bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships between cerebral tau and glucose metabolism in cognitively normal older adults
Authors: Crook Harry , Debatisse Justine , Nowell Joseph , Edison Paul 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterised by the accumulation of amyloid‐β and tau in the brain and subsequent neurodegeneration. The relationship between tau accumulation and glucose metabolism has been elucidated in AD, however the relationship between the two in the early stages of the AD trajectory remains elusive. Here, we examine this relationship using fluorodeoxyglucose (FDG) and flortaucipir (FTP) positron emission tomography (PET) in a cohort of cognitively normal older adults.Method72 cognitively normal participants (mean±SD age 78.7±6.3 years old) were recruited through the Harvard Ageing Brain Study and had available FDG‐PET, FTP‐PET, and structural MRI scans. Region of interest analysis was utilised to determine the regional uptake of each PET tracer. 40 participants were split into high‐tau and low‐tau groups based on the highest 20 and lowest 20 FTP uptake values from the medial temporal lobe excluding the hippocampus (MTL (no hippocampus)). FDG uptake was compared between high‐tau and low‐tau groups, while correlations between FDG and FTP uptake were examined.ResultGlucose metabolism was significantly higher in the low‐tau group than the high‐tau group in the whole brain (p = 0.023), frontal lobe (p = 0.028), temporal lobe (p = 0.014), parietal lobe (p = 0.027), MTL (p = 0.01), MTL (no hippocampus) (p = 0.002), anterior cingulate cortex (p = 0.045), and posterior cingulate cortex (p = 0.023). Significant negative correlations were found between FTP uptake in the MTL (no hippocampus) and FDG uptake in the whole brain (r = ‐0.317,p = 0.046), temporal lobe (r = ‐0.383,p = 0.015), parietal lobe (r = ‐0.316,p = 0.047), MTL (r = ‐0.437, p = 0.005), MTL (no hippocampus) (r = ‐0.444,p = 0.004), anterior cingulate (r = ‐0.320,p = 0.044), and posterior cingulate (r = ‐0.361,p = 0.022). FTP uptake in the temporal lobe negatively correlated with FDG in the temporal lobe (r = ‐0.326, p = 0.04) and MTL (no hippocampus) (r = ‐0.337,p = 0.034).ConclusionHigh tau levels in the MTL was associated with hypometabolism in cognitively normal older adults, suggesting that tau accumulation may cause decreased glucose metabolism without inducing cognitive deficits. Furthermore, negative correlations between FDG and FTP uptake highlight the link between tau accumulation and neurodegeneration before the onset of cognitive decline. The association between tau accumulation and reduced glucose metabolism in cognitively normal participants supports the need for research and intervention to be aimed at the preclinical stages of AD.
Prevalence and clinical associations of atrophy subtypes using clinical routine image analysis software in MCI patients from a memory clinic population
Authors: Schwarz Adam J. , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Longo Clarisse ,   the MEMENTO Study Group
Published: June 2023

AbstractBackgroundThree patterns of brain atrophy have been consistently identified in cases of Alzheimer’s dementia [1]: a limbic‐predominant (LP) phenotype, with atrophy of the hippocampus but relatively spared neocortex; a hippocampal sparing (HS) phenotype, with atrophy in the cortex (especially lateral temporal and parietal lobes) but sparing of the hippocampus; and a typical/diffuse (TD) phenotype that presents with atrophy in both. A recent study extended this concept to a less severely affected memory clinic population (the MEMENTO Study). Here, we assessed atrophy subtypes in that same population using an approach based on the output of QyScore® an FDA‐approved and CE‐marked image analysis software.Method1642 MCI participants from the MEMENTO cohort (Age 71±9, MMSE 27.8±2.0, CDR‐SB 0.6±0.7) had 3DT1 MRI scans analyzed with QyScore®. 678 (41%) had amyloid status from CSF or PET, of which 193 (28%) were amyloid‐positive (A+). Neurodegeneration‐positive (N+) atrophy subtypes were defined on individual scans using z‐scores from parietal cortex and hippocampus volumes referenced to 1290 cognitively normal individuals. LP and HS were defined by atrophy (z←1.64) of parietal lobe or hippocampus only, and TD by atrophy in both structures (otherwise N‐).ResultThe proportion of single‐domain amnestic (aMCIsd), multi‐domain amnestic (aMCImd), single‐domain non‐amnestic (naMCIsd) and multi‐domain non‐amnestic (naMCImd) individuals was 10%, 50%, 21% and 18% respectively. N+ subtypes were more prevalent in amnestic (aMCIsd 18%, aMCImd 17%) than non‐amnestic (naMCIsd 8%, naMCImd 10%) presentations. N+ subtypes were more common in A+ participants, especially the amnestic presentations (aMCIsd 42%, aMCImd 29%). Overall, the HS subtype was the most common (8% of all cases, 16% of A+ cases), followed by LP (4%/6%) and TD (2%/3%). The LP subtype was more prevalent in amnestic presentations.ConclusionThe relatively low prevalence of the TD subtype in this cohort is consistent with [2]. The overall prevalence of N+ subtypes in MEMENTO by this method is intermediate between those previously reported using a similar method for ADNI CN A+ and aMCI A+ cohorts [3].[1] Ferriera et al. (2020) Neurology 94:436 [2] Planche et al. (2021) Alz & Dem 17(4):651 [3] Charil et al. (2018) AAIC
Resistance and resilience to Alzheimer’s disease pathology associated with lower severity of other neuropathologic diseases
Authors: Culhane Jessica E. , Mock Charles , Chan Kwun Chuen Gary , Chen Yen‐Chi , Kukull Walter A. 
Published: June 2023

AbstractBackgroundOlder adults with multiple types of neuropathologic disease may be at higher risk for cognitive impairment, but the impact of specific combinations of disease on cognition is unclear. Alzheimer’s disease neuropathologic change (ADNC) is the most common neuropathologic disease found in dementia cases. Cognitively normal participants without ADNC are “resistant”; those with ADNC are “resilient.” To determine if resistant and resilient participants have lower levels of non‐AD neuropathologic diseases, we compared neuropathologic features against participants with clinical Alzheimer’s dementia.MethodWe included autopsied participants from the National Alzheimer’s Coordinating Center Uniform Data Set whose last visit was within two years of death. Participants were excluded if they had rare neuropathologic diseases or were not evaluated for each neuropathologic feature. For both resilient (normal cognition, moderate or high NIA‐AA ADNC score) and resistant (85+ years old, normal cognition, no or low NIA‐AA ADNC score) individuals, we calculated the odds of having non‐AD pathologic features against a control group (moderate or high NIA‐AA ADNC score, clinical dementia), adjusting for age at death, sex, education, and presence of APOE e4 allele(s). Features included vascular pathology (number of infarcts and microinfarcts; severity of arteriosclerosis, atherosclerosis, and cerebral amyloid angiopathy), Lewy body disease (LBD) staging, and limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy (LATE‐NC) staging.ResultOf 1,190 participants who met inclusion criteria, 59 were resistant, 41 were resilient, and 1,090 were controls. Both resistant and resilient participants had lower severity of LATE‐NC (resistant aOR: 0.23, 95% CI: 0.19‐0.27; resilient aOR: 0.49, 95% CI: 0.42‐0.56) and LBD (resistant aOR: 0.71, 95% CI: 0.63‐0.80; resilient aOR 0.52, 95% CI 0.44‐0.60). Resistant individuals also had lower odds of CAA, and resilient individuals had lower odds of arteriosclerosis.ConclusionResistance and resilience to ADNC is associated with lower odds of other neuropathologic disease, including Lewy bodies and LATE‐NC. This supports prior research indicating an interactive effect of multiple neuropathologic diseases on risk of dementia, and specifically that having LBD or LATE‐NC contributes to the risk of developing Alzheimer’s dementia. Understanding how to prevent LBD and LATE‐NC could lead to higher resistance and resilience to Alzheimer’s dementia.
Long‐term memory over 1‐week and markers of brain pathology in cognitively unimpaired individuals from a Colombian cohort with autosomal dominant Alzheimer’s disease
Authors: Ezama Laura , Chen Kewei , Vila‐Castelar Clara , Baena Ana Y. , Martinez Jairo E. , Aduen Paula , Munera Diana , Noriega Daisy , Langella Stephanie , Ramirez‐Gomez Liliana A. , Lopera Francisco , Quiroz Yakeel T. 
Published: June 2023

AbstractBackgroundLong‐term forgetting (LTF) over days or weeks may be a sensitive early marker of Alzheimer’s disease (AD), useful for preclinical AD trials. We examined associations between LTF and markers of brain pathology in individuals from the world’s largest kindred with autosomal dominant AD due to the Presenilin‐1 (PSEN1) E280A mutation.MethodsA total of 14 cognitively unimpaired PSEN1 mutation carriers (mean age: 35.9 years) and 16 matched non‐carriers (mean age: 32.8 years) from the Colombia‐Boston Biomarker Study of autosomal dominant AD were included. Participants underwent amyloid (11‐C Pittsburgh compound B) and tau (Flortaucipir) PET imaging, and memory tasks (NEUROPSI word list, stories and semi‐complex figure). We examined performance on learning and delayed recall after a 20‐min, 1‐day and 7‐day interval. LTF was calculated for the three tasks as the proportion of material retained at 20 min that was recalled 7 days later. Mann‐Whitney tests were conducted to compare memory performance and LTF between PSEN1 mutation carriers and non‐carriers. Spearman’s correlations were used to examine the association between LTF and brain pathology markers of amyloid burden and regional tau (entorhinal and inferior temporal cortices). Fisher’s exact tests were used to compare correlation coefficients between groups.ResultsLearning did not differ between carriers and non‐carriers. Compared to non‐carriers, carriers had lower 20‐min recall in all three tasks (p<0.05), and lower 1‐day and 7‐day recall of word list and stories. There were no group differences in word list, stories or figure LTF. Further, no group differences were observed in the association of amyloid burden and LTF on any of the tasks. Lower word list LTF was associated with greater entorhinal burden among carriers, and the strength of this association was significantly different between carriers and non‐carriers (p = 0.046; carriers: r = 0.73, p = 0.003; non‐carriers: r = 0.43, p = 0.094).ConclusionsOur preliminary findings show that, while rates of LTF over 7 days did not differ between PSEN1 carriers and non‐carriers, carriers had lower verbal memory recall over 1 and 7 days. Further, LTF was associated with early tau accumulation, suggesting that longer recall intervals may be more sensitive to detect subtle memory changes in cognitively unimpaired individuals at risk for AD.
Identification of SNP interactions in chromosome 19 for Alzheimer’s Disease through Capsule Network
Authors: Bae Jinhyeong , Nho Kwangsik , Saykin Andrew J. , Risacher Shannon L. , Penchev Valentin , Apostolova Liana G. 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is highly heritable. Genome‐wide association studies and whole genome sequencing have uncovered many AD‐risk variants but are still falling short from providing an explanation of the full heritability. To address this issue, we devised a novel deep learning approach that can quantify the polygenic risk score (PRS) of genetic variants and their interactive effects at the individual level.MethodWe applied a novel deep learning model to the 266,161 SNP chromosome 19 data of 313 AD and 457 cognitively unimpaired (CU) ADNI patients. Through occlusion maps, we quantified the predictive value of 70,643 possible AD‐determining SNPs and identified the top 0.05%, i.e., 35 SNPs, without imposing any additional pre‐assumptions. Epistatic effects increasing or decreasing the risk of AD were further investigated by using the co‐occlusion method. The top 35 AD‐determining SNPs were validated in an external dataset.ResultThe model achieved 68.18% in predicting AD vs. CU. The top 35 AD SNPs showed dominant impact in AD prediction as single as well as an interactive factors. 574 interactions that increased AD risk were found for AD‐predicted patients while 358 interactions predictive of cognitively unimpaired performance were found for CU‐predicted patients. Rs56131196 (APOC1) was recognized as the most significant AD‐determining SNP. It showed interactions with at least 8 other SNPs that further influenced the risk of AD. Rs2229918 (EERC1) was recognized as the most powerful SNP influencing CU diagnostic accuracy.ConclusionOur deep learning model provides a novel approach for assessing the genetic risk for AD at the individual chromosomal level. The results indicate that APOC1 and ERCC1 are strong genetic risk factors for the development of AD. These findings are consistent to the previous medical research. Our model’s capability in deciphering the impact of SNPs on AD development could prove critical for early presymptomatic risk assessment and personalized therapeutic strategy approaches.
Clinically relevant monitoring of long‐term night‐time behaviour and physiology from the homes of people living with dementia
Authors: Kolanko Magdalena A , Soreq Eyal , Barnaghi Payam , Lai Helen , Dijk Derk‐Jan , Sharp David J 
Published: June 2023

AbstractBackgroundDisturbances of sleep and night‐time behaviours are amongst the most disabling symptoms of dementia. They often increase carers’ burden and the risk of institutionalization. The causes are complex and are difficult to investigate because of a lack of acceptable methods for monitoring behaviours in the home. Here we show that a passive under‐mattress can be used to track changes in night‐time behaviour and physiology, and that a range of digital biomarkers produced are informative in understanding the effects of medication changes, disease progression and intercurrent illness in patients living with dementia (PLWD).MethodWe used contactless Withings Sleep Mattress (WSM) to monitor bed‐occupancy in 4 PLWD (age 74‐93, 3males) enrolled into the CR&T MINDER cohort study. Each participant was tracked over 1000 nights between 2019 and 2021. Minute‐to‐minute timeseries were extracted from WSM to calculate bed occupancy metrics and nocturnal physiology measures (heart and breathing rates (HR/BR)). Raw measures were standardized within subjects by comparing each time point to the mean of the time points that preceded it. We then investigated the relationship between these metrics and clinical events such as infections and medication.ResultThe 4 case studies illustrate the potential of this technology for passive health monitoring in PLWD. High levels of intraindividual variability in behavioural and physiological metrics were observed. Progressive changes in bed occupancy were observed in two patients with frontotemporal dementia and Alzheimer’s disease (Cases 1&2). Intercurrent illness and medications changes influenced the measures. For example, Patient 1 showed progressive night‐time wandering with increasing time spent out of bed, which improved following the initiation of risperidone. Case 2 showed recurrent episodes of heart failure accompanied by increased nocturnal HR. Cases 3 and 4 showed urinary tract infections, which were accompanied by transient changes in bed occupancy measures.ConclusionPassive monitoring of night‐time behaviour and physiology is a simple and cost‐effective way to monitor the effects of medication change and medical events in PLWD. Digital biomarkers derived from these simple measures hold great promise as measures of dementia progression, to enhance dementia care by identifying at risk individuals and as novel clinical outcome measures in clinical trials.
The microglial challenge to encapsulated cell mediated drug delivery in brain tissue
Authors: Mitra Sumonto , Gera Ruchi , Sundheimer Julia , Lemee Marine , Wahlberg Lars , Linderoth Bengt , Behbahani Homira , Eriksdotter Maria 
Published: June 2023

AbstractBackgroundDementia disorders affect millions of people worldwide, among which Alzheimer’s disease (AD) accounts for 60% cases. Treatment of these disorders are constrained due to inefficient brain availability of peripherally administered drugs. Conversely, direct intracerebroventricular injections are counterintuitive due to unspecific side‐effects. Recently, Aducanumab has shown potential to clear amyloid plaques from AD brain, but its efficacy to revive clinical symptoms are under debate. In this regard, direct delivery of regenerative biological drugs utilizing encapsulated cell biodelivery (ECB) has gained much attention. Conversely, how the pathological microenvironment of the AD brain affects these encapsulated drug‐delivering cells are scarcely understood. The ECB approach nullifies immune reaction from host tissue by protecting drug‐delivering cells from direct physical contact with the host tissue. Thus, in this study we probe the effect of factors released from activated human microglial cells (HMC3 cell line) on ECB devices harboring nerve growth factor (NGF) releasing cells (NGC0211; modified human ARPE‐19 cells).MethodECB devices harboring NGC0211 cells were manufactured and maintained in DMEM/F12 culture medium containing 10% serum until used. HMC3 cells were activated using AD related molecules including 1µM amyloid beta (Aβ40 and Aβ42) peptides and 10ng/mL inflammatory cytokines (interferon‐γ, IFN‐γ; interleukin‐1β, IL‐1β; or both) for 24hrs, and a cell free microglia conditioned medium (MCM) was obtained. ECB devices were then exposed to various MCMs, and NGF release was followed for several weeks assessed by ELISA (DY256, R&D systems). Similarly, non‐encapsulated NGC0211 cells grown in multi‐well slides were exposed to MCMs and cellular proliferation (Ki67 expression) along with senescence parameters (SA‐β‐galactosidase) were evaluated.ResultWe found that factors released from activated microglia hampered NGF release from ECB devices. Simultaneously, MCMs reduced Ki67 expression and elevated SA‐β‐galactosidase activity in NGC0211 cells.ConclusionActivated microglia, a common feature of all neurodegenerative conditions, impair NGF release, cellular proliferation and induce senescence in NGC0211 cells. Similar impact of microglia on other types of drug‐delivering cells (stem cells or genetically modified) needs to be studied. Our study highlights one of the probable underlying causes for impaired long‐term cell mediated drug delivery in neurodegenerative diseases and helps guide improvements in the technologies.
Sex differences in the prevalence of mild behavioral impairment: A systematic review and meta‐analysis
Authors: Mudalige Dinithi M , Ebrahim Inaara , Guan Dylan X. , Goodarzi Zahra , Ismail Zahinoor 
Published: June 2023

AbstractBackgroundMild behavioral impairment (MBI) is an early indicator of dementia risk characterized by the later life onset of persistent changes in behaviour or personality. An under‐investigated feature of MBI is the difference in symptoms and risk based on sex. This systematic review and meta‐analysis investigates the differences in the prevalence of MBI domains based on sex.MethodEMBASE, MEDLINE, PsycINFO and the grey literature were systematically searched for articles mentioning MBI. Participants with dementia were excluded. Abstracts and full‐text articles retrieved from the search were screened by two independent reviewers and included if sex‐specific prevalence data were reported. A standardized data extraction sheet was used for included articles, with data items for demographics, cognitive diagnosis, prevalence of females within each MBI domain, stratified by sex. There was insufficient evidence to look at gender. A random‐effects meta‐analysis was performed to combine the extracted data to identify pooled prevalence.ResultA total of 5476 articles were retrieved from the initial search, and 3435 papers remained after deduplication. After full‐text screening, 35 papers were selected for data extraction. In normal cognition, four out of five MBI domains were more prevalent in males (decreased motivation, impulse dyscontrol, social inappropriateness and abnormal perception or thought content). In mild cognitive impairment (MCI), three out of five domains were more prevalent in males (decreased motivation, impulse dyscontrol, and abnormal perception or thought content). However, in the mixed cognitive category, four out of five domains were more prevalent in females (decreased motivation, emotional dysregulation, impulse dyscontrol and social inappropriateness (Table 1).ConclusionIn this group of dementia‐free older adults, sex differences in prevalence of MBI domains varied by baseline cognitive status. Although the differences are not large, these findings raise interesting questions about sex‐specific trajectories of neuropsychiatric symptoms across the cognitive spectrum. This study highlights the need to explore differences in MBI by factors such as sex and gender.
Bioenergetic and vascular predictors of potential super‐ager and cognitive decline trajectories – A UK Biobank random forest classification study
Authors: Parvin Mohammadiarvejeh , Klinedinst Brandon S , Wang Qian , Pollpeter Amy , Larsen Brittany A , Moody Shannin , Li Tianqi , Barnett Neil , Pappas Colleen , Willette Sara A , Jonathan Mochel , Allenspach‐Jorn Karin , Willette Auriel A 
Published: June 2023

AbstractBackgroundAging is often characterized by progressive cognitive decline in memory and executive function. Yet, some adults aged 80 years or older, are “Super‐Agers” that exhibit cognitive performance akin to younger adults. It is unknown if there are adults in mid‐life with similar superior cognitive performance (“positive‐aging”) versus cognitive decline over time, and if there are blood biomarkers that can distinguish between these groups.MethodAmong 1303 participants in UK Biobank, latent growth curve models classified participants into different cognitive groups based on longitudinal Fluid Intelligence (FI) scores over 7‐9 years. Random Forest (RF) classification was then used to predict cognitive trajectory types using longitudinal predictors including demographic, vascular, bioenergetic, and immune factors. Feature ranking importance and performance metrics of the model were reported.ResultDespite model complexity, we achieved a precision of 77% when determining who would be in the “positive‐aging” group. Among the top fifteen features, an equal number were related to either vascular health or cellular bioenergetics but not demographics like age, sex, or socioeconomic status (see figure).ConclusionOur results suggest that optimal cognitive aging may not be driven by age per se, but biological factors that may be amenable to lifestyle or pharmacological changes.