bluuebunny/crossref_metadata_2025 huggingface dataset:
The solely A+ CSF Aβ42/40 ratio using Elecsys® assays performs similar to A/T and A/N ratios in predicting amyloid PET positivity
Authors: Grimmer Timo , Amft Michaela , Ortner Marion , Eichenlaub Udo , Goldhardt Oliver , Müller‐Sarnowski Felix , Diehl‐Schmid Janine , Förstl Hans , Yakushev Igor
Published: December 2020

Background

pTau181/Aβ42 (A+/T+ as per A/T/(N) classification) and tTau/Aβ42 (A+/(N)+) ratios using fully automated Elecsys® cerebrospinal‐fluid (CSF) immunoassays have been shown to perform well in distinguishing amyloid‐positivity (A+) by positron emission tomography (PET) among patients with subjective and mild to severe cognitive impairment. Higher performance has also been demonstrated for the CSF Aβ42/40 ratio compared to CSF amyloid 42 (Aβ42) alone. We aimed to further evaluate the performance of the Elecsys® Aβ42/40 ratio in a clinical cohort.

Methods

Frozen (‐80°C) CSF samples from 103 patients treated in the Centre for Cognitive Disorders, Technical University of Munich were selected based on availability of visual amyloid‐PET status (n=54 PET+; 49 PET‐) determined during standard treatment around the time of CSF collection. In total, 71 patients were undergoing treatment for mild cognitive impairment (MCI) (n=44) or mild to moderate dementia (n=27) due to Alzheimer’s disease (AD) and 32 patients for non‐AD related fronto‐temporal lobar degeneration (n=17), MCI (n=8), depression (n=5), alcohol dependence (n=1), or subjective cognitive impairment (SCD) (n=1). CSF was measured using Elecsys® assays. CSF status for Aβ42 , pTau181/Aβ42 , and tTau/Aβ42 CSF (positive/negative) was determined based on pre‐defined biomarker cutoffs previously established using a different pre‐analytical protocol in MCI/SCD patients with suspected AD (CSF positive if Aβ42<1000 pg/ml, pTau181/Aβ42>0.024, and tTau/Aβ42>0.028). Sensitivity and specificity were calculated for CSF‐cutoff‐based status and ROC analysis was performed to determine AUC each versus visual amyloid‐PET status.

Results

Pre‐defined biomarker thresholds were considered off‐label due to deviation from recommended sample collection protocol and storage parameters. Point estimates for sensitivity and specificity for each biomarker were; CSF Aβ42 alone (sensitivity = 0.93, specificity = 0.57), pTau181/Aβ42 (0.96, 0.69), and tTau/Aβ42 (0.92, 0.69). For AUC point estimates (95% confidence interval) were; CSF Aβ42 alone [0.78 (0.68‐0.88)], pTau181/Aβ42 [0.88 (0.81‐0.95)], tTau/Aβ42 [0.87(0.80‐0.95)], and Aβ42/40 [0.90 (0.83‐0.95)].

Conclusion

Fully automated Elecsys® cerebrospinal fluid (CSF) immunoassay predicted amyloid positivity with high accuracy. In this study, the solely A+ marker CSF Aβ42/40 ratio outperformed Aβ42 alone and performed similarly to Tau ratios. These results support those of previous studies showing high performance for the non‐Tau marker CSF Aβ42/40.
A multifunctional chemical agent as an attenuator of amyloid and p‐tau burden and neuroinflammation in Alzheimer’s disease
Authors: Mirica Liviu M
Published: December 2020

Background

New therapeutic agents are being developed that target not only the amyloid plaques in Alzheimer’s disease (AD), but also the extracellular p‐tau aggregates, Aβ‐metal induced oxidative stress, and neuroinflammation.

Method

We have developed two novel multifunctional compounds (MFC) that exhibit high binding affinity for Aβ aggregates ‐ including soluble Aβ oligomers, and a series of ex vivo and in vivo immunostaining and imaging studies were employed to probe the beneficial properties of these MFCs.

Result

Upon treatment of 5 × FAD mice with one of the MFC, fluorescence imaging of the brain sections shows that the MFC can easily penetrate the blood‐brain‐barrier and selectively bind to the Aβ oligomers, as confirmed by the colocalization with an Aβ oligomer‐specific antibody. Furthermore, when comparing the MFC‐treated mice vs. the vehicle‐treated mice, the total amount of Aβ species and the associated p‐tau aggregates was significantly decreased by ∼50%, along with a significant reduction in the amount of activated microglia.

Conclusion

The multifunctional compounds reported herein can attenuate the formation of amyloid plaques and associated p‐tau aggregates, while also reducing the microglia‐mediated neuroinflammatory response, which is uncommon among the previously reported amyloid‐targeting chemical agents.
Insulin resistance is related to cognitive decline but not biomarkers of Alzheimer’s pathology in adults without dementia
Authors: Ennis Gilda E , Koscik Rebecca L , Ma Yue , Betthauser Tobey J , Jonaitis Erin M , Van Hulle Carol A , Bouges Shenikqua , Chin Nathaniel A , Engelman Corinne D , Anderson Rozalyn , Batrla Richard , Kollmorgen Gwendlyn , Carlsson Cynthia M , Asthana Sanjay , Johnson Sterling C , Zetterberg Henrik , Blennow Kaj , Bendlin Barbara B
Published: December 2020

Background

Insulin resistance (IR) has been related to increased risk for Alzheimer’s clinical syndrome. While some cross‐sectional studies have linked IR to Alzheimer’s disease (AD) pathology, others have been negative. We examined the relationship of IR to longitudinal cerebrospinal fluid (CSF) biomarkers of AD pathology, cerebral amyloid chronicity, and cognitive decline.

Method

Participants (Table 1) were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a longitudinal observational study of non‐demented adults. We utilized data from biennial visits and CSF and positron emission tomography (PET) sub‐studies. For our first study, participants (n=148) had CSF biomarker data (Aβ42: Aβ40 ratio, p‐tau181, t‐tau, and neurogranin) from 1‐5 CSF samples collected every 2‐8 years and fasting insulin and glucose (collected during 1‐5 visits before first CSF) for calculating homeostatic model assessment of insulin resistance (HOMA‐IR). CSF was assayed using the Roche NeuroToolKit on the Elecsys® platform. Linear mixed effects models tested HOMA‐IR as a moderator of aging‐related change in CSF biomarkers. In study 2, participants (n=253) had [C11]PiB PET imaging and 3‐6 HOMA‐IR values for calculating a within‐person HOMA‐IR mean and SD (i.e., fluctuation). Amyloid chronicity was calculated by subtracting estimated age at PiB positivity (i.e., estimated age when PiB DVR ≥ 1.2) (Koscik & Betthauser, et al., 2020) from age at last HOMA‐IR. Hierarchical regression tested whether HOMA‐IR and an HOMA‐IR x APOE4 interaction predicted amyloid chronicity. In study 3 (n=1,298), linear mixed effects tested if baseline HOMA‐IR moderated age‐related decline in longitudinal measures of the preclinical Alzheimer’s cognitive composite (PACC). Age, APOE4, sex, education, and systolic blood pressure (SBP) were controlled in all study models.

Result

HOMA‐IR was not a significant moderator of aging‐related change in any CSF biomarker (Figure 1 & 2). HOMA‐IR mean and SD and the HOMA‐IR x APOE4 interaction were not significant predictors of amyloid chronicity. Increased HOMA‐IR predicted greater age‐related decline in PACC (Figure 3).

Conclusion

HOMA‐IR was related to cognitive decline but not cerebral amyloid chronicity or age‐related change in CSF biomarkers of AD pathology and neurodegeneration. IR may not be directly related to preclinical AD pathology. Pathways linking IR to dementia require further investigation.
Cerebrospinal fluid biomarkers in older adults with mild cognitive impairment, with and without a major depressive disorder
Authors: Golas Angela C , Salwierz Patrick , Rajji Tarek K , Bowie Christopher R , Butters Meryl A , Fischer Corinne E , Flint Alastair , Herrmann Nathan , Mulsant Benoit H , Mah Linda , Pollock Bruce G , Taghdiri Foad , Tartaglia Maria Carmela
Published: December 2020

Background

Mild Cognitive Impairment (MCI) and Major Depressive Disorder (MDD) have been independently associated with increased risk of dementia. Cerebrospinal fluid (CSF) biomarkers associated with Alzheimer’s disease (AD) show changes prior to the onset of symptoms of dementia or neuroimaging biomarkers of AD. We examined the association between a CSF biomarker profile of AD and diagnosis in three groups: MCI alone; a diagnosis of MDD alone; or MCI plus a diagnosis of MDD.

Method

The CSF total tau, p‐tau, amyloid‐β42, and the p‐tau/ amyloid‐β42 ratio were measured in 31 participants enrolled in the PACt‐MD study diagnosed with MCI (N=13), MDD (N=7), or both (MCI+MDD) (N=11) according to NIA‐AA and DSM IV criteria. We compared AD biomarkers in the 3 groups and then compared cognitive performance in those with and without a CSF biomarker profile consistent with AD

Result

Among the 31 participants, 9 had a CSF biomarker profile consistent with AD: 7/13 with MCI; 0/7 with MDD; and 2/11 with MCI+MDD. Participants with an AD biomarker profile had significantly greater impairment in verbal memory than those without one (p=0.009). Of those without a profile consistent with AD, no significant differences were observed in cognitive performance between the MCI and MDD+MCI groups.

Conclusion

In our sample, few participants with MDD had a CSF biomarker profile consistent with AD, even if they had a neurocognitive profile consistent with MCI. The etiopathology of cognitive impairment in older patients with MDD requires further investigation.
Investigating amyloid beta‐induced toxicity in tau‐deficient human neurons
Authors: Ng Bryan , Vowles Jane , Cowley Sally A , Caffrey Tara M , Connor‐Robson Natalie , Wade‐Martins Richard
Published: December 2020

Background

Amyloid‐b (Ab) and tau aggregates are two major pathological hallmarks and known to be dysregulated in Alzheimer’s disease (AD), leading to widespread aggregation. We now know from tau‐deficient animal models that tau does not merely facilitate Ab‐induced toxicity but is also essential in that particular toxic cascade. However, a tau‐deficient human in vitro model has not been available to corroborate these studies.

Method

Here we generated the first MAPT

‐/‐
human induced pluripotent stem cell (iPSC) lines with CRISPR‐Cas9‐mediated genome editing in order to study the effects of tau deficiency in human biological context. We also established a versatile and scalable cortical neuron differentiation protocol which successfully produced a heterogeneous population of functional neurons manifesting cortical identity in co‐culture with rat astrocytes. Furthermore, we extracted brain homogenate from an AD patient to serve as the source of extrinsic Ab in addition to synthetic Ab oligomers.

Result

iPSC‐derived MAPT

‐/‐

cortical neurons exhibited lower firing amplitude and frequency compared to MAPT

+/+

neurons at baseline, while expressing similar number of synapses. On the other hand, MAPT

‐/‐

neurons demonstrated impaired axonal outgrowth over 5 days of live imaging. Upon extrinsic AD brain homogenate and/or Ab1‐42 oligomer insults, MAPT

‐/‐

neurons appeared to be protected from axonal degeneration, cytotoxicity and hyperactivation as compared to MAPT

+/+

neurons. However, the MAPT

‐/‐

background was unable to prevent Ab‐induced loss of synapses.

Conclusion

Taken together, the absence of tau in human neurons resulted in phenotypic changes at baseline and could result in neuroprotection in MAPT

‐/‐

neurons from Ab‐induced toxicity.
Sleep duration genes associated with cognition across the adult age‐range
Authors: Tsapanou Angeliki , Gao Yizhe , Stern Yaakov , Barral Sandra
Published: December 2020

Background

Sleep is implicated in cognitive functioning in young adults, while healthy older adults do not always demonstrate clear associations between sleep and cognitive functioning. Age‐related changes in sleep include a reduction in total sleep time and a greater incidence of sleep disorders, and are also an integral part of neurodegenerations. In the present study, we aimed to: a) identify common genetic variants that may influence self‐reported sleep duration, and b) examine the association between the identified genetic variants and performance in different cognitive domains.

Method

A sample of 197 cognitively healthy participants, aged 20‐80 years, were selected from two study cohorts: The Reference Abilities Neural Network and the Cognitive Reserve. Each participant underwent an evaluation of sleep function and assessment of neuropsychological performance on four different domains (memory, speed of processing, fluid reasoning, language), and global cognition. Available imputed genome‐wide genotyped data was used to derive a Polygenic Risk Score (PRS) based on 69 genetic variants previously reported as associated with sleep duration. Multivariate linear models were used to test the associations between the PRS and sleep duration and cognitive performance. Age, sex, and education were used as covariates.

Result

Higher PRS was linked to longer sleep duration and then, lower risk of poor performance in global cognition, fluid reasoning, speed of processing, and language, but was not associated with memory.

Conclusion

We replicated the association between PRS and longer sleep duration. We additionally found a significant association between the PRS and cognitive function. Our results suggest that common genetic variants influence the link between sleep duration and cognitive health. Sleep duration may represent a potential causal pathway for cognition, and, thus, improving sleep habits might be as useful as a potential therapeutic target to improve cognitive performance. Funding: National Institute of Health (NIH)/ National Institute of Aging (NIA) [Grant numbers: R01 AG026158 and RF1 AG038465], and the Bodossakis foundation.
MALDI‐TOF IP‐MS quantification of plasma amyloid peptides in Alzheimer’s disease
Authors: Lehmann Sylvain , Vialaret Jérôme , Kindermans Jana , Gabelle Audrey , Hirtz Christophe
Published: December 2020

Background

The use of biomarkers which reflect Alzheimer’s disease (AD) improved the stratification of patients and the ability to propose personalized care. Their detection using either cerebrospinal fluid analysis (CSF), which is invasive, or using PET imaging, which is costly, is not adapted to large‐scale use. In 2018, Nakamura et al. using MALDI‐TOF IP‐MS generated a new composite biomarker with the amyloid‐ß precursor protein (APP)669–711/Aß42 and Aß40/Aß42 ratios with an AUC above 0.94 to identify subjects with PETAß+. Our primary objective here was to validate the use of this approach to identify AD and predicts its apparence in MCI and pre‐symptomatic patients.

Method

The blood‐based Aß markers were measured with an innovative MALDI‐TOF IP‐MS approach adapted from Nakamura et al., 2018. Briefly, 250 μl of plasma was diluted and spiked with 10 pM of stable‐isotope‐labelled (SIL) Aβ1–38 peptide. Aβ‐related peptides were immunoprecipitated, washed, and eluted with with 70% acetonitrile / 5 mM HCl to a 900‐μm μFocus MALDI plateTM (Hudson Surface Technology) which was pre‐spotted with a mix of α‐cyano‐4‐hydroxycinnamic acid (CHCA) and methanediphosphonic acid (MDPNA). Mass spectra were acquired using a MALDI‐linear TOF mass spectrometer (AXIMA Assurance, Shimadzu/KRATOS) equipped with a 337‐nm nitrogen laser in the positive ion mode. References AD cohorts with CSF biomarkers and longitudinal follow‐up were used.

Results

Quality controls (QC) plasma pools with Low (LQC), Medium (MQC), and High (HQC) (APP)669–711, Aß42 and Aß40 levels were generated to perform the analytical validation. Intra‐day variability were for LQC, MQC and HQC ≈19% for raw MS intensities and ≈6% after internal normalization. Inter‐day variability were ≈16% after normalization. Dilution integrity indicated linear results between 100% and 50% of the initial plasma volume. Three cycles of freeze/thaw test showed a good stability for the 3 target peptides. A cohort of >200 subject’s plasma samples from the memory consultation of the CMRR of Montpellier with Alzheimer’s disease, Mild Cognitive Impairment and other degenerative diseases are being analyzed to demonstrate the clinical interest of this measurement.

Conclusion

MALDI‐TOF IP‐MS quantification of plasma amyloid peptides reached satisfactory analytical performance for clinical use. Its relevance for Alzheimer disease will be illustrated.
Care trajectories in a cohort of nursing home long‐stay residents with dementia, 2011‐2016
Authors: Xu Dongjuan , Arling Greg , Hass Zach
Published: December 2020

Background

Care transitions are very common among nursing home (NH) residents with dementia and many of these are deemed inappropriate or avoidable. The study aimed to identify the main care trajectories where NH residents with dementia were receiving care in a cohort from entry to death (or censoring).

Method

This is a retrospective cohort study of Minnesota NH residents with dementia. The study cohort consisted of 2,550 long‐stay residents (≥ 100 days) aged 65 years and older with a diagnosis of dementia who received NH care in Minnesota beginning at 2011. Monthly health care transitions for the cohort was tracked over a 60‐month period.

Result

We found four distinct trajectories among long‐stay NH residents with dementia over the 5‐year period were: 1) residents who died early with high hospitalization and ER visits (n = 967, 37.9%), 2) residents who died later and before death had high hospitalization and ER visits (n = 743, 29.1%), 3) residents who remained in NH (n = 643, 25.2%), and 4) residents who transferred from NH to community (n = 197, 7.7%). Relative to residents who remained in the NH (trajectory 3), residents who died early with high hospitalization and ER visits (trajectory 1) had the severest cognitive impairment, the highest level of depression, and the highest percentages of heart failure, renal failure, cancer, coronary artery disease, and lung disease. Residents who died later (trajectory 2) had the second severest cognitive impairment and the highest percentages of hip fracture and delirium. Residents who transferred to community (trajectory 4) had the best cognitive function and lowest percentages of hip fracture, cancer, lung disease and respiratory failure.

Conclusion

Residents in the cohort with more severe dementia and multiple comorbidities tended to die either early (trajectory 1) or later in their stays (trajectory 2). In both trajectories, the residents bounced back and forth between nursing facility, ER, and hospital before death. Findings point to the importance of advanced care planning and palliative care for the large percentage NH residents (67% in this study) who are at increased risk of multiple acute care transfers at the end of life.
Patient characteristics and treatment choice in a 65‐84 vs a ≥85 year old population with dementia‐related psychosis: Results from a secondary data claims study
Authors: Ramos Brett A. , Whitford Alex , Brain Cecilia
Published: December 2020

Background

Dementia affects approximately 8 million people in the US and about 2.4 million experience dementia‐related psychosis, i.e. hallucinations and delusions,1‐15 for which there is no approved treatment. Antipsychotics (APs) are routinely used “off‐label” and carry a box warning as they have been shown to increase the mortality risk in dementia16

Method

Criteria for identifying patients with dementia‐related psychosis leveraged the Anonymized Patient Level Data from IBM Truven, a widely utilized claims database, was evaluated for either 2+ ICD 9/10 diagnosis (Dx) OR 2+ prescriptions (Rx) related to Dementia AND Psychosis AND 1+ Dx for Dementia before the first psychosis Dx or Rx. Patients were then excluded based on 2+ Dx on the ICD excluded list (schizophrenia, bipolar, manic). Continuous enrollment criteria were applied in the 2 year washout period and index year within a 5 year study period. The patients were segmented based on age groups and key metrics were investigated to categorize the differences between the two age groups.

Result

The age group of ≥ 85 compared to the 65‐75 group, ran a significantly higher risk of cardiovascular disease, receiving APs, anti‐hypertensives, hypothyroid and diuretic drugs, despite fewer consultations with medical specialists (including psychiatrists); less brain imaging and fewer neurological diagnostics or hospitalizations yet they ran a higher risk of being admitted to inpatient ER, short‐term skilled nursing facilities and being transitioned to Long‐Term Care (LTC).

Conclusion

The ≥ 85 age group with dementia‐related psychosis were shown to have a higher comorbid disease burden and, despite an increased mortality risk in this vulnerable population, an even higher off‐label AP use compared to the 65‐75 year old group. Further studies are needed to explore the risks of AP use in this potentially sensitive elderly population of dementia‐related psychosis.
Creating dementia friendly community for social inclusion: A scoping review
Authors: Hung Lillian
Published: December 2020

Background

Social exclusion is commonly reported by people with dementia and their families. Dementia‐friendly community has emerged as an idea that holds potential to contribute to the mitigation of social exclusion. The objective of the scoping review is to identify strategies of creating dementia‐friendly communities that support people with dementia and their informal care providers.

Method

This scoping review follows the Joanna Briggs Institute scoping review methodology and takes place between March and May, 2020. The review included studies based in community settings with participants living at home with early to late stages of dementia and their families. It included a three‐step search strategy: (1) to identify keywords from CINAHL & AgeLine; (2) to conduct a second search using all identified keywords and index terms across selected databases (CINAHL, AgeLine, MEDLINE, PsycINFO, Web of Science, ProQuest and Google); and (3) to hand‐search the reference lists of all included articles and reports for additional studies.

Result

A total of 28 papers were included in the review. Content analysis identified strategies of creating dementia‐friendly communities: (a) active involvement of people with dementia and carers, (b) inclusive environmental design, (c) public education to reduce stigma and raise awareness, (d) customized strategies informed by dementia‐friendly and inclusive theories.

Conclusion

This scoping review provides an overview of current evidence on strategies that support dementia‐friendly communities for social inclusion. The findings offer insights to inform strategies for education, practice, policy and future research.
Longitudinal changes in established and exploratory cerebrospinal fluid biomarkers by PTAU/AΒ42 status in cognitively unimpaired adults
Authors: Van Hulle Carol A , Betthauser Tobey J , Jonaitis Erin M , Batrla Richard , Wild Norbert , Kollmorgen Gwendlyn , Andreasson Ulf , Bendlin Barbara B , Asthana Sanjay , Carlsson Cynthia M , Johnson Sterling C , Zetterberg Henrik , Blennow Kaj
Published: December 2020

Background

Characterizing longitudinal changes in AD and neurodegeneration related CSF biomarkers in cognitively unimpaired adults is critical to distinguishing typical aging from disease pathology, Yet longitudinal change in established and especially emerging CSF biomarkers are not well characterized. We examined linear age trends in CSF biomarkers for AD (Ab42, pTau), neurodegeneration (NFL, Neurogranin and α‐Synuclein) and glial activation (YKL40, GFAP, sTREM2, S100B) assayed using the Roche NeuroToolKit (NTK), a panel of automated prototype CSF immunoassays.

Methods

Analyses were based on a subsample of 146 cognitively unimpaired participants who underwent at least two lumbar punctures (total N=402). Cut‐offs for the ratio of pTau/Ab42 were determined using receiver operating characteristic curve analysis in a larger sample of impaired and unimpaired middle‐aged adults (N=167) treating a positive [C‐11]PiB visual rating as the standard of comparison. CSF analytes, plus ratios Ab42/Ab40 and pTau/Ab42, were fit to linear mixed models with random intercepts and slopes. Biomarker status (pTau/Ab42 +/‐) and covariates (gender, APOE4 status, years education) were entered as fixed effects. We also tested for moderation of age effects by biomarker status. P‐values were adjusted for the false discovery rate.

Results

Sample characteristics are shown in Table 1. Twenty participants were AD biomarker positive. We observed small but significant subject‐level variation in slopes for most analytes, including the core AD biomarkers, NFL, neurogranin, YKL40, and S100B. Biomarker status (pTau/Ab42) significantly predicted levels of AD related CSF biomarkers (Table 2), but not levels of neurodegeneration or glial activation related analytes. Ab42/Ab40, but not Ab42, levels significantly decreased over time; all other analytes increased over time with the exception of S100B (Figure 1). Changes in biomarker values over time was not moderated by baseline biomarker status for any of the CSF analytes (not shown).

Conclusion

Prior preliminary analyses (recreated in Figure 2) suggested that baseline values for biomarkers of neurodegeneration and glial activation are not related to core AD biomarkers until later in disease pathology. We have added to those findings, showing that among cognitively unimpaired individuals, significant longitudinal changes in both core AD‐related and emerging CSF biomarkers appear to be independent of early signs of joint amyloid and tau pathology.
A novel inducible complement C3 conditional knockout mouse model: Generation and characterization
Authors: Batista Andre Felipe , Schroeder Maren , Khan Khyrul , Yalcin Esra , Carroll Michael , Lemere Cynthia A
Published: December 2020

Background

The classical complement pathway is a complex process involved in the elimination of dead cells, debris, and pathogens, and as well as brain wiring during development. Complement protein C3 is an innate immune molecule central in the complement pathway. It participates in removing pathogens and eliminating synapses, and is elevated with aging and neurodegenerative diseases, including Alzheimer’s Disease. Previously, we showed that lifelong, germline C3‐deficiency protected aged male wild‐type and APPswe/PS1dE9 mice against hippocampal neuronal dysfunction and cognitive decline, despite increasing the Aβ plaque load. However, it remains unknown whether suppressing complement C3 signaling during early stages of AD pathogenesis, when relevant therapeutic interventions might be considered, would confer neuroprotection.

Method

To address this question, we generated the first‐ever C3 floxed (C3fl/fl) mouse line, and then crossed the C3fl/fl mice with an inducible, global Cre line (Rosa26‐Cre‐ERT2+/‐) for 2 generations to generate novel inducible C3 conditional knockout C3fl/fl; Rosa26‐Cre‐ERT2+/‐ mice. Mice aged 2‐3 months received intraperitoneal injections of either corn oil or tamoxifen (75 mg/kg) once a day for 5 consecutive days. We analyzed the C3 serum levels at 7, 14, 30, 60, and 90 days post‐tamoxifen treatment. We also analyzed the mRNA expression of complement C1q and C3 in the brain and liver 60 days following tamoxifen treatment.

Result

C3fl/fl;Rosa26‐cre‐ERT2+/‐ mice had a significant 70% reduction in serum C3 levels compared to controls, which was consistent at all timepoints analyzed. We also showed that C3 expression in the liver, the main source of complement proteins, as well as in the brain was reduced, demonstrating effective recombinase activity in these organs. Intriguingly, C1q mRNA expression was increased in the brain and liver following tamoxifen treatment; further studies are underway.

Conclusion

In conclusion, we present a novel mouse model in which tamoxifen treatment resulted in sustained lowering of C3 in the serum, liver, and brain. We will next cross this model with AD‐like mouse models of amyloidosis and tau pathology to evaluate whether global C3 lowering in early stages AD pathogenesis is protective and if so, our data would support targeting complement as a therapy for AD.
Driving performance and its correlation with cognitive tests in elderly drivers with cognitive impairments
Authors: Peng Zhouyuan , Kinoshita Ayae
Published: December 2020

Background

With the rapid aging of the population, the driving problem of dementia patients has caused increasing concerns among the government, researchers and the public worldwide1. We aim to investigate driving behaviors of elderly drivers with cognitive impairments using a driving simulator. And we are further interested in exploring the correlation between neuropsychological tests and driving performance.

Methods

Elderly subjects with driving experience who visited the outpatient neurology clinic in the Kyoto university hospital for cognitive complaints from July 2018 to December 2019 were investigated. Cognitive tests were carried out, as well as a questionnaire asking both demographic and driving characteristics. Participants who wished to continue driving were asked to complete the driving tests.

Results

A total of 45 participants were included in the study, ranged in age from 66 to 92 years, of which 57.8% were male. Slightly more than half of participants have returned their driving licenses whereas 20 still hold a valid driving license. Though current drivers had better cognitive functions than retired drivers, poor performance was found on reaction, starting and stopping, signaling, and general. The score of Mini‐mental state examination (MMSE), trail making test (TMT), block design test (BDT) and Alzheimer’s disease assessment scale–cognitive subscale (ADAS‐Cog) were correlated with reaction tests, especially TMT‐B, revealing a slightly higher correlation coefficients for the choice reaction test. MMSE, BDT and ADAS‐Cog had quite high correlation coefficients for sudden braking (ρ1=‐0.806, ρ2=‐0.727, ρ3=0.786, p<0.001). TMT‐B was associated with no signaling (ρ4=0.625, p<0.05) while clock drawing test (CDT) had a correlation with wrong signaling (ρ5=‐0.545, p<0.05). In addition, CDT also showed a negative correlation with going the wrong way (ρ6=‐0.655, p<0.05). MMSE and ADAS‐Cog were moderately correlated with lateral control (ρ7=‐0.620, ρ8=0.560, p<0.05).

Conclusions

Current elderly drivers had better cognitive functions, but a considerable part of them showed poor performance in the driving tests. Single cognitive tests were shown to have moderate to high correlations with specific driving maneuvers segmented from driving performance. Reference: Kim YJ, An H, Kim B, Park YS, Kim KW. An International Comparative Study on Driving Regulations on People with Dementia. J Alzheimers Dis. 2017;56(3):1007‐1014.
A family‐based genetic study identifies mutations in TLR9 impairing receptor activation: A role for innate immunity in AD pathogenesis
Authors: Cacace Rita , Hoogmartens Julie , Hens Elisabeth , Buist Arjan , Cras Patrick , Sieben Anne , Vandenberghe Rik , Engelborghs Sebastiaan , De Deyn Peter Paul , Martin Jean‐Jacques , Moechars Diederik , Van Broeckhoven Christine ,   BELNEU Consortium
Published: December 2020

Background

Family‐based genetic studies in early‐onset Alzheimer disease (EOAD), prompting early gene discoveries, remain powerful for the identification of novel genes in AD. Causal mutations in APP, PSEN1 and PSEN2 explained <10% of EOAD patients, while several EOAD families remained genetically unexplained. We identified a multigenerational Flanders‐Belgian family with autosomal dominant EOAD. DNA, biomaterials and clinical data from two consecutive informative generations were available: 5 AD patients (onset 64.2±13.2 years, range 52‐85) of which 2 with a definite neuropathological diagnosis and 9 unaffected/at‐risk individuals.

Method

Whole exome sequencing of 4 patients. Selection of shared rare non‐synonymous variants, validation of co‐segregation with disease and variants frequency assessment using massive parallel‐targeted sequencings (MPS). We used genotyping of STR markers to define haplotypes. Coding regions of candidate genes were sequenced using MPS in a Belgian cohort of 320 EOAD (onset 57.8±5.9y, range 33‐65) and 1166 late‐onset (LO)AD (onset 77.1±6.5y, range 66‐96) patients and a control cohort of 934 persons (inclusion 70.45±9.2y, range 52‐100). Variants pathogenicity was predicted using CADD scores cutoff>20. Evaluation of functional effects by NF‐κB luciferase assay.

Result

Three rare variants co‐segregated with AD in the family: CCR3 p.F249Hfs*23 (rs561062190), ZNF589 p.T355M (rs376706270) and TLR9 p.E317D (novel) and are located within a co‐segregating haplotype block of 15.3 cM at ch3p21. Only the TLR9 variant was absent in controls. TLR9 is a DNA‐sensing receptor expressed in immune cells, recognizes unmethylated CpG oligonucleodides and is responsible for innate immune cells activation and mounting acquired responses. The NF‐κB luciferase assay showed that p.E317D, located within the ligand sensor pocket of TLR9, caused a 50% reduction in receptor activation. TLR9 resequencing identified additional rare variants carriers: 7 in EOAD (7/320, 2.19%) and 19 in LOAD (19/1166, 1.63%) patients and 8 in controls (8/934, 0.86%), while TLR9 p.E317D was absent. Of the rare variants, 16 were in patient‐only, 3 in patients and controls and 5 in controls‐only. The NF‐κB luciferase assay indicated reduced TLR9 activation for the novel variants specific to EOAD patients and with a CADD score >20.

Conclusion

We discovered TLR9 as candidate gene in AD with a mechanism of loss of receptor activation.
Describing trends in the quality of health care and services for men and women living with dementia
Authors: Bui Tammy X , Arsenault‐Lapierre Genevieve , Sourial Nadia , Godard‐Sebillotte Claire , Rochette Louis , Vedel Isabelle
Published: December 2020

Background

As the Canadian population ages, challenges have emerged with the quality and healthcare utilization of services for persons living with dementia (PWD). These challenges may be exacerbated when we consider the sex inequalities. A disconcerting trend in sex differences has arisen among older adult women, where they are more disadvantaged compared to older men when seeking and receiving treatment. The aims of this study are to describe the quality of dementia care and healthcare utilization among PWD by sex.

Methods

The study will employ a repeated annual cross‐sectional cohort design over 15 years using linked administrative databases to examine health service use data. All incident cases of dementia in community‐dwelling persons aged 65 and over occurring between April 1st and March 31st for each year will be included. Dementia diagnosis will be ascertained using a validated algorithm. Quality of care indicators include: most regularly seen doctor (Overall UPC index), hospitalization for ambulatory care sensitive conditions, continuity of care (Bice‐Boxeman index), degree of coordination (30‐day hospital readmission). Healthcare utilization indicators include: emergency department visits, hospitalizations, alternate level of care, visits to primary care physicians and cognition specialists, long‐term care admission and mortality. Data will be stratified by sex.

Results

237,259 people (62.7% women) were included in the analyses. Variations over time and between men and women are observed in healthcare utilization indicators including emergency department visits, hospitalizations, alternate level of care, visits to primary care physicians and cognition specialists, long‐term care admission and mortality. For each indicator, graphs will be presented with an annual rate, adjusted for age and follow‐up time in the study.

Conclusion

Addressing the knowledge gap in the quality of care and healthcare utilization in PWD by sex is essential to inform decision‐makers for the implementation of adequate policies to promote equity in dementia care and ultimately improve the health among men and women living with dementia.
RNA aptamers that recognize amyloid β oligomers in AppNL‐G‐F/NL‐G‐F mice as a model of arctic Alzheimer disease
Authors: Murakami Kazuma , Obata Yayoi , Kawase Taiji , Hirose Kenji , Izuo Naotaka , Shimizu Takahiko , Irie Kazuhiro
Published: December 2020

Background

RNA aptamers have garnered attention for diagnostic applications due to their ability to recognize diverse targets. Oligomers of Aβ42 are among the most difficult molecules for aptamer recognition because they are prone to aggregate in heterogenous forms. In addition to designing haptens for in vitro selection of aptamers, the difficulties involved in determining their effect on Aβ42 oligomerization impede aptamer research. We previously developed three RNA aptamers (E22P‐AbD4, ‐AbD31, and ‐AbD43) with high affinity for protofibrils (PFs) derived from a toxic Aβ42 dimer (Murakami, K. et al., J. Biol. Chem.
2020, 295, 4870–4880). In this study, these aptamers were further validated for specificity to oligomers using ion‐mobility mass spectrometry and a knock‐in AppNL‐G‐F/NL‐G‐F
mouse harboring the Arctic mutation (E22G‐Aβ).

Method

The ability to inhibit oligomer formation of Aβ42 was evaluated by ion mobility‐mass spectrometry, which can avoid the disruption of non‐covalent interactions among Aβ oligomers without using organic solvents, leading to observation of the near‐native status of oligomers in the presence of aggregation inhibitors. The immunostaining of Aβ oligomers in the brain was carried out using a knock‐in AppNL‐G‐F/NL‐G‐F
mouse that is prone to induce PF formation as a Arctic AD model, provided by Dr. Saido (RIKEN). The prediction of G‐quadruplex was estimated based on quadruplex‐forming G‐rich sequences (QGRS) Mapper.

Result

RNA aptamers recognized diffuse aggregates, which likely originated from PFs in a knock‐in AppNL‐G‐F/NL‐G‐F
mouse in addition to a PS2Tg2576 mouse. E22P‐AbD43 formed the adducts with Aβ42 monomer and dimer, leading to suppression of further oligomerization. In particular, the G‐quadruplex structure might be relevant to the binding of the aptamers (E22P‐AbD4 and ‐AbD31) to oligomers.

Conclusion

The current data support the utility of these RNA aptamers as a promising diagnostic tool for AD research.
Relationship of parieto‐occipital brain energy phosphate metabolism and cognition using 31P MRS at 7TESLA in preclinical stages of Alzheimer’s disease
Authors: Das Namrata
Published: December 2020

Background

Neuroenergetics, a study of brain energy metabolism (BEM), may uncover cues for early disease biomarkers that potentially trigger downstream neuropathological changes in amnestic mild cognitive impairment (aMCI), a transitory stage of Alzheimer’s disease (AD). Advancements in brain imaging modalities, such as in vivo 31phosphorus magnetic resonance spectroscopy (31P MRS) at higher magnetic strength, offer promising platforms to measure energy and membrane phospholipid metabolites, a window to understand BEM. The primary goal was to quantify distinct features of phosphorus metabolites in parieto‐occipital lobes using 31P MRS at 7Tesla in aMCI. Another objective was to examine the clinical significance of the metabolites to brain‐behavior relationships. Specifically, we examined the correspondence across BEM and membrane phospholipid indices in parieto‐occipital regions of the brain with cognitive performance‐ executive functions (EF), memory, attention, and visuospatial skills.

Methods

19 aMCI participants enrolled in the study. Each participant completed a cognitive assessment and a scan using partial volume‐coil 31P MRS over parieto‐occipital lobes at 7Tesla. BEM indices were measured using three energy indicators: energy reserve (PCr/t‐ATP), energy consumption (intracellular_Pi/t‐ATP), and metabolic state (PCr/intracellular_Pi) along with regulatory co‐factors of BEM‐intracellular Mg2+ and pH; whereas the ratio of phosphomonoesters (PMEs) to phosphodiesters (PDEs) represented membrane phospholipid indicator.

Results

31P MRS data over parieto‐occipital lobes showed thirteen well‐resolved peaks of the energy and membrane phospholipid metabolites at 7Tesla. The higher BEM indices were associated with lower cognitive performance of memory [(energy reserve indicator: CVLT p=0.004), (metabolic state indicator: CVLT p=0.007)], executive function [(metabolic state indicator: TOSL (p=0.044)], and attention [(pH: selective auditory task, p=0.044)]. The finding of higher brain energy indices in the parieto‐occipital lobes associated with lower cognition may represent compensatory hypermetabolism during the early stages of brain disturbances in aMCI.

Conclusion

The critical contribution of this work was to develop and test a methodology to quantify neurometabolic markers of energy and membrane phospholipid metabolites at 7Tesla in aMCI. Additionally, the study findings implicated the role of BEM as an early neurometabolic marker of brain changes linked to cognitive decline in the preclinical stages of AD.
Transcranial detection of tauopathy in vivo in P301L mice with high‐resolution large‐field multifocal illumination fluorescence microscopy
Authors: Ni Ruiqing , Chen Zhenyue , Gerez Juan A , Shi Gloria , Zhou Quanyu , Riek Roland , Nilsson K Peter R , Razansky Daniel , Klohs Jan
Published: December 2020

Background

Tau abnormal aggregates have been visualized in‐vivo using intravital microscopy techniques with high resolution, but are limited to a small field‐of‐view and depth. Here, we report a new method for the transcranial detection of tau deposits accross the brain with 6 μm resolution.

Method

In vitro Thioflavin T fluorescence assay was performed to screen fluorescence imaging probes that bind to tau fibrils. P301L (Thy1.2) mouse models of frontal temporal lobe dementia with four repeat tau and non‐transgenic littermates were imaged in vivo using a novel large‐field multifocal illumination (LMI) fluorescence microscopy technique using luminescent conjugated oligothiophenes h‐FTAA. Immunohistochemical staining were performed on P301L mouse brain tissue sections using anti‐phosphorylated tau antibodies AT8 and AT100.

Result

In vitro Thioflavin T fluorescence assay and LMI imaging shows that h‐FTAA bind to recombinant full‐length tau fibrils. In vivo LMI imaging using h‐FTAA showed higher retention in the cortex of P301L mice at 10 month‐of‐age compared to age‐matched non‐transgenic littermates. Immunohistochemical staining on P301L mouse brain tissue sections showed co‐localization of h‐FTAA with anti‐phosphorylated tau antibodies AT8 and AT100, thus verifying the specificity of the probe to tauopathy in P301L mice.

Conclusion

We demonstrate a new in vivo high‐resolution imaging platform for detection of tauopathy in murine models of frontal temporal lobe tauopathy.
Microglial senescence: The missing link between hypertension and neurodegeneration?
Authors: Al‐Shama Rushd , Naessens Daphne MP , van Bavel Ed , Bakker Erik NTP
Published: December 2020

Background

Hypertension is a major risk factor for dementia. Hypertension is associated with neuroinflammation and neurodegeneration, however, the exact link is unclear. Microglia can undergo senescence, resulting in primed and dystrophic cells that can contribute to the development of Alzheimer’s disease. We hypothesized that microglia are affected by cumulative hypertensive brain injury and reflect an ongoing inflammatory and neurodegenerative pathology.

Method

An in‐depth immunohistochemical analysis of microglia was done on the brains of Spontaneously Hypertensive Rats (SHR) and their genetic controls, Wistar Kyoto rats (WKY); n=5 each. The number of cells and morphological features, such as size, number of branches, and branch length, were measured. We qualitatively assessed microglia for the presence of characteristic dystrophic cells then performed fractal analysis on individual cells to quantitate their morphologies.

Result

SHR microglia were more numerous and exhibited signs consistent with senescence and priming, with shorter, fewer branches and the sizes of their cell bodies were larger and more heterogeneous (p<0.05). In SHR, 2.91% of microglia were dystrophic as compared to 0.32% in WKY (p=0.01). Using fractal analysis, we confirmed the presence of dystrophic cells and distinctly characterized them against ramified cells based on 3 main characteristics: complexity, shape, and branching.

Conclusion

Microglial senescence, an indicator of neuroinflammation and neurodegenerative pathology, is associated with hypertension. It could thus serve as a therapeutic target and may help identify novel biomarkers. Moreover, fractal analysis is a useful tool to quantify meaningful subtleties.
Hypertension produces a cumulative negative effect on cognition independently of diabetes in late life
Authors: Moll Allison C. , Woodard John L.
Published: December 2020

Background

Hypertension impacts approximately 33% of US adults broadly, and specifically 65% of persons over 60 years of age. Previous research has shown that hypertension produces damage in cerebral blood vessels, leading to neuropathological changes and possibly promoting Alzheimer’s disease pathology. Hypertension is often comorbid with diabetes mellitus (DM). While most studies show an association of hypertension and DM with worse cognition, the time course of emerging cognitive deficits related to hypertension in late‐life is less clear. This study contrasted older adults with and without self‐reported hypertension and diabetes at two time points in late‐life (MBaseline age
=64.3 years, SD1
=0.7; MFollow‐up age
=71.2 years, SD2
=0.9), separated by approximately seven years.

Methods

Participants included 4,594 1957 high school graduates from the Wisconsin Longitudinal Study, a publicly available database that includes high school graduates who were followed longitudinally until 2011. Cognitive, demographic, and health variables from the 2003‐2005 (baseline) and 2011 (follow‐up) waves were used. Cognitive assessment included Letter Fluency, Category Fluency, Digit Ordering, Similarities, and Immediate and Delayed Recall of a 10‐word list. Bayesian independent t‐tests examined the effect of self‐reported hypertension on cognition at baseline and follow‐up, as well as the effect of self‐reported hypertension on cognition in persons with and without diabetes.

Results

Self‐reported hypertension over seven years was associated with worse Digit Ordering and Letter and Category Fluency performance at follow‐up, relative to persons without self‐reported hypertension. No baseline cognitive differences were observed between groups. Participants with self‐reported hypertension showed greater decline in Letter Fluency and Digit Ordering compared to persons without self‐reported hypertension. Diabetes negatively impacted cognition at baseline, follow‐up, and over the seven‐years. However, the negative effect of hypertension on cognition was still present in the absence of diabetes.

Conclusions

While no cognitive differences between persons with and without hypertension in their mid‐60s were observed, cognitive decline in persons with self‐reported hypertension was observed over seven years. These findings suggest a cumulative negative impact of hypertension on cognition, particularly in late‐life, exclusively on measures of executive functioning rather than on episodic memory measures. Additionally, the effects of hypertension on cognition were independent of the cognitive effects of diabetes.