bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitively defined subtypes of Alzheimer's disease
Authors: Crane Paul K. ,   for the ADNI Psychometrics Study Group
Published: December 2020

AbstractBackgroundWe have developed a framework for using cognitive test results at Alzheimer’s disease (AD) diagnosis to categorize people into AD subgroups. We have shown that risk factors and genetic variant associations vary across subgroups. We also showed differences in gray matter volume (GMV) using voxel‐based p‐values. Here we present new findings with beta coefficient maps and a movie showing regional atrophy associated with greater global atrophy.MethodWe use data from the first ADNI study visit with AD for 624 amyloid positive patients, and the first visit for 119 amyloid negative cognitively normal controls (CN). We generated voxel‐wise gray matter (GM) W‐scores as (actual GM‐expected GM)/SD. Expected GM is based on voxel‐wise regressions in CN in SPM12 with age, sex, ICV, and field strength. SD is the voxel‐specific SD of residuals from the regression analyses. We obtained global W‐scores as the number of voxels with W<‐1.65. We generated beta‐coefficient maps from SPM, controlling for global W‐score, age, sex, ICV, and field strength. We obtained regional W‐scores using the Desikan‐Killiany cortical parcellation atlas and performed regression analyses predicting regional W‐scores as a function of total W‐score as a continuous predictor, and present the results as a movie for each region.ResultThere were 267 people with no prominent differences across domains (AD‐No Domain), 189 with AD‐Memory, 14 AD‐Executive, 46 AD‐Language, 85 AD‐Visuospatial, and 23 AD‐multiple domains. Groups did not differ with respect to sex, years of education, handedness, or proportion who were non‐Hispanic white. Mean age at diagnosis ranged from 73 (AD‐Visuospatial and controls) to 77 (AD‐Language; omnibus p = 0.015) Compared to other groups, the AD‐Memory group consistently had greater GMV loss in medial temporal lobes (Figure 1). Each of the other groups had substantial areas of cortex with greater GMV loss than the AD‐Memory group (Figure 2). Regions associated with more global atrophy varied substantially across groups (Figure 3: this is a still of coordinated movies for each subgroup).ConclusionCognitively defined AD subgroups differ in patterns of GMV in regions that make sense with the cognitive phenotype.
Progressive dysexecutive syndrome due to Alzheimer’s disease: A description of 55 cases and comparisons to other clinical AD phenotypes
Authors: Townley Ryan A , Graff‐Radford Jonathan , Mantyh William G. , Botha Hugo , Polsinelli Angelina J. , Przybelski Scott A. , Machulda Mary M. , Senjem Matthew L. , Murray Melissa E. , Reichard Ross R. , Savica Rodolfo , Boeve Bradley F. , Drubach Daniel A. , Josephs Keith A. , Knopman David S. , Lowe Val J. , Jack Clifford R. , Petersen Ronald C. , Jones David T. 
Published: December 2020

AbstractBackgroundWe report a group of individuals presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions and positive biomarkers for Alzheimer’s pathophysiology.MethodIn this retrospective review, we report on 55 participants with a clinically defined progressive dysexecutive syndrome with 18F‐fluorodeoxyglucose‐positron emission tomography (FDG) and AD biomarker positivity. A subset of these individuals enrolled in our ADRC were compared to other phenotypic variants of AD.ResultSixty‐two percent were female with a mean of 15.2 years of education. Mean age of symptom onset was 53.8 while mean age at diagnosis was 57.2 years. Multi‐domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently and severely affected. The frontal and/or parietal regions demonstrate clear hypometabolism on positron emission tomography in all cases. Genetic testing for autosomal dominant genes was negative in all 8 participants tested and at least one APOE ε4 allele was present in 14/26. EEG was abnormal in 14/17 cases. CSF and neuroimaging biomarkers (PIB‐PET and Tau‐PET) were consistent with Alzheimer’s disease pathophysiology, although CSF p‐tau was normal in 24% of cases. In two participants that came to autopsy, the hippocampus was relatively spared compared to frontal and parietal cortex. Participants presenting with a progressive dysexecutive syndrome and evidence of AD pathology are labeled dAD. Comparing FDG in dAD relative to other AD phenotypes revealed unique areas of relatively greater hypometabolism in parieto‐frontal cortex and relative sparing of medial temporal (vs typical AD), visual (vs PCA), and left temporal (vs lvPPA) (Figure 1). Controlling for age did not alter patterns of regional differences. This demonstrates regional variability related to clinical phenotype not accountable by variation in age, duration, stage, or severity (Figure 2).ConclusionA progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype. This clinical presentation can be due to Alzheimer’s disease but is not specific for any single etiology (non‐AD cases of progressive dysexecutive syndrome will be discussed). Prominent impairment of executive task performance, young‐age of onset, normal CSF p‐tau, and relative preservation of the hippocampus were commonly encountered in this case series of dAD.
How ‘atypical’ is the neuroimaging signature of Alzheimer’s atypical variants? MRI and PET imaging of posterior cortical atrophy and logopenic variant of primary progressive aphasia
Authors: Joie Renaud La , Damasceno Pablo F. , Visani Adrienne , Iaccarino Leonardo , Strom Amelia , Edwards Lauren , Gorno‐Tempini Marilu , Jagust William J. , Miller Bruce L. , Raj Ashish , Rabinovici Gil D. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease clinical expression is highly heterogeneous: cognitive and anatomical variations exist on a multi‐axis spectrum with well‐described variants like posterior cortical atrophy (PCA) or logopenic variant of primary progressive aphasia (lvPPA) representing extreme phenotypes of so‐called “atypical” AD. Here, we provide an overview of our investigations of PCA and lvPPA using structural MRI and amyloid/tau‐PET imaging, emphasizing both the differences and the similarities between these phenotypes and more typical presentations of AD.MethodWe investigated 97 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 18 patients with PCA and 19 with lvPPA; the remaining patients are referred to as typical (tAD; Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Standardized Uptake Value Ratio (SUVR) images were created using specific reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions, and cortical asymmetry indices were calculated.ResultAtypical variants tended to be younger and less likely to carry APOE4 than tAD (Table1). Global amyloid burden did not vary across phenotypes or with any clinical measure (Figure 1A). The cortical distribution of PIB was widespread and only showed minor differences between variants (Figure 2A). In contrast, global Flortaucipir‐SUVR was higher in atypical groups compared to tAD, and was lower in older patients across phenotypes (Figure 1A). Flortaucipir was consistently elevated in temporo‐parietal regions but also showed strong between‐variant regional differences (Figure 2B) that mirrored differences in cortical volume (Figure 3B). Flortaucipir and MRI asymmetries were strongly inter‐related and very common across all AD phenotypes rather than specific to atypical variants (Figure 3). However, asymmetry was systematic in lvPPA (84‐95% left‐predominant, 5% right‐predominant) and PCA (33% left‐predominant, 66% right‐predominant)ConclusionAtypical phenotypes share various features with tAD: i) widespread cortical amyloid deposition, ii) tau pathology in the temporo‐parietal areas, iii) higher tau burden associated with earlier disease onset, iv) a strong negative relationship between tau and local cortical volume. The main between‐phenotype differences were related to the distribution of tau and associated atrophy that were more left‐predominant and perisylvian in lvPPA, and more occipital and asymmetric in PCA.
Raising awareness of clinical trials in dementia: A national survey testing concept designs tailored to African American caregivers and individuals at risk
Authors: Massett Holly A , McGowan Melissa , Han Sae H , Watson Jennifer , Emmerson Karen , Burns Adam , Robinson Candice Watkins , Hummel Allyson , Silverberg Nina , Elliott Cerise L , Donley Grayson , Bernard Marie A 
Published: December 2020

AbstractBackgroundLow enrollment of African Americans into clinical trials for Alzheimer’s Disease (AD) and related dementias (ADRD) is partly a result of too few researchers offering trial opportunities and inadequate information that is culturally relevant. The National Institute on Aging (NIA) sought to develop a culturally acceptable/effective toolkit of AD/ADRD clinical trial (CT) outreach materials for community health professionals to use with African American audiences. This abstract presents the results of a national online survey testing several AD/ADRD concept designs with adults/caregivers to guide the toolkit’s development.MethodAn online national panel survey was conducted with African American adults who: 1) had a family history of AD/ADRD (n=206); 2) had no family history of AD/ADRD (n=204); and, 3) were caregivers of persons with AD/ADRD (n=206). Respondents reported their AD/ADRD and CT knowledge/attitudes/intentions; they reviewed four concept designs and indicated preferences/likelihood of each concept to impact five variables (visit website, interest in trials, attention, believability, salience). Concepts featured messages that tested well in focus groups.ResultCaregivers and those at‐risk self‐reported higher familiarity with AD/ADRD signs/symptoms than those with no family history; all groups self‐reported limited understanding of CTs. Two concepts ranked highest among all participants: emphasizing helping future generations and noting that AD/ADRD affects races differently. Most caregivers (61‐87%) and at‐risk participants (46‐89%) gave favorable scores for all impact variables across all concepts, indicating they found most concepts motivating and acceptable. Those with no family history provided lower impact scores (39‐78%). After viewing all concepts: all groups significantly increased (p<.05) their “interest in participating in clinical trials”; and, the at‐risk and no‐history groups were significantly more likely to disagree with “there is nothing I can do to reduce my risk of [AD]”.ConclusionThis research identifies effective AD/ADRD ad concepts that are culturally tailored and acceptable to African Americans nationally, and addresses a known obstacle to recruitment. The combination of the messages/images successfully increased interest in CTs as an option to address AD/ADRD. Using these findings, NIA developed and offers an outreach toolkit to assist community health professionals who do not otherwise have resources to develop their own materials.
Evaluation of 18F‐JNJ‐067 as a tau tracer
Authors: Baker Suzanne L. , Provost Karine , Thomas Wesley P. , Whitman A. J. , Janabi Mustafa , Schmidt Mark E. , Timmers Maarten , Kolb Hartmuth C. , Rabinovici Gil D. , Jagust William J. 
Published: December 2020

AbstractBackgroundCurrent tau PET tracers have obvious shortcomings. 18F‐JNJ‐64326067 (18F‐JNJ‐067) is a new tau tracer that binds to aggregated tau in Alzheimer’s Disease (AD) brain tissue with Ki=2.4nM. Our objective was to evaluate 18F‐JNJ‐067 in individuals with AD (N=3), Mild Cognitive Impairment (MCI, N=3), Progressive Supranuclear Palsy (PSP, N=2) and healthy controls (HC, N=4).MethodFollowing a 50‐70min 11C‐PIB PET scan (Siemens Biograph PET/CT), 12 subjects underwent 90 min dynamic PET scan after 18F‐JNJ‐067 injection. MPRAGEs were acquired on a Siemens 3T and segmented using FreeSurfer. Time activity and SUVR curves were viewed for commentary on steady state. Logan DVR quantification was calculated from 35‐90min (k2ref=0.025 min‐1 derived from SRTM2 analysis) using inferior cerebellar gray as a reference region. Data quantification was done in native space; images were warped to template space for visualization.ResultSubject information is shown in figure 1; all AD and MCI subjects were PIB positive with MMSE scores from 18‐30, all PSP and HCs were PIB negative. Steady state was not reached in ROIs with high levels of tracer retention within 90 minutes (SUVR curves shown in figure 2). Figure 1 shows native space DVR quantification for ROIs. ADs had 18F‐JNJ‐067 binding in typical AD regions, one MCI had elevated binding, the others showed low binding (DVR images in figure 3). HCs showed no binding in entorhinal cortex, and had elevated signal in basal ganglia, midbrain, superior cerebellar gray, and white matter but no binding in the choroid plexus or meninges (figure 4). MMSE was correlated with Braak I/II (r2=0.80), Braak III/IV (r2=0.73) and Braak V/VI (r2=0.50) ROIs.Conclusion18F‐JNJ‐067 shows relatively slow pharmacokinetics in brain regions with high target density, has low levels of probable off‐target binding in the basal ganglia and white matter but not elsewhere, and low entorhinal signal in HCs and MCIs. Binding in AD patients reflects a typical pattern of tau distribution seen with other tracers, and MCI patients are intermediate. Braak ROIs are significantly correlated to MMSE. These data suggest that 18F‐JNJ‐067 is suitable for investigation of the AD continuum.
Changes in cardiac structure over 25 years are associated with lower midlife cognition: The CARDIA study
Authors: Rouch Laure , Hoang Tina D , Xia Feng , Sidney Stephen , Lima Joao , Yaffe Kristine 
Published: December 2020

AbstractBackgroundCardiovascular risk factors are associated with worse cognition, yet less is known about the impact of cardiac structure and function and their adverse effects on the brain possibly from decreased perfusion. The few studies included older patients with cardiovascular disease and relied on single echocardiographic assessment.MethodWe included 2256 subjects from the CARDIA (Coronary Artery Risk Development in Young Adults) study (60% women, 44% black). Echocardiograms were repeated at Years 5, 25, 30 (mean age 30, 50, 55 years, respectively) to assess cardiac structure: left ventricular mass (LVMi), left atrial volume (LAVi) and systolic function: left ventricular ejection fraction (LVEF). Diastolic function was assessed at Year 25 as the ratio of early peak mitral velocity (E)/early peak mitral annular velocity (e’). Five cognitive domains were assessed at Year 30: verbal memory [Rey Auditory Verbal Learning Test (RAVLT)], category and letter fluency, processing speed [Digit Symbol Substitution Test (DSST)], executive function [Stroop] and global cognition [Montreal Cognitive Assessment MoCA]. We investigated the association of (1) 25‐year change and (2) Year 25 cardiac structure and function on midlife cognition using linear regressions.ResultOver 25 years, LVMi and LAVi increased with mean change (SD) of 5.7 g/m² (21.7) and 9.6 mL/m² (7.4) while LVEF decreased by mean (SD) change of 1.5% (9.0). After adjustment for demographics and education, abnormal cardiac structure assessed by greater 25‐year increase (≥ 1‐SD) in LVMi was associated with lower cognition on most tests: RAVLT (6.2 vs. 6.8, p<0.001), DSST (59.7 vs. 61.7, p=0.02), Stroop (29.0 vs. 27.2, p=0.01) and MoCA (19.1 vs 19.7, p=0.001). Similarly, greater 25‐year increase in LAVi was associated with lower MoCA (19.8 vs. 20.3, p=0.04). Further adjustment for hypertension, diabetes and smoking reported similar findings. 25‐year decrease in LVEF was not associated with cognition. In addition, higher Year 25 LVMi, LAVi and E/e’ ratio were significantly associated with worse cognition on most cognitive tests.ConclusionMidlife cardiac structure and its change from early to middle adulthood are associated with lower midlife cognition. Moreover, midlife diastolic but not systolic function is linked to cognition. Our results provide novel information linking cardiac structure and function to cognition.
A single dose of melatonin fails to reduce brain damage following cardiac I/R injury
Authors: Apaijai Nattayaporn , Singhanat Kodchanan , Jaiwongkam Thidarat , Kerdphoo Sasiwan , Chattipakorn Nipon , Chattipakorn Siriporn C. 
Published: December 2020

AbstractBackgroundCardiac ischemia/reperfusion (I/R) injury caused the detrimental effects not only to the heart but also to the brain. We previously reported that cardiac I/R injury led to blood brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and microglial hyperactivation, resulting in amyloid beta (Aβ) aggregation. Pretreatment with melatonin showed a neuroprotective effect against cerebral I/R injury. However, the effects of melatonin on the brain pathologies following cardiac I/R injury have never been investigated. Therefore, we hypothesize that melatonin treatment at various time points of cardiac I/R including pretreatment, during cardiac ischemia, and at the onset of reperfusion attenuate brain damages via decreasing inflammation, mitochondrial dysfunction, and Alzheimer’s proteins levels in rats with cardiac I/R injury.MethodMale Wistar rats (n=45) were subjected to either sham operation (n=5) or cardiac I/R injury (30 min of cardiac ischemia, followed by 120 min of reperfusion). Rats were divided into 4 groups (n=10/group) including 1) vehicle (normal saline solution), 2) Pretreatment with melatonin, 3) Melatonin treatment during cardiac ischemia (15 min after ischemia), and 4) Melatonin treatment at the onset of reperfusion. Melatonin was administered at the dose of 10 mg/kg via intravenous injection. At the end of reperfusion, brains were rapidly removed, and brain tissue was used to determine brain mitochondrial function, microglial morphology, BBB and Alzheimer’s protein expression.ResultCardiac I/R led to brain inflammation as indicated by increasing the number of activated microglia and reducing number of resident microglia. Moreover, brain mitochondrial dysfunction was observed after cardiac I/R as indicated by increasing mitochondrial oxidative stress, mitochondrial membrane depolarization and mitochondrial swelling. Our results also showed that Aβ/APP and p‐Tau/Tau were increased after cardiac I/R, together with a reduction of occludin protein levels. These data suggested that cardiac I/R led to brain damages. Treatment with melatonin at all time points did not affect the number of activated and resident microglia, brain mitochondrial function, Alzheimer’s related proteins, or BBB protein after cardiac I/R, when compared with vehicle group (Figure 1).
ConclusionA single dose of melatonin administration failed to reduce brain damage following cardiac I/R injury.
Meta‐analysis of mouse transcriptomic studies supports a context‐dependent astrocyte reaction in acute CNS injury versus neurodegeneration
Authors: Das Sudeshna , Li Zhaozhi , Noori Ayush , Hyman Bradley T. , Serrano‐Pozo Alberto 
Published: December 2020

AbstractBackgroundNeuronal damage in both acute central nervous system (CNS) injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction, which has traditionally been depicted with GFAP immunohistochemistry. However, whether and how the nature of the CNS insult —acute versus chronic — influences the astrocyte response is unknown. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, in addition to a shared “pan‐reactive” signature common to both types of conditions.MethodWe performed a meta‐analysis of 15 publicly available astrocyte transcriptomic datasets from acute injury (n=6) and chronic neurodegeneration (n=9) mouse models. We identified a pan‐reactive, acute injury‐ and chronic neurodegeneration‐specific signatures, with both up‐regulated (UP) and down‐regulated (DOWN) genes.ResultThe number of UP/DOWN genes for each signature was: 67/21 for pan‐reactive, 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan‐reactive‐UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (i.e. Gfap, Vim), plus extracellular matrix (i.e. Cd44, Lgals1, Lgals3, Timp1), and immune response genes (i.e. C3, Serping1, Fas, Stat1, Stat2, Stat3). The acute injury‐UP signature was enriched in protein synthesis and degradation (both ubiquitin‐proteasome and autophagy systems), and anti‐oxidant defense genes, whereas the acute injury‐DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which were transcriptional repressors. The chronic neurodegeneration‐UP signature was further enriched in astrocyte‐secreted extracellular matrix proteins (Lama4, Cyr61, Thbs4), while the DOWN set included genes such as Agl (glycogenolysis), S1pr1 (immune modulation) and Sod2 (antioxidant).ConclusionWe conclude that acute and chronic injuries to the CNS are associated with distinct astrocyte gene expression programs beyond their common astrocyte reaction signature.
Reduction of neurogranin immunostaining in the hippocampus of post‐mortem brain of Alzheimer’s disease
Authors: Vontell Regina T. , Davis David A. , Barreda Ayled , Blennow Kaj , Zetterberg Henrik , Gultekin Sakir Humayun , DeKosky Steve , Scott William K. , Sun Xiaoyan ,   Brain Endowment Bank
Published: December 2020

AbstractBackgroundNeurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potential. It plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. In contrast, the expression of Ng protein in the human brain and its association with AD pathology are less well studied.MethodUsing immunohistochemical detection methods, we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated tau (AT8) in the post‐mortem hippocampus from four AD patients and four normal controls (NC). We quantitively compared the number of Ng positively stained cells in the hippocampal sub‐regions (dentate gyrus, CA3, CA2 and CA1) in post‐mortem donors with intermediate AD (i.e., Braak stage III‐IV) to NC (Braak 0) using Image Pro Premier automated image analysis software. The data was normalized to the number of Ng cells/mm2 and analyzed using a one‐way ANOVA. The AT8 and Aβ were scored using a scale that ranged from 0‐3; based on the number of immunopositive structures identified per mm2. The Ng data was correlated to the AT8 and Aβ using the Pearson’s correlation.ResultWe showed that Ng was localized mainly in neuronal cell soma and dendritic processes of the hippocampus of AD and NC donors. On average there was a 30% reduction (p<0.05) of Ng immunopositive neurons in the dentate gyrus, CA2 and CA1 hippocampal sub‐regions in cases of AD compared to that of NC. Ng positive cells did not significantly change in the CA3 hippocampal region in cases with AD when compared to NC. In cases with AD the reduction of Ng immunostaining was correlated with increased AT8 immunopositive neurofibrillary tangles (r=‐ 0.80; p<0.05), but not with Aβ plaques.ConclusionLoss of Ng immunostaining in CA1, CA2 and dentate gyrus confirms that synaptic damage in AD is a region‐specific event. The mechanism underlying such regional synaptic damage and the changes in Ng expression will be key in understanding the selective vulnerability of brain regions and systems to AD.