positive and negative (A+ and A‐) PET scans. We sought to characterize the assay’s ability to discriminate cognitively unimpaired APOE4 homozygotes, heterozygotes, and non‐carriers from the Arizona APOE Cohort.MethodsPlasma Aβ42/40 concentration ratios and APOE4 gene dose (0, 1, 2 alleles) were characterized blindly using 0.5 cc plasma aliquots from 121 cognitively unimpaired 66±8 (47‐85) year‐old participants, including 21 APOE4 homozygotes, 37 heterozygotes and 63 non‐carriers whose blood samples and PiB or florbetapir PET scans were acquired at the same visit. Neuropathologically validated PiB 1.47 and florbetapir 1.17 SUVR cut‐offs were used to determine A+ and A‐ PET scans. Receiver operating characteristic (ROC) analyses were performed calculating the areas‐under‐the curve (AUCs) before and after adjustment for APOE4 gene status or dose, age and sex. The optimal Aβ42/40 cut‐off, sensitivity and specificity were retrospectively characterized.ResultsPlasma Aβ42/40 ratios discriminated between individuals with A+ and A‐ PET scans with 0.87 and 0.89 AUCs, respectively, before and after adjustment for APOE4 status. Further adjustment for APOE4 gene dose, age and sex did not significantly influence these results. In the APOE4 status‐adjusted ROC, a plasma Aβ42/40 0.096 cutoff, with 91% sensitivity and 82% specificity had the maximum Youden Index. We observed trends of a greater percentage of A‐ PET APOE4 homozygotes than heterozygotes or non‐carriers being plasma A+ (29%, vs. 11%; p=0.08, and vs. 11%; p=0.05, respectively). Further, individuals with an A+ plasma test but an A‐ PET scan at baseline were at 9‐fold increased risk of conversion to A+ PET compared to individuals with an A‐ plasma test.ConclusionAPOE4‐adjusted plasma β42/40 assays have great promise in AD research, prevention trials and clinical care, with demonstrated high accuracy for cognitively unimpaired persons with two, one or no copies of the APOE4 allele. This study suggests that an A+ plasma test result predicts progression from an A‐ to an A+ PET scan in the near future.
Screening characteristics of PSEN1 E280A mutation carriers and non‐carriers in the API Autosomal Dominant Alzheimer’s Disease Colombia Trial
Authors: Rios‐Romenets Silvia , Giraldo‐Chica Margarita , Acosta‐Baena Natalia , Tobon Carlos , Ramos P Claudia , Lopez Hugo , Aguirre‐Acevedo Daniel C. , Muñoz Claudia , Bocanegra Yamile , Henao Eliana , Tirado Victoria , Ospina Paula , Sink Kaycee M. , Hu Nan , Langbaum Jessica B. , Reiman Eric M. , Tariot Pierre N. , Lopera Francisco 
Published: December 2020

AbstractBackgroundThe Colombia Alzheimer’s Prevention Initiative (API) Registry was a resource for enrollment into the API Colombia clinical trial. Potentially eligible candidates from the Colombia API Registry went through a prescreening and then in‐person screening process with the goal of enrolling them in the API ADAD Colombia Trial. Analysis of screening data might provide additional information to consider for other AD prevention trials. We present descriptive screening data from the API ADAD Colombia trial in Presenilin 1 (PSEN1) E280A mutation carriers vs non‐carriers.MethodConsent was obtained from 319 potentially eligible participants after prescreening. Screening data from 315, including 210 mutation carriers, were used to compare demographics, medical comorbidities, toxic and reproductive antecedents, selected clinical, functional, and anthropometric measurements, vital signs, and brain MRI and laboratory results in the mutation carrier and non‐carrier groups. Descriptive statistics comparing mutation carriers and non‐carriers were performed using generalized linear regression models using link function according to whether the outcome was categorical or numerical. Results were adjusted for age, sex, level of education, depression or body mass index (BMI) depending upon which measurements were compared.ResultResults of the above characteristics at screening for carriers and non‐carriers will be presented. Briefly, compared to mutation non‐carriers in screening, carriers were younger (mean 40 vs 48 years), had similar educational attainment (mean 8.3 vs 7.5 years), and showed generally lower cognitive performance, especially in memory (e.g., mean (sd) CERAD world list scores were 20.30 (3.82) vs 19.46 (3.68), respectively). There were no differences in other demographic characteristics, medical comorbidities, toxic and reproductive antecedents, anthropometric measurements, vital signs, MRI findings or laboratory results. Mutation non‐carriers compared to carriers showed a non‐significant trend towards more vascular risks according to medical comorbidities (hypertension, dyslipidemia), borderline higher level of triglycerides and cholesterol, microvascular changes in the brain and higher BMI. The higher prevalence of vascular risk factors among non‐carriers may be explained by an 8‐year age difference between non‐carriers vs carriers.ConclusionThe API ADAD Colombia Trial screening data provide insights into demographics as well as clinical, cognitive and non‐cognitive characteristics, and medical comorbidities of a (PSEN1) E280A population.
Identifying early markers of synaptic dysfunction in a mouse model of tauopathy
Authors: Meftah Soraya , Witton Jonathan , Cavallini Annalisa , Murray Tracey K. , Jankowski Lukasz , Bose Suchira , Ashby Michael , Brown Jonathan T. 
Published: December 2020

AbstractBackgroundSynaptic degeneration is currently the best correlate of cognitive decline in Alzheimer’s Disease. Tau pathology, one of the hallmarks of the disease, correlates well with synaptic degeneration and has been shown to abnormally mislocate to synapses in the disease. This process is thought to induce changes in the activity, number and structure of synapses leading to widespread synaptic dysfunction prior to neurodegeneration. However, the precise mechanistic and functional changes are unclear. Therefore, identifying early markers of synaptic dysfunction will provide novel insights into mechanistic changes that precede neurodegeneration and underlie symptomatic onset in tauopathy.MethodTo investigate this, we used a multi‐faceted approach to characterise synaptic changes in the somatosensory cortex of the rTg4510 model of tauopathy, just prior (5.5 months) and post (7.5 months) neurodegeneration. Synaptic, neuronal and network function was assessed using in vitro and in vivo whole‐cell patch clamp electrophysiology, which allows for post‐hoc complementary analysis of morphology in recorded neurons. Protein expression of glutamatergic receptors, synaptic markers and tau were also quantified in crude synaptosomes by western blot.ResultPrior to neurodegeneration, glutamatergic synaptic function was altered (decreased NMDA:AMPA ratio) and dendritic structure was altered (increased branching proximal to soma). Protein expression of synaptic markers and AMPA receptors were significantly decreased in the somatosensory cortex. Post neurodegeneration, a reduction in AMPA mediated synaptic communication was observed (sEPSC frequency), matched with a progressive decrease in AMPA receptor expression and the synaptic marker, PSD95.ConclusionOur results suggest that glutamatergic signalling is altered differently at the regional and single cell level just prior to neurodegeneration. For example, whilst regional AMPA receptor expression decreases pre‐neurodegeneration in the brain, it appears to be partially compensated for functionally within single neurons and the larger network. We predict that there may be a degree of compensation within the network, which when past a threshold leads to widescale network alterations and symptomatic changes. Deconstructing how functional compensation occurs in the brain in neurodegenerative diseases will shed light on how to delay symptomatic onset in tauopathies.
EVOO polyphenols can relieve autophagy dysregulation in Alzheimer's disease
Authors: Leri Manuela , Stefani Massimo , Bucciantini Monica 
Published: December 2020

AbstractBackgroundAutophagy, a key process involved in cell proteostasis, regulates lipid metabolism and organelle turnover and contributes to clear materials of endogenous or exogenous origin. Abnormalities in the autophagic flux may contribute to several pathophysiological conditions, associated with ageing and neurodegeneration. Alterations of the autophagy machinery are involved in the onset of Alzheimer’s disease (AD), the most common form of dementia in the elderly increasingly occurring in developed countries. Indeed, several studies have revealed that the maturation of autophagolysosomes and the inhibition of their retrograde transport creates favourable conditions for accumulation of the Ab peptide whose aggregation into extracellular plaques is considered a main responsible for neuronal damage in AD. Recent data have shown that oleuropein aglycone (OleA), a polyphenol found in olive oil (EVOO), stimulates cell defences against plaque‐induced neurodegeneration and triggers autophagy. After ingestion, about 30% OleA is metabolized to hydroxytyrosol (HT), the most powerful antioxidant compound in the olive tree.MethodAccordingly, we investigated the molecular mechanism involved in autophagy activation by a mixture of OleA and HT. To this purpose, we performed a set of in vitro experiments on SH‐SY5Y cell model such as confocal microscopy;MTT assay; western‐blotting and ROS production evaluation, to extend and to deepen the knowledge on the molecular determinants of the beneficial properties of olive polyphenols.ResultOur results show that a mix of OleA/HT is able to activate the autophagy pathway more than the same amounts (in molar terms) of OleA or HT. Moreover, a reduction of ROS production with a significant recovery of cell viability was observed in cells exposed to toxic Ab1‐42 oligomers.ConclusionThese studies confirm and extend previous data and provide the rationale for consideration of these molecules as promising candidates for prevention and long‐term nutraceutical treatment of neurodegeneration or as molecular scaffolds for further pharmacological development.
The visual ventral network is disconnected in Lewy body dementia with visual hallucinations
Authors: Mehraram Ramtin , Taylor John‐Paul , Murphy Nicholas , Rodriguez Luis Peraza , Cromarty Ruth , Graziadio Sara , O'Brien John T , Killen Alison , Colloby Sean J , Kaiser Marcus 
Published: December 2020

AbstractBackgroundVisual hallucinations (VH) are a common symptom in Lewy body dementias (LBD), which comprise dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Previous studies investigated functional brain network alteration associated with VH in different diseases. However, there is a lack of studies on VH in LBD, and a clear picture of the affected pathways is still missing. In this study, we used electroencephalography (EEG) to detect the weakened cortical connections and the functionally disconnected cortical regions in LBD with VH.MethodResting state eyes closed EEG signals (128 channels) were recorded from 45 LBD participants: 18 without VH (eight DLB) and 27 with VH (13 DLB). EEG time series were filtered (bandpass: 8‐13 Hz), and cleaned from artefacts. Magnetic resonance imaging (MRI) recordings were individually obtained with magnetisation prepared rapid gradient echo (MPRAGE) sequence, and source estimation was performed with sLORETA technique (Destrieux atlas). Connectivity was measured with weighted phase lag index (WPLI), and assessed with Network Based Statistics (NBS), including the MMSE score as covariate. Node strengths of the subnetworks detected with NBS was computed. The visual hallucination score was collected through the NPI questionnaire.ResultThe NBS revealed two subnetworks affected in VH, both comprising regions belonging to the visual ventral pathway (p<0.05, t>3.8). The first one (Figure 1) comprised connections between the right temporal lobe and the prefrontal cortex, which showed reduced strength. In the second one (Figure 2), contra‐lateral connectivity between occipital and right infra‐temporal lobe was significantly weakened.ConclusionWe propose a topography of the subnetworks affected in LBD with VH. The first and second subnetworks comprise regions involved respectively in the top‐down and bottom‐up visual perception streams. Our results resonate with the literature related to the pathology of LBD and VH. We found indeed that both affected subnetworks comprise the right inferior temporal lobe, which has been previously found to show a great burden of Lewy bodies in patients with VH. Our results support EEG as a suitable biomarker for assessing the severity of the pathology, and providing useful insights into the disease.
Promoting sustainable dementia education in African American communities
Authors: Lucas John A , Robinson Maisha T , Bergeron Caroline D , Willis Floyd B , Parfitt Francine C , Graff‐Radford Neil R 
Published: December 2020

AbstractBackgroundAfrican Americans are at higher risk of developing Alzheimer’s disease (AD) and AD‐related dementia. They are also more likely to live in communities with fewer dementia resources. The 2011 National Alzheimer’s Project Act calls for special attention to dementia‐related health disparities in high risk groups. Ensuring access to dementia‐specific information is one tactic for addressing disparities; however, the method by which information is delivered may play a role in how effectively that information is understood and retained over time.MethodWe delivered the same dementia education presentation to two comparable, predominantly African American neighborhoods in Jacksonville, FL. In one (intervention) community, the presentation was followed by an hour‐long focus group on what makes a community “dementia friendly”, using modified materials from the Dementia Friendly America (DFA) toolbox. In the other (control) community, the presentation was followed by a social hour allowing participants to interact with presenters and ask questions informally. Our primary objective was to assess the impact of the different conditions on AD knowledge.ResultsA 7‐item scale assessing AD knowledge was administered to immediately before and after the educational presentation (pre‐test, immediate post), and again two months later (Intervention group n=40; Control n=37). Additional, one‐year follow‐up was completed on the intervention community (n=21). Groups did not differ in AD knowledge at pre‐test (M=4.5 vs. 4.2, p=NS). At immediate post‐test, both groups improved their scores, but there was again no difference between groups (M=5.8 vs. 5.4, p=NS). At two‐month post‐testing, both groups declined in their knowledge score, but the control group declined more precipitously, yielding a significant group mean difference (M= 5.4 vs. 4.7, p=0.02). At one year follow‐up, a subsample of the intervention group (n=21) was re‐examined and demonstrated no significant decline in knowledge scores as compared to 2‐month follow‐up (M=5.7 vs. 5.4, p=0.36).ConclusionResults suggest that focus group discussion following dementia education as per the DFA model may contribute to greater retention of information and exert a sustainable impact on AD knowledge over time in an African American community setting.
Ultra‐performance liquid chromatography‐tandem mass spectrometry method for analysis of tau in human cerebrospinal fluid without the need of immunocapture
Authors: Korecka Magdalena , Leinenbach Andreas , Gobom Johan , Delatour Vincent , Becher Francois , Blennow Kaj , Zetterberg Henrik , Pannee Josef , Hofving Katarina , Shaw Leslie M. 
Published: December 2020

AbstractBackgroundReliable tau protein measurement in CSF is required for detection of Alzheimer’s disease pathology when combined with Aβ42/40 measurement. Tau is present at a very low concentration in CSF, has 6 different isoforms and many forms with post‐translational modification including methylation, glycosylation and phosphorylation. Immunoassays are sensitive enough to measure low tau concentration however poor linearity and lack of specificity in regards to tau’s isoforms have been reported. Thus, mass spectrometry is a candidate alternative technology. Additionally, the possibility of avoiding immunocapture would be important for a protein with multiple isoforms.MethodHere we describe our efforts to develop an LC‐MS/MS (triple quadrupole) assay for quantification of tau in CSF. Sample preparation includes selective protein precipitation, neutralization and on‐filter digestion with trypsin without the need of immunocapture. Following trypsinization the peptide mixture is washed/centrifuged through the filters, injected onto the analytical column and eluted with water/ acetonitrile/0.1% formic acid gradient. For quantification we use the tryptic peptide ‐ GAAPPGQK [(156‐163, m/z‐ 363.26/526.28 (quantifier ion)], which is present in all tau isoforms and does not contain a phosphorylation site, and whose quantity is directly proportional to tau concentration. The same peptide labelled with 15N is used as the internal standard (IS) (m/z‐ 368.19/267.14 and 368.19/533.28, quantifier ions).ResultThe method is still under development however several parameters have been established: surrogate matrix (0.5% serum in water), amount of IS added at the beginning of sample preparation (4ng/mL), lower (350pg/mL) and upper (30000pg/mL) limit of measuring interval, analytical recovery of human peptide from the filters (67‐83%), duplicates precision (5.0 3.9%). No background peaks found at the retention time of the analyte/IS from a matrix‐matched double blank sample confirms good assay specificity. Collection of a full set of imprecision/accuracy data using surrogate matrix and human CSF are underway.ConclusionThe assay will be assessed for tau quantification in human CSF by evaluating each parameter of the full validation process. This newly developed and validated assay will be important for direct measurement of tau in CSF samples, and may be applied as a candidate reference measurement procedure for CSF tau in standardization projects on this biomarker.
Evaluation of the effects of a systematized music stimulation program on cognition and mood aspects of the elderly: The possibility of cognitive rehabilitation based on art in the Brazilian Amazon
Authors: Silva Vanessa Feitoza , da Silva Laís Rafaelly Rodrigues Justino , Pinheiro Livian Maria da Silva , de Almeida Maria Emília Pirovano , Bozi Brenno Silva , de Lima Lucas Aguiar , da Silva Lucia Cristina Cavalcante , Shigaeff Nadia 
Published: December 2020

AbstractBackgroundIn Brazil, the elderly population has the highest growth rate. The estimated number of aged is 32 million for the year 2020. The city of Maraba, in the state of Para, located in and Brazil's Amazon region presents a very low Urban Development Index for Longevity. Previous studies have shown that music can enhance the willingness of the elderly to participate in other social activities, contributing to social interaction and, consequently, to prevention of depression. In addition to an important resource to stimulate memory and attention.MethodThe study was developed with 13 elderly from two public long term care institutions who completed all the stages of this study. They were evaluated through a neuropsychological assessment tool. It was composed of 9 objective tests about memory, executive function, attention, praxis and information processing speed. The instruments was applied in two moments: before and after the musical stimulation intervention which consisted of 12 weekly sessions lasting one and a half hours.Result92.3% were man, 69.2% aged 60‐70 years and 73% with a low level of formal education (Table 1). All had the diagnosis of mild to moderate dementia. There was significant improvement in cognitive performance of sustained attention and immediate recall short‐term memory between the baseline application and the post‐intervention (‐3.8 ± 2.0 vs. ‐2.2 ± 1.8, p = 0.07 and 3.6 ± 1.1 vs. 4.8 ± 2.0, p = 0.02, Table 2 and Figures 1 and 2). Significant improvement in mood symptoms was also observed (5.5 ± 2.0 vs. 4.5 ± 1.8, p = 0.04, Table 2 and Figure 3).ConclusionThe results corroborate with other studies, demonstrating the effectiveness of musical stimulation as a way to slow the progression of cognitive impairment, also contributing to euthymic mood. Thus, this would be an accessible and low cost technique for performing cognitive stimulation/rehabilitation in elderly with dementia and possibly delaying the onset or progression of mood and/or cognitive symptoms. Even to elderly people living in long‐term care institutions who show a faster progression of cognitive decline compared to community‐dwelling elderly also benefit from this intervention strategy.