bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of synaptic density and glucose metabolism with cognitive performance in early Alzheimer's disease: a PET imaging study with [11C]UCB‐J and [18F]FDG
Authors: O'Dell Ryan S. , Mecca Adam P , Waszak Julia , Sharp Emily , Chen Ming‐Kai , Naganawa Mika , Toyonaga Takuya , Lu Yihuan , Chupak Anna , Cooper Emma , Lam Jessica , Miller Alyssa , Waldner Emma , Weibley Hannah , Zhao Yize , Nabulsi Nabeel B. , Huang Yiyun , Arnsten Amy F. T. , Carson Richard E. , van Dyck Christopher H 
Published: December 2022

AbstractBackgroundTraditionally, [18F]FDG PET has been used in Alzheimer’s disease (AD) as a surrogate marker of disease progression and is highly correlated with cognitive and functional decline. Synaptic loss is an early pathological event and a major structural correlate with cognitive impairment, although this is based on limited post‐mortem studies at more severe disease stages. Recently, we have confirmed these neuropathologic studies in vivo, using [11C]UBC‐J PET to demonstrate significant correlations between synaptic density and cognitive performance in early AD. In this study, we examined the relationship between synaptic density, glucose metabolism, and cognitive performance in early AD using [11C]UCB‐J PET, [18F]FDG PET, and an extensive neuropsychological battery.Method[11C]UCB‐J and [18F]FDG binding was measured in 46 amyloid+ participants with AD (18 aMCI and 28 mild dementia) and 17 amyloid‐ cognitively normal participants aged 50‐85 years. Synaptic density was calculated as DVR and glucose metabolism as SUVR in a composite of AD‐affected regions, using a whole cerebellum reference region for both tracers. A validated neuropsychological battery assessed performance across six cognitive domains. Domain scores were calculated for each participant by averaging z‐scores within that domain, and global cognition scores averaged the domain scores.ResultIn a multiple linear regression model controlling for age, sex, and education, glucose metabolism was a stronger predictor of global cognitive performance compared to synaptic density in participants with AD (beta=2.90,eta2=0.38,P=0.000005 vs. beta=2.48,eta2=0.22,P=0.001), as well as executive function, language, processing speed, visual memory, and visuospatial ability. Synaptic density was a stronger predictor of verbal memory compared to glucose metabolism (beta=1.68,eta2=0.22,P=0.001 vs. beta=1.02,eta2=0.10,P=0.03). Using William’s tests, exploratory analyses demonstrated stronger correlations between medial temporal synaptic density and performance across all cognitive domains. In neocortical ROIs, glucose metabolism was more strongly correlated with cognitive performance across all domains with the exception of verbal memory, which demonstrated stronger correlations with synaptic density across all analyzed ROIs.ConclusionConsistent with a hypothesis of divergent synaptic loss and hypometabolism in early AD, these results demonstrate synaptic density is more strongly correlated with cognitive decline in medial temporal regions, while cerebral hypometabolism is more strongly correlated with cognitive decline in neocortical regions.
Biomarkers and clinical presentations in Creutzfeldt‐Jakob Disease
Authors: Shir Dror , Lazar Evelyn , Graff‐Radford Jonathan , Aksamit Allen , Cutsforth‐Gregory Jeremy , Jones David T. , Botha Hugo , Ramanan Vijay K , Prusinski Christian C , Porter Amanda , Day Gregory S 
Published: December 2022

AbstractBackgroundThe ability to detect malformed prion proteins using real‐time quaking‐induced conversion (RT‐QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt‐Jakob disease (CJD), facilitating earlier recognition of affected patients. Recognizing this, we evaluated the frequency of clinical features and biomarker results at initial evaluation in patients with CJD and determined the relationship between these early features and CJD diagnosis and prognosis.MethodClinical data were extracted from the electronic medical records of patients with probable or definite (pathologically confirmed) CJD assessed at Mayo Clinic from 2014‐2021. Diagnoses of probable CJD were established by clinical consensus, referencing the Centers for Disease Control and Prevention diagnostic criteria. Clinical features and biomarkers results were evaluated at presentation, and associations with CJD diagnosis and symptomatic disease duration determined.ResultOne‐hundred fifteen patients were included (40, [35%] with definite CJD). Mean age‐at‐symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD (e.g., stereotyped EEG abnormalities (16%), CSF 14‐3‐3 (60%)) was poor. Biomarkers with good diagnostic sensitivity included RT‐QuIC (93%), t‐tau levels >1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%). Multivariable linear regression confirmed shorter survival for patients with myoclonus (125.9 days, 95%CI 23.3‐15.5, p=0.026), visual/cerebellar signs (180.19 days, 95%CI 282.2‐78.2, p<0.001), positive 14‐3‐3 (193 days, 95%CI 304.9‐82.9; p<0.001), and elevated t‐tau levels (each 1000 pg/ml increase was associated with a nine‐day shorter time‐to‐death, 95%CI 1‐18; p=0.041).ConclusionCSF RT‐QuIC and elevated t‐tau levels, and stereotyped MRI abnormalities continue to be strongly associated with the diagnosis in the modern era, while other clinical findings (myoclonus) and biomarkers results traditionally ascribed to CJD (e.g., PSWC on EEG, 14‐3‐3) offered less value in the diagnostic evaluation. Detection of visual or cerebellar features, myoclonus, CSF 14‐3‐3, and t‐tau levels may predict disease duration, justifying inclusion in the evaluation of CJD‐suspected patients.
Examining an endogenous modulator of chaperone‐mediated autophagy in neurons across Braak stages of Alzheimer's disease
Authors: Weickhardt Alexander F. , Lee Yoo Bin , Piergies Antonia M. H. , Li Song , Lew Caroline , McCabe Mericka , Bourdenx Mathieu , Scrivo Aurora , Gavathiotis Evripidis , Cuervo Ana Maria , Grinberg Lea Tenenholz 
Published: December 2022

AbstractBackgroundDefective clearance of tau by neuronal autophagy has been implicated in the accumulation of toxic forms of tau in Alzheimer’s disease (AD). A novel, endogenous activator of chaperone‐mediated autophagy (CMA‐modulator) was identified in cell culture experiments (Cuervo laboratory, unpublished data). It is unclear what role this endogenous CMA‐modulator plays in AD. We hypothesized that loss of the CMA‐modulator in neurons could lead to decreased clearance of abnormal tau monomers, promoting the accumulation of toxic forms of tau. This study examined the proportion of neurons with CMA‐modulator in postmortem brain tissue from subjects with a range of AD neuropathologic changes as well as both amnestic and non‐amnestic AD presentation.MethodWe used multiplex immunofluorescence (CMA‐modulator, NeuN for neurons, 1F3C for acetyl‐tau, AT100 for phospho‐tau) on tissue microarrays in the inferior temporal gyrus of 17 subjects (Table 1) and for each subject quantified neurons within a gray matter area of 7.4 ‐ 7.6 mm2 using digital pathology. To analyze the change in percentage of neurons positive for CMA‐modulator across Braak stages, we fit a linear regression model.ResultIn amnestic AD, the percentage of neurons positive for CMA‐modulator declined linearly with advancing Braak stage, but this trend was not statistically significant (slope = 2.42% loss per Braak stage, p = 0.086). The predicted percentage of positive neurons was 22.8% at Braak stage 0 and 8.25% at Braak stage 6 and amnestic presentation. All non‐amnestic cases were Braak stage 6, and the proportion of neurons positive for the CMA‐modulator varied greatly from 0.2% to 77.1%. There was no significant association between the percentage of CMA‐modulator positive neurons and either age or gender. Quantification for the acetyl‐tau and phospho‐tau markers is ongoing.ConclusionThere may be a gradual loss of the endogenous CMA‐modulator across Braak stages in amnestic AD, but this study was underpowered to draw definitive conclusions. We are increasing the sample size.
Plasma phosphorylated‐tau181 is an indicator of early manifestations of neuropsychiatric symptoms in younger subclinical individuals
Authors: Gontrum Eva Q. , Saloner Rowan , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Casaletto Kaitlin B , Kramer Joel H. 
Published: December 2022

AbstractBackgroundNeuropsychiatric symptoms (NPS) can be the first manifestations of Alzheimer’s disease (AD), predict faster disease progression, and are more prevalent in early‐onset AD. Plasma P‐tau181 is strongly linked to cognitive impairment due to AD, yet it is unclear whether plasma P‐tau181 similarly relates to NPS in non‐demented adults, and whether this association is age‐dependent.MethodPlasma p‐tau181 concentrations (Quanterix Simoa) were measured in 265 non‐demented adults (212 cognitively unimpaired, 53 mild cognitive impairment; age = 74.4 [7.7], 51.5% female). NPS were measured via the informant‐based Neuropsychiatric Inventory Questionnaire (NPI‐Q) with the total severity score selected for analysis. Linear regression examined NPI‐Q score as a function of plasma P‐tau181, age, and their interaction, covarying for sex and diagnosis. To probe interaction effects, region of significance analyses identified the threshold along the distribution of age at which statistically significant plasma P‐tau181 and NPS associations emerged.ResultNPI‐Q scores ranged from 0–15, with the largest proportion of total scores reflecting anxiety (35%), sleep disturbance (16%), depression (14%), and irritability (14%). In the full sample, higher plasma P‐tau181 related to higher NPI‐Q total severity scores (β = .21, p<0.001). Age moderated the relationship between plasma P‐tau181 and total severity scores (β = ‐.18, p < 0.02) such that higher plasma P‐tau181 was significantly related to higher NPS at younger ages, yet this association was no longer statistically significant after age 72.5.ConclusionPlasma p‐tau181‐related elevations in NPS were most prominent in mid‐life through early old age (50’s to early‐70’s), yet this association was attenuated at later age stages, suggesting that the emergence of NPS at younger ages may be more closely linked to tau pathology than late‐life NPS. Importantly, age‐dependent effects on plasma P‐tau181 on NPS were independent of diagnosis, possibly reflecting a unique link between tau pathology and the neurocircuitry underpinning NPS.
Effects of Masupirdine (SUVN‐502) on Agitation/Aggression and Psychosis in Patients with Probable Alzheimer’s Disease: A Post Hoc Analysis
Authors: Nirogi Ramakrishna , Jayarajan Pradeep , Abraham Renny , Tadiparthi Jayaprakash , Benade Vijay , Shinde Anil K , Rasheed Mohammed Abdul , Badange Rajesh Kumar , Goyal Vinod Kumar , Palacharla Veera Raghava Chowdary , Ravulu Jyothsna , Jetta Satish , Subramanian Ramkumar 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder in older people with manifestations of cognitive and functional decline and neuropsychiatric symptoms (NPS). Agitation/aggression and psychosis are regarded as the most distressing NPS.Serotonin‐6 receptor (5‐HT6) is a G protein‐coupled receptor and is localized almost exclusively in the central nervous system regions which are important for control of mood regulation. Masupirdine is a potent and selective 5‐HT6 receptor antagonist. Masupirdine has been evaluated for its effects on cognition in patients with probable Alzheimer’s disease.MethodMasupirdine has been evaluated in a phase‐2a proof‐of‐concept, 26‐week, randomized, double‐blind, placebo‐controlled, multicenter, parallel group clinical study in United States under active US IND. Subgroup analyses of phase‐2a study results was carried out to evaluate the beneficial effects of masupirdine on agitation/aggression, and psychosis using Neuropsychiatric Inventory (NPI‐12) scale.Masupirdine was also evaluated in animal models to assess its effect on behavior and brain neurotransmitter modulations.ResultMasupirdine showed robust efficacy in agitation/aggression scores in patients who had baseline symptoms of agitation/aggression. In patients with baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores were observed in masupirdine treatment arms. Behavioral observations from the animal models were also in accord with the post hoc observations from the masupirdine clinical trial.ConclusionObservations from the masupirdine clinical trial suggest the potential utility of masupirdine for the management of neuropsychiatric symptoms associated with agitation/aggression, and psychosis in patients with AD. Masupirdine is currently being evaluated for the management on agitation in patients with dementia of the Alzheimer’s type.
Using telepresence robots to support family virtual visits during the COVID‐19 Pandemic
Authors: Hung Lillian , Mann Jim , Wong Joey , Young Erika 
Published: December 2022

AbstractBackgroundThe COVID‐19 pandemic has disproportionately impacted older adults living with dementia in Long‐Term Care (LTC). Social isolation and loss of connections with families among residents have been detrimental and severely impacted quality of life.MethodThis project aims to enhance LTC homes' capacity to support virtual family visits using a telepresence robot. Research question: Is it feasible to implement robotic‐assisted virtual care in LTC homes? We applied a Collaborative Action Research (CAR) approach to work with stakeholders (frontline leaders, staff, patient and family partners) to explore the experiences of virtual family visits in four Canadian LTC homes. Guided by the Consolidated Framework of Implementation Research (CFIR), we conducted an online survey, interviews, focus groups, and observations to explore implementation experience.ResultsOur analysis identified three themes: (a) Relative advantage: Easy to visit, (b) Capacity for change: Readiness and organizational support, (c) Cultural safety for robot adoption: Champions leading the way during challenging times.ConclusionOur preliminary results suggest staff, residents, and families appreciated the robot for easy connection. Future research should apply inclusive methods to bring relevant stakeholders together to fully explore user experiences ‐ who is affected in what ways and the benefits, risks, and burdens of emerging technologies.
Decreased Peripheral Endothelial Function is Associated with Mild Cognitive Impairment and Lower Performance on Memory and Language
Authors: Cheng Michael L , Rogers Steven , Thomas Tiffany , Okafor Maureen , Seyfried Nick , Kulshreshtha Ambar , Goldstein Felicia C , Quyyumi Arshed , Hajjar Ihab 
Published: December 2022

AbstractBackgroundThe association between cardiovascular risk factors and cognitive decline is known, but the underlying mechanisms remain unclear. We investigated whether peripheral microvascular and endothelial function, measured by pulsatile arterial tonometry (EndoPAT), is associated with cognitive performance and mild cognitive impairment (MCI).MethodThis study is based on data from 340 participants (150 with MCI, 190 with normal cognition (NC); mean age 64.9 (SD: 7.7) years, 61% female, 48% African American) enrolled in the VAScular ContribUtors to prodromaL AlzheimeR’s disease (VASCULAR) study. Peripheral microvascular function was assessed using EndoPAT (Itamar Inc.), and a reactive hyperemic index (RHI) was derived after a 5‐minute arterial occlusion period and includes a continuous or discrete (dichotomous or tertile) variable. Cognitive assessment and diagnostic categorization performed at the baseline visit included Montreal Cognitive Assessment (MoCA), Boston Naming Test, Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Trail Making Test. Groups were compared with a t‐test and multivariable logistic and linear regression analyses were performed to adjust for demographic and risk factor covariates.ResultParticipants with MCI had lower RHI, indicative of greater peripheral microvascular and endothelial dysfunction, compared to NC (mean 1.9 (SD: 1.4) vs 2.2 (0.7) AU, p=0.014), which remained significant after adjustment for age, education, sex, race, systolic blood pressure, history of diabetes, hyperlipidemia, and smoking (OR: 3.91 for each 1‐unit change in RHI (95% CI: 1.00, 7.08), p=0.03). When analyzed in tertiles, a lower RHI (<1.75 AU) was also associated with poorer expressive language (Boston Naming Test, p=0.03), and verbal memory performance (HVLT‐R delayed recall, p=0.01; HVLT‐R retention, p=0.02). Executive function (Trail Making Test) and overall cognitive status (MoCA) were not significantly associated with RHI.ConclusionPeripheral microvascular endothelial dysfunction, measured as RHI, was associated with MCI and with lower performances on measures of language and memory. These data highlight the importance of systemic microvascular health in cognitive health. Strategies targeting microvascular endothelial function may need further investigation in cognitive therapeutics.
How does a diagnosis of mild cognitive impairment impact everyday behaviours, quality of life and healthcare utilisation? A systematic review of people with MCI and their carers.
Authors: Connolly Evie Margaret , Slight Sarah , Ardle Ríona Mc 
Published: December 2022

AbstractBackgroundThe UK National Dementia Strategy was developed to improve professional and public attitudes and understanding around dementia, and to ensure through all stages of dementia that patients receive high‐quality care and support(1). Mild cognitive impairment (MCI) is a prodromal stage of dementia that can impact on patients’ everyday behaviours and quality of life (QOL). Carers may undertake additional responsibilities, which may ultimately impact on their health. We conducted a systematic review on the impact of an MCI diagnosis on the lives of both the individual and carers/families, focusing on everyday behaviours, QOL, and healthcare utilisation.MethodThis systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) checklist. We searched five large databases including Web of Science, Scopus, Medline, Embase and Psychinfo for studies published after Jan 2004, using appropriate key terms. Titles, abstracts and full texts were screened against set inclusion criteria. Data were extracted onto a customized data extraction sheet, and a narrative synthesis of all eligible studies was undertaken. This review was registered with PROSPERO (no CRD42021291995).ResultsTen papers were included. Patients diagnosed with MCI and cares/families described a lack of understanding of the term MCI itself, particularly around ‘mild’ and the anxiety around further cognitive decline. There was a perceived lack of information provided to both patient and carers around the diagnosis, with carers not perceiving themselves as carers up until that point. Carers also reported increased levels of depression and distress as they undertook more caring responsibilities. Carers experienced frustration with loved ones, who denied that they had memory problems and took longer to process and do things; this led to increased family conflict.ConclusionThis review identified the functional and psychosocial impact of a MCI diagnosis on people and carers. There is a critical need to combat stigma, increase information and support for people with MCI, and provide psychosocial interventions for people and carers post MCI diagnosis to enhance them to better cope and potentially reduce related depression, anxiety, and carer burden.1 Banerjee S. Living well with dementia–development of the national dementia strategy for England. Int J Geriatr Psychiatry. 2010;25:917‐922.
Brain insulin signaling and neurodegeneration: IRS‐1 isolated from neuronal enriched extracellular vesicles associates with frontal lobe gray matter volume in cognitively unimpaired adults
Authors: Peter Darby , Ennis Gilda E. , Eren Erden , III Doug C Dean , Oh Jennifer M. , Asthana Sanjay , Johnson Sterling C. , Kapogiannis Dimitrios , Bendlin Barbara B. 
Published: December 2022

AbstractBackgroundBrain insulin signaling, as measured by insulin signaling proteins in neuronal enriched extracellular vesicles (nEVs), has previously been associated with gray matter (GM) volume in the temporal lobe of nondemented older adults and in multiple brain regions in those with Alzheimer’s clinical syndrome (Walker et al, 2021; Mullins et al, 2017). We sought to extend these findings by performing a voxel‐wise analysis to test the relationship between whole‐brain GM volume and nEV tyrosine phosphorylated IRS‐1 (pY‐IRS‐1) in a cognitively unimpaired sample enriched for AD risk.MethodCognitively‐unimpaired adults (n=47) from the Wisconsin Registry for Alzheimer’s Prevention underwent MRI and blood collection (Table 1). nEVs were isolated from plasma samples by immunoprecipitation targeting neuronal marker L1CAM. pY‐IRS‐1 was measured in nEVs using an electrochemiluminescence assay (Meso Scale Discovery, Rockville, Maryland) (Mustapic et al, 2017). T1‐weighted images were analyzed using the FMRIB Software Library (FSL), where images were first normalized to MNI space and segmented into WM, GM, and CSF using FSL’s FLIRT, FNIRT, and FAST tools and resulting GM maps were smoothed with a Gaussian kernel (sigma = 3.5mm). General linear models and non‐parametric testing (FSL randomise) were used to assess voxelwise associations between nEV pY‐IRS‐1 concentration and GM volume, while controlling for sex and age effects. Significant associations between GM volume and nEV pY‐IRS‐1 were defined as p < 0.01, uncorrected.ResultWe observed lateralized positive associations between nEV pY‐IRS‐1 and GM volume in the right frontal lobe (Figures 1 and 2). After correcting for multiple comparisons, we observed no significant relationships between nEV pY‐IRS‐1 concentration and GM volume.ConclusionPrevious studies indicate that lower nEV pY‐IRS‐1 is associated with lower GM volume in regions such as the temporal and parietal lobes. Here, we determined that lower nEV pIRS‐1 concentrations were associated with lower GM volume laterally in the right frontal lobe of healthy middle‐aged and older adults. Future studies are needed to determine the mechanism by which disrupted insulin signaling in the brain may cause GM loss in these regions.