bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline cerebrospinal fluid biomarkers of amyloidosis, phosphorylated tau, and total tau relate to greater longitudinal atrophy in regions susceptible to Alzheimer’s disease‐related neurodegeneration
Authors: Moore Elizabeth E. , Khan Omair A. , Liu Dandan , Pechman Kimberly R. , Acosta Lealani Mae Y. , Bell Susan P. , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L. 
Published: December 2020

AbstractBackgroundCerebral atrophy patterns can distinguish normal cognition from Alzheimer’s disease (AD), but neuropathological drivers of these patterns are still not well understood. This study examined baseline cerebrospinal fluid (CSF) biomarkers of AD pathology (amyloid‐beta (Aβ), phosphorylated tau (p‐tau)); neurodegeneration (total tau (t‐tau)); synaptic dysfunction (neurogranin); and neuroaxonal injury (neurofilament light (NFL)) in relation to longitudinal atrophy patterns for two common AD neuroimaging signatures.MethodVanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=153, 72±6 years) underwent baseline fasting lumbar puncture for CSF collection and serial T1
‐weighted neuroimaging at 3T (baseline, 18‐months, 3‐years, 5‐years). Images were post‐processed using FreeSurfer. AD imaging signatures were calculated using published guidelines (McEvoy et al., 2009; Schwarz et al., 2016). Linear mixed effects models related each baseline CSF biomarker to each AD signature trajectory using biomarker x follow‐up time interactions, adjusting for age, sex, race/ethnicity, education, diagnosis, apolipoprotein (APOE)‐ε4 status, and follow‐up time. Secondary models tested CSF biomarker x APOE‐ε4 interactions on longitudinal AD signature trajectory.ResultMean follow‐up time was 3.4±1.1 years. Lower baseline CSF Aβ (p<0.001), higher t‐tau (p=0.04), and higher p‐tau levels (p=0.01) were associated with a faster rate of cortical thinning in the McEvoy AD signature. Baseline CSF biomarkers were unrelated to Schwarz AD signature trajectory (p‐values>0.16). APOE‐ε4 interacted with baseline CSF p‐tau, t‐tau, neurogranin, and NFL on both AD signatures (p‐values<0.04). APOE‐ε4 also interacted with CSF Aβ on the Schwarz AD signature (p=0.008). Associations linking baseline CSF Aβ, p‐tau, t‐tau, and neurogranin with faster atrophy patterns were driven by APOE‐ε4 carriers (p‐values<0.05).ConclusionIncreased baseline evidence of cerebral amyloidosis, phosphorylated tau, and neurodegeneration related to faster rates of cortical thinning in AD‐affected regions over a mean 3.4 year follow‐up period. Associations linking amyloidosis, phosphorylated tau, neurodegeneration, and synaptic dysfunction to cortical thinning are driven by APOE‐ε4 carriers, suggesting grey matter regions susceptible to the longitudinal neurodegenerative effects of AD pathology may be even more susceptible in APOE‐ε4 carriers, perhaps due to the effects of APOE‐ε4 on blood‐brain barrier compromise, vascular dysregulation, or inflammatory activation.
Ubiquilin‐2 exacerbates tau toxicity in vivo
Authors: Gerson Julia E. , Pistorius Stephanie , Welday Jacqueline , Gregory Jordan , Rodriguez Aleija L. , Sharkey Lisa M. , Paulson Henry L. 
Published: December 2020

AbstractBackgroundUbiquilin‐2 (UBQLN2) is a protein quality control protein involved primarily in shuttling ubiquitinated substrates to the proteasome for degradation and by modulating autophagy. UBQLN2 has been implicated in neurodegenerative disease due to its accumulation in neuropathological deposits and its potential role in regulating protein dyshomeostasis common across different neurodegenerative disorders. The relationship of UBQLN2 to one of the most common aggregating proteins in disease, tau, is unknown.MethodTo evaluate whether UBQLN2 regulates tau clearance, we assessed levels of tau in human embryonic kidney‐293 cells with and without UBQLN2. To determine whether UBQLN2 acts on tau in vivo, P301S tau transgenic mice were crossed with UBQLN2 transgenic and knockout mice and brain levels of tau were assessed at 3, 6 and 9 months of age. To define changes in UBQLN2 in human disease, we measured levels of soluble and insoluble UBQLN2 in human tauopathy brain tissue.ResultCo‐expressed UBQLN2 markedly lowered levels of tau in a cellular model. Conversely, siRNA knockdown of UBQLN2 significantly elevated levels of tau. Surprisingly, a UBQLN2 mutant incapable of binding ubiquitin was more effective at lowering tau than wildtype UBQLN2, suggesting that ubiquitin‐independent pathways may allow UBQLN2 to “handle” tau. In contrast, wildtype UBQLN2 overexpression in vivo did not alter total levels of tau at 3, 6 or 9 months of age. However, UBQLN2 overexpression specifically increased phosphorylated tau while UBQLN2 knockout decreased phosphorylated tau at 9 months. Furthermore, UBQLN2 overexpression increased premature hindlimb paralysis and fatality. The possibility that UBQLN2 also undergoes alterations in disease was evidenced by the fact that UBQLN2 solubility is decreased in human brains with tau pathology.ConclusionOur findings highlight a new role for UBQLN2 in altering tau in the brain. Collectively, our results suggest that while on a rapid time scale UBQLN2 can decrease tau levels, long‐term expression of UBQLN2 in vivo exacerbates tau toxicity. Ongoing research will determine how changing UBQLN2 levels alters components of proteostasis pathways to affect tau toxicity and whether ubiquitin‐independent processes may compete with UBQLN2’s function as a ubiquitin‐proteasome shuttle factor to yield differential effects on tau toxicity.
Severity of subjective cognitive complaints and worries in older adults are associated with cerebral amyloid‐β load
Authors: Schwarz Claudia , Lange Catharina , Benson Gloria , Horn Nora , Wurdack Katharina , Lukas Mathias , Buchert Ralph , Wirth Miranka , Flöel Agnes 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) is considered an early risk stage for the development of Alzheimer's disease (AD) and pathological brain alterations, including the aggregation of amyloid‐β plaques (Jessen et al., Alzheimer's & Dementia 2014). This prospective study evaluates the association between specific features of SCD, including severity of subjective cognitive complaints and trait worry, and regional cerebral amyloid‐β load in cognitively normal older individuals.MethodCerebral amyloid‐β load was assessed by positron emission tomography with 18F‐florbetaben in 30 individuals with SCD (age 67 ± 4 years) at baseline in an ongoing interventional study (clinicaltrial.gov: NCT03094546) and in 10 healthy older adults (age 72 ± 8 years) following the same baseline protocol. Regional amyloid‐β load was quantified for frontal, temporal, parietal, and cingulate cortex using whole cerebellum as reference. Subjective complaints regarding different cognitive domains (memory, language, visuospatial abilities, planning, organization, and divided attention) were determined using the 39‐item Everyday Cognition Scales. Trait evaluation of pathological worry was captured by the self‐reported 16‐item Penn State Worry Questionnaire. Associations between specific features of SCD and cerebral amyloid‐β load were tested by age‐adjusted Spearman rank partial correlation analyses, uncorrected for multiple testing.ResultAcross all participants, severity of subjective cognitive complaints regarding memory, organization, and divided attention was positively correlated with amyloid‐β load in the frontal cortex (p = .008, .018, .024, respectively). Severity of subjective cognitive complaints regarding planning was positively correlated with amyloid‐β load in the parietal cortex (p = .025). Higher trait level of pathological worry was associated with higher amyloid‐β load in the frontal cortex (p = .031).ConclusionIn cognitively normal older individuals, severity of subjective cognitive complaints and level of trait worry are positively associated with cortical amyloid‐β burden, particularly in the frontal cortex. This region is considered a core region of the default mode network that is affected early in AD (Palmqvist et al., Nature Communications 2017). Interventions aiming to reduce rumination and worries may help prevent amyloid deposition in these regions, a hypothesis to be tested in future interventional trials.
Moving together: Livestream virtual group movement classes for persons living with dementia and caregivers—Feasibility and satisfaction
Authors: Benjamin Cynthia , Lee Amanda , Lee Jennifer Ann , Mehling Wolf , Chesney Margaret A , Sudore Rebecca L , Barnes Deborah E 
Published: December 2020

AbstractBackgroundPaired PLIÉ (Preventing Loss of Independence through Exercise) is an in‐person, group movement program for people living with dementia (PLWD) and caregivers (CGs) that targets physical movements, mindful body awareness, and social engagement. We have previously found Paired PLIÉ to be associated with CG‐reported improvements in physical, cognitive, social/emotional function, and relationship quality. However, CGs also reported logistical challenges related to attending in‐person classes. To address these challenges, our goal was to assess feasibility and satisfaction with an online version of the program developed by Together Senior Health, Inc., called Moving Together.MethodStudy participants were PLWD and CGs who participated in Moving Together livestream virtual classes from home using their existing technology. Feasibility was assessed based on completion of the 12‐week program. Satisfaction at 12‐weeks was assessed using a 5‐point Likert scale (highly satisfied to highly unsatisfied). Open‐ended questions asked what participants liked and found challenging about the online program.ResultTwenty‐one people participated (11 PLWD: 36% women, mean age 78±12 years; 10 CGs: 70% women, mean age 70±16 years). Fifteen (70%; 8 PLWD, 7 CGs) successfully completed the program, of whom all (100%) reported being highly satisfied with online delivery. Participants described physical, social and emotional benefits of participating: “I liked the activities with partner and that I could feel various parts of my body getting massage and movement (PLWD);” “Really enjoyed this class, so did my body, brain and my spirit (CG);” and “[I liked] feeling part of a group and seeing the range of issues with others (CG).” Despite reporting challenges with technology related to broadband internet access and older devices, participants strongly supported the online format: “[I liked] BEING AT HOME! …Getting ready to go out, going out and coming home takes a lot of energy and we are not sure we would participate if it were not online (PLWD).”ConclusionWe found that online delivery of Moving Together is feasible and acceptable to PLWD and CGs. Offering livestream virtual group movement classes such as Moving Together could enhance accessibility to evidenced‐based programs for PLWD and CGs.
Neuropsychological, clinico‐pathologic, neuroimaging, and biomarker profiles of the MGH FTD Unit posterior cortical atrophy (PCA) cohort
Authors: Wong Bonnie , McGinnis Scott , Putcha Deepti , Dev Sheena Isha , Lucente Diane E. , Quimby Megan , Brandt Katie , Eldaief Mark C. , Sherman Janet C. , Frosch Matthew P. , Dickerson Brad C. 
Published: December 2020

AbstractBackgroundObjective: To present comprehensive data on the MGH FTD Unit PCA cohort. PCA is a neurodegenerative clinical syndrome usually arising from Alzheimer’s Disease (AD) neuropathologic changes (ADNC). While visuoperceptual and spatial problems are typical early presenting symptoms, patients also report problems with spelling, calculation, and word retrieval. Due to significant heterogeneity in the syndrome, further classification of PCA by subtypes based on predominant cognitive impairments (dorsal, ventral, caudal, dominant parietal) has also been proposed. We launched our multidisciplinary MGH PCA program in 2008 to address the special care needs of this population, and to advance our scientific understanding of PCA and its treatment.Methods39 participants were recruited for research participation based on clinical diagnostic criteria consistent with PCA, including a dominant hemisphere variant (i.e., progressive Gerstmann‐like syndrome minimal visuospatial disturbance). Participants underwent structured review of symptoms and history; systematic neurological exam; comprehensive neuropsychological and speech‐language assessments; multimodal imaging (MRI and/or functional MRI and FDG, amyloid, and tau PET); and CSF analysis. Some patients have come to autopsy. We used the Neuropsychological Assessment Rating (NAR) scale to quantify performance in cognitive domains pertinent to PCA and for subtype classification.ResultsOf seven individuals for whom we have autopsy‐confirmed neuropathology, five had ADNC; one had lobar atrophy and tau pathology in a cortico‐basal degeneration (CBD) distribution; and one had Frontotemporal Lobar Degeneration TDP43 Type A (GRN mutation). 22 patients had biomarkers consistent with ADNC (17 with elevated PiB PET imaging signal, 5 with AD‐like CSF ). Mean NAR domain scores (impairment level ratings: 0=Normal, .5=questionable/very mild, 1=mild, 2= moderate, 3=severe) revealed relatively normal Attention/Processing Speed (0.2); mildly impaired Executive Function (0.8) and Memory (1.1); questionably/very mildly impaired Language (0.5); and moderately impaired Visuospatial Function (2).ConclusionThe MGH PCA program has a robust cohort of patients with a comprehensive data set that includes standardized characterization of the PCA neurocognitive and neurologic profiles, high‐resolution MRI (structural, functional), multimodal PET imaging, CSF biomarkers, and in some cases neuropathology. This data set will allow for detailed examination and improved understanding of this atypical neurodegenerative syndrome. Additional analyses are ongoing, including tau imaging profiles.
Diffusion kurtosis imaging suggests sex‐specific alteration of white matter in mild cognitively impaired participants
Authors: Mishra Virendra R , Ritter Aaron , Cordes Dietmar , Caldwell Jessica ZK 
Published: December 2020

AbstractBackgroundSex differences in Alzheimer’s disease (AD)‐dementia is well documented. However, whether sex differences in white‐matter (WM) microstructural integrity could serve as potential biomarker to identify sex‐specific participants progressing to AD‐dementia is currently unexplored.Method78 participants were recruited at our center, of which 38 were diagnosed with MCI based on expert consensus, using results of a neuropsychological test battery and the Clinical Dementia Rating (CDR) interview (Table.1). Isotropic 1.5mm3 multi‐shell dMRI (b‐values=500s/mm2, 1000s/mm2, and 2500s/mm2) each with 71 directions was acquired for each participant. Diffusion kurtosis (DKI) model was fitted from every participant along with conventional single‐tensor (ST) diffusion tensor imaging (DTI) model. DKI metrics such as axonal water fraction (AWF), axonal kurtosis (AK), radial kurtosis (RK), and mean kurtosis (MK) was estimated at every voxel. Tract‐based Spatial Statistics (TBSS) was used to extract the WM skeleton from ST‐fractional anisotropy (FA), and various DKI‐derived metrics were mapped to a common space using the registration parameters from ST‐FA. Nonparametric statistical comparisons were conducted between each group to test for mean difference in these metrics. Significance was established at familywise error corrected (FWE) p<0.05.ResultMale‐HC showed a significantly higher AK as compared to female‐HC in the WM regions encompassing corpus‐callosum, cingulum, inferior longitudinal fasciculus, and thalamic and cerebellar WM fibers. However male‐MCI only showed a higher AK in the thalamic and cerebellar WM fibers (Fig.1). There were also significant differences in other metrics such as MK and RK, both within (male vs female HC and MCI) and between groups of HC and MCI (Fig.1). Significantly lower AWF was observed in male‐HC as compared to female‐HC, and in male‐MCI as compared to female‐HC in the entire WM skeleton but selectively sparring the corpus callosum (Fig.1). DTI metrics showed no significant sex‐specific differences within groups in our cohort.ConclusionMulti‐shell dMRI imaging is a promising avenue to explore sex‐specific alterations in the WM microstructural integrity in MCI participants, and could be utilized to identify the most promising imaging biomarker to predict AD‐dementia which is sex‐specific. Similar analysis with other complex models such as free‐water corrected DTI and NODDI models are currently underway.
Cognitive indices correlate with [18F]GTP1 tau PET signal and white matter hyperintensities in prodromal‐to‐mild Alzheimer's disease: Baseline data from the Tauriel Study
Authors: Teng Edmond , Manser Paul T. , Pickthorn Karen , Blendstrup Mira , Anegondi Neha , Krishnan Anithapriya , Song Zhuang , Carano Richard A.D. , Keeley Michael , Wildsmith Kristin R. , Weimer Robby , Bohorquez Sandra Sanabria 
Published: December 2020

AbstractBackgroundIn prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer’s disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD.MethodWe analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression.ResultUnivariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p’s<0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p’s<0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR.ConclusionAmongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline.
Biomarker profiles in a memory clinic population according to new Alzheimer diagnostic framework
Authors: Öhlund Ulf , Wiggenraad Fleur , Hagman Göran , Rosenberg Anna , Kivipelto Miia 
Published: December 2020

AbstractBackgroundDifferent research diagnostic criteria and frameworks for Alzheimer’s disease have recently been proposed, but their applicability in clinical settings is unclear. This cross‐sectional study aimed at classifying biomarker profiles of memory clinic patients according to the ATN scheme and assessing patient characteristics in each category.Method284 consecutive patients from the Karolinska University Hospital, Theme aging, memory clinic with available CSF, MRI and clinical data were included (50% diagnosed with SCI, 24% with MCI, 26% with dementia). ATN classification was based on CSF β‐amyloid42 (A), CSF phosphorylated tau (T), and medial temporal atrophy (N), and clinical cut‐offs were used to determine biomarker positivity. When available, automated ratings of medial temporal lobe atrophy were used in the classification. Comparisons between the ATN categories were conducted with Kruskal‐Wallis and chi‐square tests.ResultThe most frequent biomarker profile was A‐T‐N‐ (49% of the whole study population). 36% had a SNAP profile (A‐T+N‐, A‐T‐N+ or A‐T+N+) and 15% had any Alzheimer profile, i.e. abnormal amyloid (A+T‐N‐, A+T+N‐, A+T‐N+ or A+T+N+). Proportion of A+T+N+ patients increased with the severity of symptoms (0% in SCI and MCI, 22% in dementia), whereas the opposite was observed for A‐T‐N‐ patients (72% in SCI, 39% in MCI, 14% in dementia). Some biomarker profiles (A+T‐N‐, A+T‐N+, A+T+N‐) were underrepresented in the whole sample and in all diagnostic groups. Compared to normal biomarker profile, patients with an Alzheimer profile were older and more often APOE4 carriers, had a poorer cognitive performance (MoCa, MMSE, memory, attention), and had fewer depressive symptoms. Except for age and depressive symptoms, same differences were observed between SNAP and normal biomarker profile categories. There were no differences in white matter hyperintensities or education level between the profile categories.ConclusionProportion of patients with either a normal or SNAP biomarker profile was high in this memory clinic‐based study. Many of the proposed ATN categories were also not relevant in this patient population. Follow‐up studies are needed to assess cognitive decline and disease progression in the different ATN categories.
Exploring polypharmacy and hyperpolypharmacy in dementia
Authors: Zafeiridi Evi , McMichael Alan J , McGuinness Bernadette 
Published: December 2020

AbstractBackgroundPolypharmacy is defined as receiving multiple medications and has been shown to increase the risk for developing dementia. Polypharmacy is also prevalent in people with dementia (PwD) who transition to a care home. This study explored whether people receiving multiple medications are more likely to be diagnosed with dementia. Another aim was to assess the prevalence of polypharmacy (≥4 drugs) and hyperpolypharmacy (≥10 drugs) in community‐dwelling PwD and care home residents in Northern Ireland, as well as to investigate whether higher polypharmacy scores are associated with increased likelihood of transitioning to a care home for PwD. Data from the Enhanced Prescribing Database and other national databases was linked through the Honest Broker Service. Data extraction included over 50,000 people, half of which were prescribed at least one anti‐dementia medication between 2010‐2016. The results showed that, although polypharmacy was not associated with the risk of developing dementia, higher scores of polypharmacy were associated with lower risk of transitioning to a care home for PwD. A possible explanation could be the increased mortality rates in people who received four or more medications. Within care homes, polypharmacy was more prevalent to PwD compared to controls. These findings can inform policies and clinical practices for the effect of prescribing multiple medications to PwD.