bluuebunny/crossref_metadata_2025_split huggingface dataset:
A head‐to‐head comparison of plasma phosphorylated tau assays in the real‐world memory clinic
Authors: Suárez‐Calvet Marc , Ashton Nicholas J. , Puig‐Pijoan Albert , Milà‐Alomà Marta , Fernández‐Lebrero Aida , García‐Escobar Greta , González‐Ortiz Fernándo , Kac Przemyslaw Radoslaw , Brum Wagner Scheeren , Benedet Andréa Lessa , Rodriguez Juan Lantero , Day Theresa A. , Dage Jeffrey L. , Vanbrabant Jeroen , Stoops Erik , Vanmechelen Eugeen , Triana‐Baltzer Gallen , Moughadam Setareh , Kolb Hartmuth C. , Ortiz‐Romero Paula , Karikari Thomas K , Minguillón Carolina , Sánchez Juan José Hernández , Navalpotro‐Gómez Irene , Grau‐Rivera Oriol , Manero Rosa María , Puente‐Periz Víctor , de la Torre Rafael , Roquer Jaume , Zetterberg Henrik , Blennow Kaj 
Published: December 2022

AbstractBackgroundSeveral blood phosphorylated tau (P‐tau) species (P‐tau181, P‐tau217, and P‐tau231) have shown high accuracy to detect AD pathology, but a direct comparison of the main blood P‐tau assays in a real‐world memory clinic is needed. The main aim of this study is to perform a head‐to‐head comparison of 9 plasma Tau assays and determine their accuracy to discriminate between symptomatic AD from non‐AD.MethodThis is an observational and cross‐sectional study in the BIODEGMAR cohort, which includes patients presenting with cognitive complaints at the Cognitive Decline and Movement Disorders Unit of Hospital del Mar (Barcelona, Spain). Patients were classified into an AD CSF profile group or a non‐AD CSF profile group according to their CSF Aβ42/P‐tau181 ratio (Lumipulse, Fujirebio), and the discrimination accuracy of 9 plasma Tau assays was tested. All plasma samples were treated identically and measurements were performed in a blinded fashion.ResultA total of 197 participants (109 women [55.3%]; mean [SD] age, 72.3 [5.83] years), were investigated. All plasma Tau biomarkers were significantly higher in the AD CSF profile group than in the non‐AD CSF profile group. For plasma Tau biomarkers, the largest effect sizes were found in plasma Janssen P‐tau217 (r = 0.76), Lilly P‐tau217 (r = 0.73), ADx P‐tau181 (r = 0.73), Lilly P‐tau181 (r = 0.68), and UGot P‐tau231 (r = 0.63). All plasma Tau biomarkers significantly discriminated between patients with an AD CSF profile group from those with a non‐AD CSF profile. The AUC of plasma Tau biomarkers were the following (from highest to lower): Janssen P‐tau217 (0.96; 95% CI, 0.93‐0.99), ADx P‐tau181 (0.94; 95% CI, 0.91‐0.97) and Lilly P‐tau217 (0.94; 95% CI, 0.90‐0.98), Lilly P‐tau181 (0.91; 95% CI, 0.87‐0.96), UGot P‐tau231 (0.88; 95% CI, 0.83‐0.93), Quanterix P‐tau181 (0.80; 95% CI, 0.73‐0.87), UGot P‐tau181 (0.80; 95% CI, 0.73‐0.87), Lilly Total‐tau (0.73; 95% CI, 0.65‐0.81), and ADx P‐tau231 (0.66; 95% CI, 0.58‐0.74).ConclusionThe findings indicate that there are several plasma P‐tau biomarkers that can be used in a memory clinic setting as a stand‐alone biomarker to detect AD pathology in a diverse group of patients presenting with cognitive complaints.
Validity of a contactless device for long term monitoring of sleep in a heterogenous group of older men and women
Authors: Ravindran Kiran K.G. , Monica Ciro della , Atzori Giuseppe , Lambert Damion , Revell Victoria Louise , Dijk Derk‐Jan 
Published: December 2022

AbstractBackgroundThe incidence of sleep disturbances increases with normal aging and is highly prevalent among people living with dementia (PLWD). To facilitate management and improvement of sleep quality in PLWD, validated unintrusive contactless technologies for long term objective monitoring of sleep are needed. Here we evaluate the ability of a contactless sleep tracker to accurately determine Time in Bed (TIB), Wake vs Sleep and Sleep stages (wake, light, deep, and REM sleep).MethodWe deployed the Emfit (Emfit QS), a contactless sleep tracker placed under the mattress. The Emfit uses ballistography to estimate respiration and heart rate and sleep stages. We collected data from 16 participants (Age: Mean‐72.12; SD‐4.6 years [6F:10M]) at home for a 14‐day period followed by a single overnight laboratory polysomnography (PSG) sleep assessment. The Emfit outputs a) timeseries at 30 s intervals (four sleep stages) and b) overnight summary sleep parameters. Sleep staging and sleep parameter estimation by Emfit was compared to, a) in‐lab gold standard PSG, and b) at‐home wristworn accelerometer (Actiwatch spectrum (AWS)) and sleep diary (SD) data. The epoch‐to‐epoch sleep staging concordance of Emfit was estimated over the total recording interval (∼10hrs) of the PSG for the laboratory session and between 1800hrs and 1200hrs for each SD entry for the home recordings. The concordance analysis for the sleep parameters, bed entry and exit times were performed using the summary data automatically generated by Emfit.ResultThe concordance between the four‐class sleep staging of the Emfit and PSG was poor (Figure 1). The two class (sleep/wake) analysis (Table 1) showed high sleep classification accuracy (sensitivity) but poor wake classification accuracy (specificity) compared to PSG. The sleep parameter estimates of Emfit also showed poor agreement with PSG (Figure 2). The home analysis indicated excellent accuracy for Time in Bed (TIB) (i.e., the bed entry and exit times) as registered by the SD (Table 2) and total sleep time (TST) for both sleep diary and AWS (Figure 3).Conclusion: The contactless sleep tracker provides accurate information about Time in Bed (TIB), but there is a lack of consensus of the sleep state classification with the PSG.
CSF proteome profiling reveals novel specific diagnostic biomarkers for Dementia with Lewy bodies
Authors: Campo Marta Del , Vermunt Lisa , Peeters Carel F.W. , Hok Yanaika S. , Lleó Alberto , Alcolea Daniel , van Nee Mirrelijn , Chen‐Plotkin Alice , Irwin David J. , van der Flier Wiesje M. , Lemstra Afina W. , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundDiagnosis of dementia with Lewy bodies (DLB) remains challenging and biomarkers discriminating DLB from Alzheimer’s disease (AD) are highly needed. We aimed to establish the specific cerebrospinal fluid (CSF) proteomic changes that underlie DLB and to identify translatable diagnostic biomarkers.MethodsProximity extension‐based multiplex immunoassays were used to measure 665 proteins in 534 CSF samples from patients with Dementia with Lewy bodies (n=109), AD‐dementia (n=235) and cognitively‐unimpaired controls (CON, n=190) from the Amsterdam Dementia cohort (ADC) and Penn University. An additional multicenter cohort (n=307) from ADC and SPIN was used for validation of custom assays. A positive/negative AD CSF profile supported the diagnosis of AD and CON respectively.ResultsNested linear models identified 97 CSF proteins with altered abundance in DLB compared to controls (p<0.05). After comparison with the AD CSF proteome, we observed that 52 of these proteins (54%) were especially associated to DLB (e.g. DDC, GH, FCER2, MMP1), while 15 proteins (16%) showed opposite changes to those detected in AD patients (CRH, MMP3). The protein with the highest fold‐changed observed in DLB was L‐amino acid decarboxylase (DDC; >1.5 fold‐change vs.CN or AD; q<1E‐16), an enzyme involved in dopamine biosynthesis. DDC could optimally discriminate DLB from controls and AD patients (AUC: 0.91 and 0.81 respectively). Using penalized generalized linear modelling we identified a panel of 7‐CSF markers including DDC that could discriminate DLB from AD patients with high accuracy (AUC: 0.93, 95%CI: 0.86‐0.98), which have been successfully translated into customized multiplex assays (correlations > 0.84 with discovery measurements).ConclusionsWe unveil CSF changes specifically related to DLB and identified a panel of 7‐CSF markers associated to several aspects of DLB pathophysiology that enables discrimination of these dementia types with high accuracy. Multiplex custom assays containing these markers are currently being clinically validated in independent cohorts for their potential use in diagnostic settings or clinical trials.
Sedation‐associated medications at dementia diagnosis, their receptor activity, and associations with adverse outcomes in a large clinical cohort
Authors: Mbazira Agnes , Bishara Delia , Perera Gayan , Rawlins Elizabeth , Webb Silas , Archer Matthew , Balasundaram Bharathi , Shetty Hitesh , Tsamakis Konstantinos , Taylor David , Sauer Justin , Stewart Robert , Mueller Christoph 
Published: December 2022

AbstractBackgroundWe aimed to investigate whether sedative medications are associated with adverse outcomes in people with dementia, and whether specific characteristics of these medications predict a higher risk of harm.MethodA retrospective cohort study was carried out of 15,210 patients diagnosed with dementia between 2008 and 2017 in South London. From recorded medications at dementia diagnosis, we ascertained those with drowsiness listed as a side effect (termed ‘sedative’ hereafter) and subdivided them by frequency and strength of sedation, receptor profile, half‐life and whether they were psychotropics. Multivariable Cox regression models were applied to determine risk of mortality and emergency hospitalisation, and generalised estimating equations to investigate cognitive decline. Final models were adjusted for 19 potential confounders, including measures of physical and mental health, functioning and central anticholinergic burden.ResultAt diagnosis 70.4% of patients with dementia were receiving at least one sedative medication. Median survival time was 4.0 years and median time to first hospitalisation 1.4 years. After controlling for potential confounders, receipt of any sedative medication at dementia diagnosis was associated with accelerated cognitive decline and a higher hospitalisation risk, but only medications with a cautionary warning yielded an increased mortality hazard. Medications acting through gamma‐aminobutyric acid agonism, psychotropic sedatives and those with a short half‐life were associated with a higher risk of mortality. Gamma‐aminobutyric acid agonists, N‐methyl‐D‐aspartate receptor antagonists and non‐psychotropic sedatives were associated with an increased hospitalisation risk. Alpha‐1 antagonist, antihistamines, N‐methyl‐D‐aspartate receptor antagonists, psychotropic sedatives, and those with shortest or longest half‐life were associated with accelerated cognitive decline.ConclusionReceipt of any sedative agent was associated with hospitalisation and accelerated cognitive decline. Differences in hazard appear to exist between frequency/strength of sedation, receptor profiles, half‐life, and prescribing indication. These differences should be taken into consideration in medication reviews at the time of dementia diagnosis.
Psychosocial Correlates and Perceived Needs of Family Caregivers of Persons Living with Dementia in India.
Authors: Vasanthra Cicil R , Thirumoorthy A , Antony Sojan , Prasad Krishna , Rao Girish N , PT Sivakumar 
Published: December 2022

AbstractBackgroundIn India, caregivers of persons living with dementia (CGPwD) often have limited access to dementia care resources. The aim of the study is to understand and deliver psychosocial interventions based on the perceived needs of the CGPwD in accordance with their socio‐cultural background and clinical characteristics of the persons with Dementia (PwD).MethodA sample of 32 CGPwDs attending a Dementia clinic at the NIMHANS, India, between July 2021 – October 2021 was chosen purposively. Cross‐sectional in‐depth interviews were carried out along with Zarit Burden Interview, (Zarit et al., 1980) and Hindi Mental Status Examination (Ganguli et al., 1995).ResultThe mean age of the CGPwD was 42.5 ± 8.5 years with MMSE score 9±7 indicating moderate to severe dementia. Those caregivers who spent more than 6 hours per day towards day‐to‐day caregiving brought out need for information about the illness seeking clarity about mental health care, support in Activities of daily living (ADLs), managing behavioural and psychological symptoms of Dementia (BPSD) and sharing of caregiver responsibilities, whilst those caregivers who took health related decisions for the PwD where concerned about problems associated with instrumental activities of daily living (iADLs), availability and affordability of caregiving resources such as day care, assisted living options, welfare services. Further results will be presented.Conclusion: The perceived needs of CGPwD vary based on severity of illness, socio‐economic status of the CGPwD, age of onset of illness, social support network, relationship between the caregiver and person living with Dementia, spiritual values, readiness to participate in support programs, and much more. Though mental health professionals can develop broader themes for intervention, individualised interventions may warrant poor rates of attrition.
References
Zarit, S. H., Bach‐Peterson, J., & Reever, K. E. (1980). Burden interview. The gerontologist.Ganguli, M., Ratcliff, G., Chandra, V., Sharma, S., Gilby, J., Pandav, R., … & Dekosky, S. (1995). A Hindi version of the MMSE: the development of a cognitive screening instrument for a largely illiterate rural elderly population in India. International Journal of Geriatric Psychiatry, 10(5), 367‐377.
The Role of Sigma‐1‐Receptor in Endoreticulum Stress and Alzheimer's Disease.
Authors: Nguyen Thinh , Flemming Kayla , Chudalayandi Prakash , Bergeron Richard 
Published: December 2022

AbstractBackgroundOne evident hallmark of Alzheimer's Disease (AD) is the irregular accumulation of proteins such as Aβ and pTau. This accumulation could alleviate ER stress and trigger an integrated signaling cascade called the unfolded protein response (UPR). UPR reduces the number of misfolded proteins and further inhibits abnormal protein accumulation. Targeting ER stress may therefore be an effective treatment for AD. One protein of interest that plays a role in modulating ER stress is the Sigma‐1 receptor (Sig1R). Sig1R agonists have been shown to be neuroprotective and anti‐amnesic in AD mouse models. However, the mechanism of action remains largely unknown.MethodIn our study, we use primary MEF cells derived from Wild‐type and Knock‐out Sig1R mouse models to examine the role of Sig1R in ER stress. We treated cells with an acute ER stressor, DTT, and measured transcript levels of target genes under the UPR branches. Furthermore, we used Chromosomal Immunoprecipitation (ChIP) to identify regulators of SIG1R gene during stress.ResultWe observed that the loss of Sig1R compromised the PERK pathway. KO MEFs had a slow recovery from stress suggesting Sig1R plays a role in re‐establishing homeostasis following stress. Following DTT treatment, mRNA and protein levels of Sig1R increase significantly over the course of recovery. ChIP uncovered three CHOP, a major player in the UPR, binding sites within the promoter of SIG1R, and each site had a distinct temporal binding pattern over the course of cell recovery. This increase in binding correlates with an increase in Sig1R expression. This showed that Sig1R is a chaperone downstream of CHOP, and that the up‐regulation of Sig1R might be crucial in re‐establishing homeostasis. Finally, our imaging data showed an increase in localization of Sig1R with extracellular vesicles. We further hypothesized that the high expression of Sig‐1R may have a role in the removal of misfolded proteins, perhaps Aβ. Therefore, we have ongoing experiments looking at the effect of Aβ on our models.ConclusionOur study has the potential to unravel the implications of Sig1R in AD by showing that it is transcriptionally and translationally regulated in response to stress induced by misfolded proteins.
The novel FKBP51‐Hsp90 interaction inhibitor attenuates high‐fat diet induced cognitive impairment
Authors: Wang Lisha , Wojcieszak Jakub , Kumar Rajnish , Pavlov Pavel F. , Winblad Bengt 
Published: December 2022

AbstractBackgroundObesity increases the risk of several chronic diseases, such as type 2 diabetes mellitus, insulin resistance, and Alzheimer disease. As one of the co‐chaperones of heat shock protein 90 (Hsp90), FK506‐binding protein 51 (FKBP51) is an important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet‐induced obesity, exhibit elevated glucose and insulin tolerance and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51‐Hsp90 interactions. Previous study has shown that our inhibitors can dose‐dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH‐SY5Y cells. This study aims to investigate the potential roles of our inhibitors on metabolic and cognitive dysfunction in vivo.MethodsPharmacokinetic studies have been performed at first. Plasma and brain samples were collected and analyzed by liquid chromatography‐mass spectrometry. Male C57BL/6J mice were fed either the control or high‐fat diet (HFD) for 4 weeks and then treated with vehicle or inhibitor E8 (20 mg/kg, s.c.) and their respective diets for another 4 weeks. Behaviors, body composition measuremnets by EchoMRI, fasting glucose/insulin detections and glucose/insulin tolerance tests were performed during the last week. Hippocampus was collected for western blot, RNA sequencing and quantitative real‐time PCR analysis.ResultsAfter subcutaneous injection, E8 can be quickly absorbed into the blood and penetrate the blood‐brain barrier. In HFD model, E8 can attenuate the impairment of locomotor activity and short‐term memory. But it could neither reduce body weight gain nor improve insulin sensitivity and glucose/insulin tolerance. In the hippocampus, E8 reduces the elevated p‐tau (Ser214)/tau levels induced by HFD but does not show any effects on insulin signaling. It suggests that E8 reverses the behavioral impairments independently of metabolic regulation in vivo. The underlying mechanisms were further investigated by RNA sequencing and quantitative real‐time PCR analysis.ConclusionWe showed that inhibiting FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets on cognitive dysfunction in obesity.
Tau Loss of Function, by Deletion or Aggregation, Contributes to Peripheral Insulin Resistance
Authors: Al‐Lahham Rabab , Mukherjee Abhisek , Dinamarca Nicolas Mendez , Banerjee Victor , Soto Claudio 
Published: December 2022

AbstractBackgroundEpidemiological association between Alzheimer’s disease (AD) and type 2 diabetes is a critical health concern that has not been resolved yet at the molecular mechanistic level. While brains of AD patients and AD transgenic mouse models display impaired insulin signaling, there is no clear understanding of the role of peripheral insulin resistance in the pathogenesis of AD. Moreover, alterations in key insulin signaling proteins have been also implicated in AD, among which GSK‐3β, is also one of the important kinases for the phosphorylation of the microtubule‐associated protein tau (tau), one of the pathological hallmarks of AD. The goal of this study is to determine the role of systemic insulin resistance in the pathophysiology of AD by testing the hypothesis that functional tau is important for peripheral insulin sensitivity, and its deletion or loss‐of‐function promotes peripheral insulin resistance.MethodPrimary hepatocytes were isolated from transgenic mouse models (P301L, tau KO), and wild type mice (C57BL/6), and their insulin sensitivity was assessed by an insulin challenge, using biochemical analysis of insulin signaling markers, and glucose uptake assays. To confirm the involvement of tau, we treated wild type hepatocytes with tau aggregates and investigated their effect on insulin sensitivity. To investigate the involvement of p38 MAPK, a stress‐response protein, we pre‐treated wild type hepatocytes with a pharmacological inhibitor of p38 prior to tau aggregates treatment.ResultWe found that tau deletion or loss‐of‐function promotes peripheral insulin resistance as seen by the inhibition of insulin signaling proteins and the reduction of glucose uptake into primary hepatocytes isolated from tau KO and P301L mice, respectively. We also found that sub‐toxic exposure of wild‐type primary hepatocytes to tau aggregates resulted in inhibition of insulin signaling and glucose uptake, in a dose‐dependent manner. Our data also show that p38 MAPK may be involved in tau aggregates‐induced inhibition of insulin signaling.ConclusionThis is the first study testing the potential role of tau in peripheral insulin resistance at the cellular level using multiple mouse models. Our findings suggest that functional tau is required for insulin sensitivity, therefore, any loss‐of‐function by aggregation or deletion would result in insulin resistance.
Comparison of the Telephone‐Montreal Cognitive Assessment (T‐MoCA) and Telephone Interview for Cognitive Status (TICS) as Remote Screening Tests for Early Alzheimer’s Disease.
Authors: Chappelle Sheridan D. , Gigliotti Christina , Leger Gabriel C. , Peavy Guerry M. , Jacobs Diane M. , Banks Sarah J , Little Emily A , Galasko Douglas R. , Salmon David P. 
Published: December 2022

AbstractBackgroundThe number of Americans with Alzheimer’s disease (AD) is expected to rise to nearly 14 million by 2060. This alarming number shows a critical need for brief mental status tests that can be administered remotely (e.g., by telephone or videoconferencing) to large numbers of individuals while maintaining the ability to reliably detect cognitive impairment related to AD. Therefore, we sought to validate a recently developed, remotely administered cognitive screening measure, the T‐MoCA, against an established remote measure, the TICS, and prior in‐person clinical and cognitive assessment that provided clinical diagnosis. Relationships with CSF biomarkers of AD were also examined.MethodsThe TICS and T‐MoCA were completed approximately one‐week apart by 215 participants at the UCSD ADRC. Test order was partially counterbalanced. Extensive in‐person clinical and neuropsychological assessment had been completed on average 1.5 years prior and participants classified as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25) or dementia (n = 23). CSF had been obtained from 79 participants within 48 months of remote testing and levels of Aβ 1–40 and 1–42, phosphorylated tau (p‐tau), and total tau were measured.ResultsTICS and T‐MoCA scores were highly correlated overall (r = .787;p<.001), and moderately within specific MCI (r = .657;p<.001) and dementia (r = .673,p = .001) groups (r = .309, p<.001 for CN only). Groups differed significantly on TICS (F(2,212) = 156.66;p<.001) and T‐MoCA (F(2,210) = 143.72;p<.001), with dementia<MCI<NC on both (p’s<.001). TICS and T‐MoCA had excellent ability to discriminate CN from cognitively impaired (i.e., MCI/dementia) with ROC areas under the curve of .889 and .902, respectively. Optimal cut‐off scores were <17/22 for T‐MoCA (90.4% sensitivity, 76.6% specificity) and <34/41 for TICS (91.0% sensitivity, 74.5% specificity). A composite CSF biomarker of AD (total tau/Aβ 1–42 ratio) was negatively correlated with TICS (r = ‐.372;p = .001) and T‐MoCA (r = ‐.480;p<.001).ConclusionThe T‐MoCA and TICS are valid brief cognitive screening tests with remote administration that can distinguish individuals with cognitive impairment from those who are cognitively normal. The two tests have similar discriminative ability and degree of association with levels of AD biomarkers in CSF. Thus, the T‐MoCA and TICS are promising measures to meet the growing need for remote cognitive screening for AD.