bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding the Neuronal Requirement for Glycolysis
Authors: Li Huihui , Shields Lauren , Lo Iris , Rathmell Jeffrey , Heiden Matthew Vander , Nakamura Ken 
Published: December 2022

AbstractBackgroundThe brain has a high energy demand and consumes large amounts of glucose. In Alzheimer’s disease (AD), glucose uptake is reduced, but the significance of this change for neurodegeneration is unclear. Furthermore, whether or not neurons directly take up glucose has been debated in the field. Indeed, the lactate‐shuttle hypothesis predicts that glucose is primarily metabolized by glia or astrocytes into lactate, which is subsequently delivered to neurons and utilized continuously under aerobic conditions. However, studies utilizing glucose analogs challenge that model, and support direct glucose uptake by neurons. Here, we sought to understand the essential role of the neuronal glucose metabolism, to provide a starting point for new approaches to understand and target metabolic changes in AD.MethodTo interrogate the role of neuronal glucose metabolism, we generated mice with targeted deletion of the dominant glucose transporter (GLUT3), or the enzyme that catalyzes the final step in glycolysis (PKM1), specifically in CA1 and other forebrain neurons from postnatal day 19. Mice were assessed with spatial learning and memory behavioral tests, and glucose metabolism and ATP production were monitored in individual neurons and synapses using a FRET‐based live imaging approach.ResultMale and female GLUT3 KO mice showed age‐dependent memory deficits beginning at 7 months of age, and PKM1 KO mice showed impaired memory at 12 months of age, although this defect was only present in female mice. GLUT3KO neurons had decreased basal glucose levels and uptake. GLUT3KO synapses also showed significantly reduced basal ATP levels, and their ATP levels were unresponsive to electrical stimulation, which increases neuronal energy demand. In hippocampal neurons, blocking the last step of glycolysis by PKM1 knockout decreased the basal level of ATP production at synapses in cultures prepared from female pups, and resulted in unresponsiveness to electrical stimulation in both female and male cultures.ConclusionOur results indicate that to function properly and maintain ATP levels at synapses, neurons require glucose that can be taken up directly and metabolized through glycolysis. Therefore, decreased glucose uptake in AD may contribute to neuronal dysfunction and degeneration.
Image‐based primary age‐related tauopathy as a risk of dementia: a five‐year longitudinal study
Authors: Kim Han‐Kyeol , Lee Jae Hoon , Chun Joong‐Hyun , Ryu Young Hoon , Lyoo Chul Hyoung , Cho Hanna 
Published: December 2022

AbstractBackgroundTo investigate cognitive and pathological (amyloid and tau) changes of image‐based primary age‐related tauopathy (PART) in a long‐term follow‐up cohort study.MethodIn this study, a total of 108 patients who were both negative in amyloid and tau PET images were enrolled. All participants completed the same two PET scans (18F‐flortaucipir for tau and 18F‐florbetaben for Aβ), and neuropsychological tests at least twice over 5 years. We defined PART+ as those who had a higher standardized uptake value ratio (SUVR) in the entorhinal cortex than the cutoff calculated by the Youden index. We investigated the cognitive and 18F‐florbetaben and 18F‐flortaucipir SUVR changes longitudinally between PART+ and PART‐ participants while adjusting for age, sex, education, and ApoE4.ResultCompared with PART‐, PART+ participants had more rapid worsening of MMSE (β=‐0.274, p<0.001), CDR‐SB (β=0.081, p<0.001), and memory function (β=‐0.140, p=0.008). No significant differences were observed in the language, visuospatial, frontal‐executive, attention domains, and total cognitive battery score. In PART+ participants, the annual Aβ accumulation rate from whole cortical SUVR was also increased (β=0.016, p=0.003), and a more rapid accumulation rate was observed in Alzheimer’s disease (AD) specific hot meta‐region‐of‐interest (meta‐ROI) SUVR, compared with PART‐ participants (β=0.019, p=0.001). The annual tau accumulation rate of PART+ was higher than PART‐ in the entorhinal cortex (β=0.010, p<0.001), however, no differences were observed in whole cortical SUVR tau.ConclusionThe PART+ participants showed a rapid cognitive decline in memory function as well as MMSE, and CDR‐SB, than those of PART‐. In addition, amyloid was accumulated at a faster rate in PART+ participants and tau was accumulated more rapidly in the medial temporal area. In conclusion, our longitudinal study suggests that image‐based entorhinal tau defined as a PART+ could be an earlier stage than the preclinical stage of AD.
The Dementia Engagement Modelling Program (DEMP): a novel Australian model of care for aged care residents affected by COVID‐19
Authors: Atee Mustafa , Morris Thomas , Alford Marie 
Published: December 2022

AbstractLike other countries, aged care homes in Australia have been significantly affected by the COVID‐19 pandemic. To ensure the safety of residents and staff, lockdown, and social restrictions (e.g., limited or no visits from family) have been introduced across Australia. These measures caused tremendous emotional, psychological, and physical burdens on residents, particularly those living with dementia.In response to the pandemic, the Australian Government has funded the Aged Care COVID‐19 Grief and Trauma support package for older people receiving aged care, their families, and aged care staff. Part of this package is the Dementia Engagement Modelling Program (DEMP), a free national support program developed by Dementia Support Australia, HammondCare to help staff support residents whose wellbeing have been affected by COVID‐19 with tailored engagement strategies. The program represents a first line multimodal support for people living with dementia in residential aged care who may have experienced withdrawal, frustration, or fear and at a greater risk of developing behaviors and psychological symptoms of dementia (BPSD), such as apathy, anxiety, and depression. Through a multidisciplinary team of dedicated consultants, the program delivers best practice, person‐centered engagement strategies to support staff, providing meaningful engagement, comfort, and reassurance to residents living with dementia. DEMP consultants work collaboratively and closely with lifestyle and care staff to develop tailored activities and provide appropriate resources (e.g., brokerage items such as music therapy) for engagement. DEMP will also provide support and coaching to staff for the individual or small groups to ensure that both staff and residents gain the full benefit from the program.The eligibility criteria for DEMP support include aged care homes that: 1) experienced an outbreak of COVID‐19 or those subject to a precautionary lockdown, and/or 2) sought engagement plans and strategies for residents living with dementia, or those at risk of developing BPSD due to COVID‐19 restrictions.This descriptive study will discuss the DEMP's model of care, eligibility criteria, activities, and outcomes and provide case examples that can guide meaningful engagement for other aged care residents living in other countries during COVID‐19.
Structural and metabolic brain correlates of excess Aβ accumulation at the earliest AD continuum
Authors: Cacciaglia Raffaele , Milà‐Alomà Marta , Shekari Mahnaz , Operto Grégory , Falcon Carles , Minguillón Carolina , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Quevenco Frances‐Catherine , Gispert Juan Domingo 
Published: December 2022

AbstractBackgroundThe discrepancy between the expected and actual level of cerebral amyloid (Aβ) deposition for any given level of soluble Alzheimer’s disease (AD) core biomarkers, has been proposed as a proxy measure of factors promoting fibrillar Aβ accumulation in the brain. However, the impact of these factors on brain structure and function in cognitively unimpaired (CU) individuals has not been reported. Here, we assessed the impact on brain structure and metabolism of the excess cortical Aβ deposition for a given level of CSF pTau/Aβ42 ratio, a marker of pathophysiological progression along the Alzheimer’s continuum. Furthermore, we analyzed whether this association is modulated by the APOE‐ε4 risk allele.MethodWe included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI), 18F‐Fluorodeoxyglucose (FDG) and 18F‐Flutemetamol positron emission tomography (PET) scans. CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). The centiloid pipeline was applied to Aβ PET and a general linear model (GLM) was implemented to regress out the effects of CSF pTau/Aβ42 ratio from centiloid values. These residualized centiloids (resCent) were used in subsequent GLMs to predict whole‐brain gray matter volume (GMv) as well as metabolism. Statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels.ResultNegative associations between resCent and GMv were observed in the dorsolateral prefrontal cortex (Fig. 1a), while for FDG, positive associations were found in the inferior frontal and superior temporal gyrus, as well as the anterior cingulate and inferior temporal cortices (Fig. 1b). The associations for GMv were further modulated by the APOE‐ε4 risk allele in a dose‐dependent manner, indicating a lower GMv in ε4‐carriers, in the inferior and middle frontal gyrus, subgenual cingulate cortex and the insula (Fig. 2).ConclusionOur results suggest that, factors associated with excessive Aβ deposition are associated with structural and metabolic brain alterations already in the earliest stages of preclinical Alzheimer’s continuum. The associations for GMv were modulated by APOE‐ε4 indicating a higher structural vulnerability to these factors for carriers of the risk allele all along the preclinical stages of AD.
Is cortical grey matter diffusivity an early biomarker for neuronal damage?
Authors: Debatisse Justine , Leng Fangda , Brooks David J , Edison Paul 
Published: December 2022

AbstractBackgroundThere is growing evidence that pathological changes in Alzheimer’s disease (AD) begin several years before the symptom onset. Neuroimaging approaches can be used to detect microstructural alterations in the early stages of neurodegeneration using diffusion‐weighted MRI. Cortical grey matter mean diffusivity (cMD) is thought to be increased in AD following pathological alterations resulting in disrupted neuronal function, neuronal death and cellular atrophy. We hypothesised that changes in MD could be detected early in the disease progression and that they would be correlated with structural imaging biomarkers.Method72 patients (mean age=69.1, SD=9.2) cognitively normal (CN, n=21) and with mild cognitive impairment (MCI, n=51) were included in this study. All participants underwent T1‐weighted MPRAGE MRI, diffusion tensor imaging (DTI) and PET amyloid ([18F]flutemetamol). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. DTI data were processed with FSL v.6.0 to compute MD maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter reference to create target‐to‐cerebellar ratio. Subjects were considered positive with an uptake value of greater than mean+2SD of the control subjects. Student's t‐test were used to compare imaging modalities between CN and MCI participants. Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.ResultThere was a significantly increased MD in MCI compared to CN participants in hippocampus (p=0.0213) and in medial temporal lobe (p=0.033). There were no significant group differences neither in whole brain mean cortical thickness (p=0.6984) nor in temporal cortical thickness (p=0.0923). Interestingly, when splitting subjects based on their amyloid status, we found that whole brain MD was significantly negatively correlated with whole brain cortical thickness in amyloid negative (CN+MCI amyloid negative, p<0.001) but not in amyloid positive (CN+MCI amyloid positive, p=0.99).ConclusionWe found that changes in gray matter diffusivity could be detected in the early stages of AD pathology. We also found that there is a direct relationship between MD and structural changes (i.e. cortical thickness) only before amyloid deposition suggesting that MD provides information about early microstructural changes before macrostructural changes.
Resistance, brain and cognitive resilience to ATN in a memory clinic population
Authors: Ribaldi Federica , Quattrocchi Lara , Garibotto Valentina , Tomczyk Szymon , Scheffler Max , Lovblad Karl‐Olof , Fernandez Aldara Vazquez , Chicherio Christian , Blennow Kaj , Frisoni Giovanni B , Altomare Daniele 
Published: December 2022

AbstractBackgroundBrain resistance (R) has been defined as the capacity of the brain to preserve its integrity and to sustain normal cognition despite aging. Resilience has been defined as the capacity to sustain a better‐than‐expected brain integrity (brain resilience,BR) or cognitive performance (cognitive resilience,CR) in presence of pathological burden. There is a high variability in the individuals’ R, BR or CR, and it has been demonstrated that individuals with high BR and CR develop symptoms later than those with low CR. The aim of this study was to investigate the association between demographics, clinical features, and blood measures and individual’s R, BR and CR. Moreover, we investigated the cognitive longitudinal trajectories of individuals with low and high R, BR and CR.Method166 patients from the Geneva Memory Center cohort (41 controls, 106 MCI, 19 dementia) who underwent amyloid‐PET (A), tau‐PET (T), MRI (N) and clinical and neuropsychological assessment were included. Linear regression models were performed to extract residuals, used as measures of individual R (age predicted by ATN), BR (thickness by AT), and CR (MMSE by ATN). The associations between R, BR, CR and demographics, clinical features, blood measures were investigated using linear models. Moreover, linear mixed models were performed to examine whether longitudinal changes in MMSE scores differed as a function of R, BR or CR.ResultMean age was 71 (8), 52% were female, mean years of education was 14 (4). Resistance predicted by ATN was positively associated with plasma NfL (β=0.50,p<0.001) and GFAP (β=0.32,p=0.007). Brain resilience predicted by AT was associated with gender (higher in males) and, yet not significantly, age (β=0.14,p=0.063). Cognitive resilience predicted by ATN was associated with age (β=0.18,p=0.020) and education (β=0.27,p<0.001). Individuals with low cognitive resilience had a lower MMSE scores at baseline but those with higher cognitive resilience showed a faster cognitive decline.ConclusionWe confirm the expected associations between BR, age and gender, and between CR and age and education, consistent with previous literature findings. The association between R and plasma markers opens novel perspectives for screening and preventive programs while the assessment of the effect of plasma biomarkers on resistance needs further investigation.
Psychosocial risk factors on hippocampal subfield volumes: the Medea‐7T study
Authors: Twait Emma L. , Blom Kim , Koek Huiberdina L. , Zwartbol Maarten H.T. , Ghaznawi Rashid , Hendrikse Jeroen , Biessels Geert Jan , Geerlings Mirjam I. 
Published: December 2022

AbstractBackgroundSpecific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial risk factors in the development of neurodegenerative diseases. The current study had two aims: to perform a systematic review on psychosocial factors and hippocampal subfield volume and to explore the association of psychosocial factors with hippocampal volume, both total volume and among subfields, using high‐field 7T MRI.MethodWithin the Memory Depression and Aging (Medea)‐7T study, 333 participants without dementia underwent 7T MRI and answered psychosocial questionnaires. Hippocampal subfields were automatically segmented from T2‐weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis (CA)1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent life events, and social support), adjusting for age, sex, and intracranial volume.ResultNeither depression nor anxiety was associated with specific hippocampal (sub)volumes. Recent life events were associated with greater total volume (B = 0.17, 95% CI: 0.07; 0.27). However, reporting childhood maltreatment was associated with smaller total hippocampal volume (B per standard deviation = ‐0.20, 95% CI: ‐0.31; ‐0.10). Among subfields, high social support was associated with greater volume in the CA3 (B = 0.47, 95% CI: 0.21; 0.73).ConclusionThis study suggests possible differential effects among hippocampal (sub)volumes and psychosocial factors, specifically reporting childhood maltreatment and social support. The systematic review highlighted inconsistencies in results, highlighting the need for future studies validating these results.
Alzheimer’s disease specific MRI brain regions are differentially associated with accelerated decline as defined using sigmoidal cognitive turning point methodology in amyloid‐positive AIBL participants
Authors: Gillis Cai , Cespedes Marcela Ines , Maserejian Nancy Nairi , Dore Vincent , Maruff Paul , Fowler Christopher , Rainey‐Smith Stephanie , Villemagne Victor L , Rowe Christopher , Martins Ralph N , Vacher Michael , Masters Colin L , Doecke James D 
Published: December 2022

AbstractBackgroundVariability in cognitive decline among adults with Alzheimer’s disease (AD) is seen across studies. While such variability is often modelled using linear models, in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, application of a sigmoidal methodology has shown excellent precision in modelling cognitive and biomarker changes. Here we expand these findings by examining associations of brain volumes in AD specific Regions of Interest (ROIs) with accelerated cognitive decline among amyloid‐beta positive (Ab+) AIBL participants.MethodLongitudinal cognitive scores for the AIBL PACC, Language, Visuospatial functioning and CDR‐SB were mapped to sigmoidal trajectories, with a threshold defining the inflection point of accelerated cognitive decline. Participants to the left of the threshold were classified as having non‐accelerated decline (non‐accelerators), and participants beyond the threshold were classed as accelerators (Figure 1B). Using these classifications, we investigated differences in 16 ICV corrected ROI (left and right hemispheres pooled) for reductions in brain volume via generalised linear models adjusted for age, gender, and APOE‐e4 status. Three participant subgroups were tested: 1) Ab+/Tau unknown, 2) Ab+/Tau‐ and 3) Ab+/Tau+. Significant t‐values for the summed ROI volumes were mapped on a standard brain mesh for visualisation.ResultOf regions tested, two stood out consistently amongst top markers in each of the participant subgroups and cognitive outcomes: 1) supramarginal volume and 2) middle temporal volume (Figure 1C). Largest volume differences between accelerators and non‐accelerators were seen in the Ab+/Tau+ group; whilst smallest p‐values were in the Ab+/Tau unknown group due to a larger sample size (Table 1). Brain mesh visualization showed most of the AD signature ROIs altered in accelerator groups as compared with non‐accelerator groups. Figure 1D shows the AD signature for each cognitive outcome amongst the Ab+/Tau participant group. Top ranked ROI for the left being middle temporal volume (T=7.10, PACC) and supramarginal volume (T=7.10, CDR‐SB).ConclusionSigmoid analyses of MRI using binary cognitive scores show decreased ROI volumes in AIBL Ab+ participants with accelerated cognitive decline. This effect was mediated by known information on Tauopathy. Whilst effect sizes were high, smaller sample sizes in some groups affected p‐values and should therefore be replicated in larger samples.
Discrete white matter hyperintensity (WMH) growth quantification is superior to measurements of total longitudinal WMH volume change: implications for clinical trials in VCID
Authors: Bahrani Ahmed Ali , Barber Justin M , Gold Brian T. , Ali Doaa , Powell David K , Van Eldik Linda J , Goldstein Larry B , Wilcock Donna M , Jicha Gregory A 
Published: December 2022

AbstractBackgroundSmall vessel ischemic disease (SVID) is a major risk factor for late‐life cognitive impairment and dementia (VCID). White matter hyperintensities (WMH) are a SVID biomarker that can be detected on MRI FLAIR imaging. Prior studies show dynamic change in WMH volumes that increase and decrease within subjects over time. We reported a method to quantify discrete WMH volume growth and regression in individuals over one‐year with instrumental validation performed within the MarkVCID consortium. The present study provides preliminary evidence for the clinical relevance of this methodology.Method3D MRI T1‐weighted and FLAIR images at baseline and 12‐month follow‐up visits for sixty‐one participants (mean age 74 ± 5.9 years, 31 women) were analyzed. The Stroop test was administered using the CANS‐MCI computerized battery. WMH growth and regression were quantified for all participants. A linear regression model was used to assess the association of dynamic WMH changes with Stroop performance.ResultWMH growth, but not regression or total WMH volume changes was associated with Stroop performance at the 12‐months (β = ‐0.24, P = 0.02) after controlling for sex, and age (graph).ConclusionThese data show that WMH growth, but not regression or total WMH volume change, was associated with a decline in performance on the Stroop test over12‐months. These findings highlight the importance of studying dynamic, within subject, WMH growth and regression rather than solely focusing on longitudinal change in total WMH volume measurements. Measurement of WMH growth may help reduce sample sizes, facilitate clinical trial conduct, and optimize the potential to identify interventions intended to mitigate SVID contributions to VCID.