bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between amyloid‐β, white matter disease, functional brain networks, and mobility function: Possible indicators of reserve and resilience
Authors: Neyland Blake R. , Hugenschmidt Christina E. , Lockhart Samuel N. , Okonmah‐Obazee Stephanie , Sai Kiran Solingapuram , Baker Laura D. , Craft Suzanne , Miller Michael E. , Laurienti Paul J. , Kritchevsky Stephen B. 
Published: December 2020

AbstractBackgroundUndetected AD pathology in cognitively normal older adults may increase risk for mobility decline by both increasing white matter pathology and directly interfering with functional networks through Aβ deposition.MethodsThirty‐one cognitively normal older adults (75.01 ± 4.15 y, 35.5% female) enrolled in the Brain Networks and Mobility Function (B‐NET) study received PiB PET and MRI. A global cortical PiB average for each participant was calculated by coregistering PET to MRI using Freesurfer v5.6 to generate masks and thresholding at 1.21 to create PiB positivity groups (PiB‐ = 16, PiB+ = 15). White matter hyperintensity (WMH) volume was calculated with the Lesion Segmentation Toolbox (LST) implemented in SPM12. Mobility function was assessed using the expanded Short Physical Performance Battery (eSPPB), a 4‐meter walk, and a 400‐meter walk. Cognitive measures included the Montreal Cognitive Assessment (MOCA) and Digit Symbol Substitution Task (DSST). Associations were explored using linear regression, correcting for age, sex, and BMI in the fully adjusted mobility model while age, sex, and education were used in the fully adjusted cognition and WMH model.ResultsPiB+ individuals had significantly faster 4‐meter gait speed (p<0.05) and a trend for higher DSST (p=0.052). These associations were independent of WMH volume. PiB+ individuals also had significantly higher total (p<0.05) and motor WMH (p<0.05).ConclusionsThe observation that PiB+ individuals had better physical function than PiB‐ was unexpected given existing literature showing associations between regional Aβ volume and slower gait speed. It was also unexpected given that the PiB+ group had higher WMH volume, which is associated with slower gait speed. The current sample, which includes primarily individuals with good physical and cognitive function, may represent a resilient phenotype. Continued recruitment of more diverse participants with lower physical function will be an important addition to this sample. Future analyses will allow for the inclusion of APOE and an increased sample size. Whole‐brain functional connectivity will also be assessed in this cohort using graph‐theory based methods.
Differentiating Aβ40 and Aβ42 with a small‐molecule fluorescence probe
Authors: Ran Chongzhao , Wang Peng , Yang Jing , Zhu Biyue 
Published: December 2020

AbstractBackgroundAmyloid beta (Aβ) plaque, one of the characteristic biomarkers for Alzheimer’s disease (AD), has been discovered more than 100 years in the postmortem brains of AD patients. However, the role of Aβ plaques in the pathology of AD has still been heavily debated, because the correlation between plaque burdens (numbers and areas) and the severity of AD is poor [2]. In the plaques, Aβ40 and Aβ42 peptides are major constituents. Nonetheless, unlike the role of plaque, there is nearly no argument that Aβ42 has much higher neurotoxicity than Aβ40 does. Conceivably, differentiating Aβ40 and Aβ42 can considerably clarify the role of plaque in AD pathology. Unfortunately, small‐molecule probes with such capacity are scarce. Due to the small difference of amino acid sequence of the peptides, discovering small‐molecule probes capable of differentiating Aβ40 and Aβ42 has been considered as an impossible mission.MethodBased on recently published structures of Aβ fibrils, we designed iminocoumarin‐thiazole (ICT) fluorescence probes to differentiate Aβ40 and Aβ42, among which Aβ42 has been considered to be much higher neurotoxic.ResultWe demonstrated that ICTAD‐1 robustly respond to Aβ fibrils, evidenced by turn‐on fluorescence intensity and red‐shifting of emission peaks. Remarkably, ICTAD‐1 showed different spectra towards Aβ40 and Aβ42 fibrils. In vitro results demonstrated that ICTAD‐1 could be used to differentiate Aβ40/42 in solutions. Moreover, our data revealed that ICTAD‐1 could be used to separate Aβ40/42 components in plaques of AD mouse brain slides. In addition, two‐photon imaging suggested that ICTAD‐1 was able to cross BBB and label plaques in vivo. Interestingly, we observed that ICTAD‐1 was specific toward plaques, but not cerebral amyloid angiopathy (CAA) on brain blood vessels.ConclusionIn summary, we demonstrated that ICTAD‐1 is the first probe of its kind for differentiating Aβ40/42. ICTAD‐1 has the potential to dissect the toxicity contributions of Aβ40 and Aβ42, and could be considered as a lead compound for developing Aβ42 specific PET tracers.
Monoclonal GW‐23B7 removes Aβ‐pathologic oligomers and produces cognitive rescue without toxicity in old TGSWDI AD model mice with advanced pathology
Authors: Goni Fernando , Pires Geoffrey , Genovese Thomas S. , Wisniewski Thomas 
Published: December 2020

AbstractBackgroundWe have previously demonstrated that a monoclonal antibody (GW‐23B7) which targets specific β‐sheet secondary structure present in all AD pathologic oligomers produces significant cognitive rescue linked to lowering of both Aβ and Tau oligomers in APP/PS1 and 3xTg mouse models. We have now tested the efficacy and safety of GW‐23B7 in a cerebral amyloid angiopathy (CAA) TgSwDI model.MethodTwo groups of 15 months old TgSwDI AD animals were used for the preclinical trial. One group was inoculated i.p. weekly for two months with 100 µg/animal of GW‐23B7 in sterile saline (IgM) or sterile saline vehicle alone. The animals then underwent locomotor and cognitive testing followed by the brains being harvested for immunohistochemical and biochemical analysis.ResultThe intact GW‐23B7 (IgM) interacted with the brain vasculature and penetrated the BBB in the treated group without inducing microhemorrhages as determined by Prussian Blue staining. Moreover, the treated group showed significant cognitive rescue compared to controls on the Barnes Maze, which correlated with a significant decrease of soluble aggregated Aβ in specific ELISA tests, and a significant decrease of vascular and parenchymal Aβ pathology, with a reduction of activated glia shown by ABl1, GFAP and CD‐45 immunohistochemistry.ConclusionWe have shown that peripherally infused GW‐23B7‐IgM that only targets Aβ pathologic oligomers, reduces soluble oligomeric and deposited vascular and parenchymal pathology by an Aβ‐sequence independent mechanism avoiding ADCC induced microhemorrhages or inflammation. Our preclinical data testing GW‐23B7‐IgM in multiple AD models suggests that it could be safely translated to human AD clinical trials with a minimal possibility of ARIA or autoimmune toxicity complications.
Rehabilitation of persons living with dementia: Using technology to improve participation
Authors: Chiusano Carrie , Zarit Steven H. , Krause Christopher , Sewell Lynne , Harrison Aime S. , Liu Yin 
Published: December 2020

AbstractBackgroundRehabilitation following an illness or injury can improve functioning for persons living with dementia (PLWD) and help them remain as independent in daily life as possible. Gains, however, may be limited, because PLWD are often not able to engage fully in treatment. This study examined how a technology system, “It’s Never 2 Late” (iN2L), may help augment traditional rehabilitation approaches for PLWD by improving engagement in therapy sessions and achieving better functional outcomes.MethodThe study used a two group quasi‐experimental design. Older adults living with dementia (N= 96) were recruited from two rehabilitation departments housed within residential care communities operated by the same organization. Participants received daily occupational and physical therapy sessions using treatment as usual (TAU) at one site (n = 49) or treatment augmented with iN2L (n = 47) at the other site. A goal attainment approach was used to assess functional outcomes. As part of standard procedures at each site, initial and final functioning was assessed across 23 measures of functioning, mobility, and activities of daily living. Therapists selected goals from these items and specified levels of function that would indicate goal attainment. Goal attainment was scored comparing functioning at completion of treatment against initial goals. Engagement was rated from observations of treatment sessions by research assistants using the Pittsburgh Rehabilitation Participation Scale. It was hypothesized that patients at the iN2L site will show greater attainment of therapy goals and greater engagement during therapy sessions than patients receiving TAU and that improvement in engagement will mediate the association of treatment type (iN2L or TAU) with greater goal attainment.ResultParticipants in the iN2L treatment had significantly higher goal attainment than TAU, significantly higher levels of engagement at baseline, and significantly steeper increases in engagement over the course of therapy. A multilevel regression model in MPLUS was used to estimate total and indirect (i.e. mediation) effects. Results showed that the effects of treatment on goal attainment was significantly mediated by increases in engagement.ConclusionFindings suggest that iN2L technology has the potential to increase treatment engagement and enhance rehabilitation outcomes among older adults living with dementia.
From source to bedside: Translational studies of centella asiatica for Alzheimer's disease
Authors: Wright Kirsten M. , Magana Armando Alcazar , Bollen Melissa , Caruso Maya , Gray Nora E. , Matthews Donald G , David Jason C. , Mepham Brigitte , Stevens Jan F. , Maier Claudia S. , Quinn Joseph F. , Soumyanath Amala 
Published: December 2020

AbstractBackground
Centella asiatica (CA) is a botanical from Eastern medicine reputed to enhance cognition. Preclinical studies on CA and its bioactive components (triterpenoids and caffeoylquinic acids) strongly support its potential as a phytotherapeutic agent for aging, cognitive decline, and Alzheimer’s disease (AD) through influences on antioxidant response, mitochondrial activity, tau phosphorylation, and synaptic density. Translation from preclinical models to humans, and developing an optimized, reproducible product for use in aging and AD clinical trials, present particular challenges for phytotherapeutic agents compared to single chemical entities.MethodTo perform translational studies, a comprehensive scientific approach was developed including: identifying an optimal dose range for clinical evaluation, analysis and characterization of phytochemical variability, assessment for contamination and adulteration of raw material, formulation and manufacture of a stable botanical intervention and matching placebo, and application to a human pharmacokinetic trial (NCT03929250). Two doses of a custom made CA water extract product (2g and 4g) were administered orally to eight healthy elders (n=4 female, n=4 male) on two separate days. Plasma was collected over 12 hours to determine bioavailability and analyzed using reversed phase liquid chromatography‐tandem mass spectrometry.ResultThe maximum plasma concentration (Cmax) of the bioactive triterpenoids (1‐1.6µM) occurred at two hours (Tmax) after oral administration.ConclusionA robust scientific approach is necessary to address the complexity and variability of raw botanicals and botanical extracts for AD. Triterpenoids from CA water extract are orally bioavailable in humans.
The association between memory and hippocampal volumes differs in young‐old versus very old patients
Authors: Wong Christina G. , Caldwell Jessica Z.K. , Miller Justin B. 
Published: December 2020

AbstractBackgroundHippocampal atrophy and declines in episodic memory are hallmark features of Alzheimer’s disease (AD). A positive association between hippocampal volumes (HCV) and memory test performance has been demonstrated; however, this relationship may not hold true in Very‐Old individuals. Relationships between other AD biomarkers and dementia severity seen in Young‐Old groups have not been found in Very‐Old groups. This study compared the associations between memory test performance and HCV in Young‐Old and Very‐Old patients in a memory disorders clinic setting.Method126 Young‐Old (Age: range=65‐75, M=70.02, SD=3.18) and 57 Very‐Old (Age: range =76‐90, M=79.98, SD=3.54) patients who had neuropsychological assessment and magnetic resonance imaging (MRI) within 6 months of each other were included. Memory measures included immediate and delayed recall raw scores from WMS‐IV Logical Memory (LM), Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Brief Visuospatial Memory Test‐Revised (BVMT‐R). Left HCV, right HCV, and total intracranial volume (TIV) were computed with FreeSurfer volumetric analysis and underwent a quality assessment process. Partial correlations, accounting for age, education, and TIV, were conducted to determine the relationship between memory performance and HCV in each group separately.ResultIn the Young‐Old, significant positive correlations were found between all memory scores and HCV (r=.37 to .57, p’s<.001), indicating greater memory impairment with decreased HCV. In contrast, in the Very‐Old, only LM immediate recall was significantly correlated with HCV (left r=.37, p=.006, right r=.29, p=.032); HVLT‐R and BVMT‐R were not significantly associated with HCV in the Very‐Old (r=‐.02 to .24, p’s>.05). Fisher’s r‐to‐z transformation indicated significant differences in the magnitude of correlations between most memory scores and HCV as a function of age group.ConclusionExpected relationships between memory test performance and hippocampal volumes were found in Young‐Old patients, but these correlations were reduced and largely not significant in Very‐Old patients. Logical Memory was the one test associated with hippocampal volumes in the Very‐Old, which supports its inclusion in neuropsychological evaluations for this age group. Mechanisms associated with cognitive decline likely differ in advanced age and more research in this growing portion of the population is need.
Omega‐3 fatty acid add‐on nutritional immunotherapy delays progression to dementia in MCI patients on cholinesterase therapy
Authors: Fiala Milan 
Published: December 2020

AbstractBackgroundCholinesterase inhibitor (CI) drugs have cognitive benefits for one year but are not disease modifying. Omega‐3 fatty acids (omega‐3) with anti‐oxidants and resveratrol increase transcription of energy molecules, enhance phagocytosis of amyloid‐β (Aβ), increase monocyte/macrophages (MM) clearance of Aβ in the AD brain, and may be disease modifying.MethodWe test cognition by MMSE, energy in peripheral blood mononuclear cells (PBMC) and macrophages using a) single cell RNA‐seq, b) respirometry in the Seahorse Analyzer; c) phagocytosis of fluorescent Aβ and P‐tau. We study glycans in PBMC using nanoLC/ESI‐QTOF‐MS system.ResultWe enrolled into the study patients with cognitive problems who had been failing CI therapy according to neurologists and caregivers. We diagnosed study patients by neurological testing and imaging: 8 as subjective cognitive impairment (SCI), 7 as MCI, 1 as fronto‐temporal dementia (FTD), 2 as vascular cognitive impairment (VCI), and 3 as dementia with Lewy bodies (DLB). In the study, the patients added supplementation by omega‐3 fatty acid drink with anti‐oxidants and resveratrol (Smartfish) to CI. On these therapies, MCI patients maintained MCI status for >1 to 4.5 years and all improved Aβ immunity and activities of daily living in short term. The ω‐3 –supplemented MCI patients up regulated in vivo and in vitro glycolytic and TCA cycle enzymes and NAD synthesis enzyme NAMPT and increased Aβ phagocytosis. DLB and FTD patients progressed to dementia in 1 to 2 years, despite omega‐3.ConclusionMCI patients have energy deficiency in macrophages and other immune cells. Omega‐3 provide ox‐phos energy for immune clearance of Aβ and neuronal homeostasis around the clock, thereby delaying progression to dementia.
Short‐ and long‐term signatures of motherhood in the hippocampus: Implications for brain aging and dementia risk
Authors: Duarte‐Guterman Paula , Skandalis Dimitri A. , Lieblich Stephanie E. , Eid Rand S. , Galea Liisa A. 
Published: December 2020

AbstractBackgroundDiagnosis rates of Alzheimer’s disease (AD) are greater in women than men, who also show greater cognitive decline and AD neuropathology. Increasing parity (pregnancy and motherhood experience) is associated with reduced grey matter volume in the brain and in the long term greater risk of dementia, earlier age of AD onset, and AD neuropathology. This suggests that parity and AD are linked. The hippocampus is one of the first areas to be affected by AD. Here, we examine the short‐ and long‐term effects of parity on neuroplasticity and neuroinflammation to assess changes in hippocampal function, and apply transcriptomics to identify novel effects of parity on hippocampal physiology.MethodFemale rats were bred once (primiparous), twice (biparous), or not at all (nulliparous). Hippocampi were collected at 7 months (30 days postpartum) and 13 months (240 days postpartum) to measure synaptic density protein (PSD‐95 electrochemiluminescence assay), numbers of immature neurons (immunohistochemistry of doublecortin expression, DCX), neuroinflammation (IL‐1β, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, CXCL1, IFN‐γ, and TNF‐α electrochemiluminescence assay), and global gene expression (RNA sequencing).ResultsSynaptic protein PSD‐95 was significantly increased in mothers relative to nulliparous females but was independent of age. In contrast, DCX expression was reduced in mothers only at 7 months, and all groups exhibited significant reductions in DCX expression with age. Neuroinflammatory markers distinguished parity levels; for example, levels of interleukin‐6 (IL‐6) were elevated in biparous females of all ages. Finally, most differentially expressed genes in the transcriptome were associated with aging, but many transcripts were associated with parity exclusively at 7 months. Through gene ontology analysis, we found biological processes enriched during aging were especially involved in synaptic plasticity and neurogenesis, whereas parity involved metabolic processes and recycling of cellular components.ConclusionOur work identifies neuroplastic and neuroinflammatory signatures of parity in the hippocampus. The effects of motherhood are identified by short‐term physiological changes that persist through middle‐age. These data contribute to understanding the influence of parity on brain aging and Alzheimer’s risk.
Relationships between oral hypoglycemic drugs and memory decline in people with type 2 diabetes: A stratified longitudinal observational study
Authors: Wu Che‐Yuan , Ouk Michael , Wong Yuen Yan , Anita Natasha , Edwards Jodi D. , Yang Pearl , Shah Baiju R. , Kapral Moira , Herrmann Nathan , Lanctot Krista L. , Macintosh Bradley J. , Rabin Jennifer S. , Black Sandra E. , Swardfager Walter 
Published: December 2020

AbstractBackgroundThere is increased recognition that diabetes can elevate Alzheimer’s disease (AD) risk and exacerbate memory decline. However, few studies have compared memory decline among patients with diabetes using different oral hypoglycemic drug classes.MethodParticipants using any hypoglycemic medications from 2005 to 2019 were identified from the National Alzheimer's Coordinating Center database. Analyses were conducted separately in elderly with normal cognition (NC), amnestic mild cognitive impairment (aMCI), and dementia due to AD. Drug classes of interest included metformin, sulfonylureas, thiazolidinedione and dipeptidyl peptidase‐4 inhibitors (gliptins). Immediate and delayed recall outcomes were assessed using the Wechsler Memory Scale–Logical Memory test. Linear mixed‐effects models (in NC and aMCI) and mixed‐effects zero‐inflated Poisson or quasi‐Poisson regressions (in AD) were used to examine the associations between drug classes (time‐varying exposures) and memory performance over time. Confounding by indications were corrected by inverse probability treatment weighting. Models were adjusted for covariates including demographics, baseline MMSE, comorbidities and concurrent medications. In post‐hoc analyses, we examined whether ApoE genotype moderated the associations between drug class and memory.ResultIn NC (n=1,201, follow‐up years=3.43±3.27), metformin use was associated with better immediate (β=0.069 [0.011, 0.12]) and delayed (β=0.089 [0.032, 0.15]) memory over time, relative to no metformin use. No oral hypoglycemic drug class exhibited significant associations with memory in aMCI (n=671, follow‐up years=1.50±2.13). In AD (n=807, follow‐up years=1.90±2.21), DPP4 inhibitor use was associated with slower rate of decline in delayed memory (RR=1.22 [1.06, 1.40]), and thiazolidinedione use was associated with a faster rate of decline in immediate memory (RR=0.89 [0.82, 0.97]). In NC, DPP4 inhibitor use was associated with better delayed memory over time specifically among ApoE ε4 carriers (interaction: β=0.038 [0.0039, 0.072]). In AD, ApoE ε4 did not significantly interact with DPP4 inhibitor use, and thiazolidinedione use was associated with a faster rate of decline in immediate memory among non‐ε4 carriers (interaction: RR=1.26 [1.07, 1.47]).ConclusionAssociations between memory and particular oral hypoglycemic medications may depend on the presence of AD symptoms. ApoE ε4 may further modify these relationships. Confirmatory analyses in other cohorts, particularly those with more complete clinical data, are required.
Association between clinical and demographic factors on cerebral amyloid angiopathy and Alzheimer dementia
Authors: Mousavi SeyedAli , Hirsch‐Reinshagen Veronica , Mackenzie Ian R. , Ducharme Blake , Chatterjee Atri , Hsiung Ging‐Yuek Robin 
Published: December 2020

AbstractBackgroundCerebral amyloid angiopathy (CAA) is common in age‐related dementia. However, the relationships between severity of CAA and other demographic, and pathological factors are unclear. Therefore, we will examine them in this case series.MethodWe reviewed records of patients with dementia who underwent autopsy at the UBC Hospital Clinic for Alzheimer’s disease between 1994 and 2017 and selected cases in which CAA is identified with AD and compared them to cases with AD pathology only. We excluded cases with other coexisting pathologies (i.e. Lewy Body, TDP‐43). CAA was evaluated with Congo Red stain and rated semi quantitatively. We examined a subset in which APOE genotype was also available. Relevant clinical and pathological characteristics were compared by chi‐square test, ANOVA and logistic regression.Result225 cases (120 females) were included: 42 no CAA, 99 mild, 57 moderate, and 27 severe. APOE genotype was available in 70 cases (30 females). There was no significant association between sex (p = 0.316), and APOE genotypes (p = 0.799) with severity of CAA. History of dyslipidemia (p = 0.004), current alcohol intake (p = 0.016) and lower level of education (p = 0.001) were associated with greater severity of CAA. Episodic memory (p = 0.044) and visuospatial problems (p = 0.049) were significantly associated with increased severity of CAA. Diffuse and lobar atrophy (p = 0.013) and ventricular dilatation (p = 0.026) were more prominent in severe CAA cases. There was a positive correlation between deep nuclear atrophy (p < 0.001) and substantia nigra paleness (P = 0.013) with moderate CAA. There were also significant associations between severity of CAA with frequency of the microscopic hemorrhage (p < 0.001), lacunar infarcts (p = 0.011), and arteriosclerosis (p = 0.003).ConclusionGreater severity of CAA is associated with certain clinical and pathological factors including dyslipidemia, alcohol intake, lower education, and presence of lacunar infarcts. Sex and APOE genotype do not appear to have any significant influence on the severity of CAA in AD. Further studies will help to confirm these potential modifiable risk factors for CAA in AD.