bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subjective cognitive impairment and biomarkers of Alzheimer’s disease
Authors: Zullo Leonardo , Fenix Brice , Rabl Miriam , Clark Christopher , Popp Julius 
Published: December 2023

AbstractBackgroundSubjective cognitive impairment (SCI) is common in older adults. It may represent the earliest clinical manifestation of cognitive decline and Alzheimer’s disease (AD).Objectives1) to evaluate associations between SCI and cerebrospinal fluid (CSF) biomarkers of AD; 2) to identify specific single questions or question combinations that are related to the presence of cerebral AD pathology; 3) to evaluate whether using SCI related scores or specific questions combined with other clinical features and biomarkers may improve prediction of cognitive decline.MethodWe conducted a longitudinal study in 164 non‐demented subjects participating on a biomarker study in a memory clinic setting, aged 53 to 88 years, with CDR scores of 0 (N = 84) and 0.5 (N = 80). SCI was assessed using the Cognitive Complaint Interview (CCI, Thomas‐Antérion et al., 2006), a validated 10 items questionnaire. Accordingly, SCI is defined as present when the subject answers “yes” to 3 or more items; and/or to item 5, and/or to items A, 4, 5, 7, 8. All participants underwent comprehensive neuropsychological evaluations and CSF biomarkers analysis. “Amyloid positivity" and “AD pathology” were defined according to the CSF Aβ1‐42 levels and pTau181/Aβ1‐42 ratio, respectively. Logistic regressions were used to address the associations of interest.ResultsParticipants with SCI had significantly lower Aβ1‐42 and higher Tau and pTau181 levels compared to those without SCI. SCI was associated with amyloid positivity while CCI total score and the question A (reporting changes in memory) were associated with both amyloid positivity and AD pathology in the whole cohort. When performing analysis separately in the CDR = 0 and CDR = 0.5 subgroups the associations remained significant in the CDR = 0.5 group. Only question 6 (difficulties in finding words) was associated with AD pathology in the CDR = 0 group. Results on the prediction of cognitive decline at follow‐up visits will be presented at the conference.ConclusionIn dementia‐free subjects from this memory clinic cohort SCI‐related scores and single questions indicate amyloid positivity and the presence of AD pathology depending on the absence/presence of mild cognitive impairment. Further studies are needed to evaluate the diagnostic and prognostic utility of cognitive complains in memory clinic patients.
Exploration of the tumorigenic, metabolic, and cognitive consequences of tau protein removal
Authors: Erichsen Jennifer M. , Garbarino Valentina R. , Rodriguez Anna , Lee Jillian K. , Shayne Justin C. , Orr Timothy C. , Orr Miranda E. 
Published: December 2023

AbstractBackgroundTau accumulation causes tauopathies and drives cellular senescence, which can lead to inflammation, neurodegeneration, and cognitive impairment. The association between intracellular tau deposition and pathogenesis has prompted therapeutic strategies that reduce tau expression. However, tau is also critical in microtubule stabilization, synaptic plasticity, and maintaining DNA integrity. We investigated the impact of tau removal on brain cell senescence and associated neurocognitive behaviors in aged tau knockout (Mapt0/0) and wild type control (Mapt+/+) mice. We also assessed physical, metabolic, histological, and biochemical outcomes in Mapt0/0 and Mapt+/+ mice and in response to high fat diet (HFD), a stressor that drives DNA damage.Method20‐month‐old female Mapt0/0 and Mapt+/+ mice were subjected to the Elevated Plus Maze to assess anxiety‐like behavior. Mice were then fed control (CTL) or HFD (60% kcal fat) for 9 weeks. Behavioral and physical measures were then assessed, and brain tissue was further analyzed via gene expression, biochemistry, and histological assays.ResultTau knockout and HFD, separately and additively, caused weight gain and insulin resistance. Removing tau primed cells to proliferate, as Mapt0/0 mice had increased body size, organ size, and tumor burden compared to Mapt+/+. We observed no difference in senescence between genotypes on CTL diet. The HFD increased senescence only in Mapt+/+ mice, whereas Mapt0/0 mice displayed increased tumor burden. Mapt0/0 mice displayed anxiety‐ and depressive‐like behaviors on both diets. Transcriptomic and protein expression data revealed that several molecules responded similarly to tau removal and HFD exposure, but Mapt+/+ and Mapt0/0 mice responded differently to HFD. Genotype differences in DNA damage and cell cycle dysregulation were also observed.ConclusionMapt0/0 mice did not accumulate senescent cells but demonstrated anxiety‐like behaviors in the presence of elevated DNA damage; thus tau knockout may drive neuropsychiatric phenotypes which can be dissociated from obesity and senescence. Mapt0/0 mice also developed tumors, suggesting that tau plays a critical role in cell fate decisions, including senescence versus cancer. Overall, we found that tau removal prevents senescent cell accumulation with the tradeoff of tumorigenic, metabolic, and cognitive consequences. We caution against removing tau until a better understanding of its physiological roles are defined.
BAG3 regulates RAB35 mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome pathway and Tau clearance
Authors: Lin Heng , Tang Maoping , Ji Changyi , Girardi Peter , Cvetojevic Gregor , Chen Daniel , Koren Shon , Johnson Gail VW 
Published: December 2023

AbstractBackgroundDeclining proteostasis with aging contributes to increased susceptibility to neurodegenerative diseases, including Alzheimer’s disease (AD). Emerging studies implicate impairment of the endosome‐lysosome pathway as a significant factor in the pathogenesis of these diseases. Our lab was the first to demonstrate that BAG3 regulates phosphorylated tau clearance. However, we did not fully define how BAG3 regulates endogenous tau proteostasis, especially in the early stages of disease progression.MethodsMass spectrometric analyses were performed to identify neuronal BAG3 interactors. Multiple biochemical assays were used to investigate the BAG3‐HSP70‐TBC1D10B‐Rab35‐Hrs regulatory networks. Live‐cell imaging was used to study the dynamic of endosomal pathway. Immunohistochemistry and immunoblotting were performed in human AD brains and BAG3 overexpressed P301S tau transgenic mice.ResultsThe primary group of neuronal BAG3 interactors identified are involved in the endocytic pathway. Among them were key regulators of small GTPases, such as the Rab35 GTPase activating protein, TBC1D10B. We demonstrated that a BAG3‐HSP70‐TBC1D10B complex attenuates the ability of TBC1D10B to inactivate Rab35. Thus, BAG3 interacts with TBC1D10B to support the activation of Rab35 and recruitment of Hrs, initiating ESCRT‐mediated endosomal tau clearance. Further,TBC1D10B shows significantly less co‐localization with BAG3 in AD brains than in age‐matched controls. Overexpression of BAG3 in P301S tau transgenic mice increased the co‐localization of phospho‐tau with the ESCRT III protein CHMP2B and reduced the levels of the mutant human tau.ConclusionWe identified a novel BAG3‐TBC1D10B‐Rab35 regulatory axis that modulates ESCRT‐dependent protein degradation machinery and tau clearance. Dysregulation of BAG3 could contribute to the pathogenesis of AD.
Brain metabolism during delirium
Authors: Caplan Gideon A 
Published: December 2023

AbstractBackgroundAltered cerebral glucose metabolism manifested by increased cerebrospinal fluid (CSF) lactate and decreased neuron specific enolase during delirium has been found in CSF analyses in multiple settings, although without change in CSF or blood glucose. These changes correlate with markers of delirium severity and outcomes of delirium.However, patients with delirium are acutely unwell in hospital and have multiple comorbidities. The contribution of acute illness and dementia have not been excluded.MethodWe studied two groups of acutely unwell older people in hospital after excluding underlying dementia by history and the Informant Questionnaire on Cognitive Decline in the Elderly. The first group had delirium and the second group had no delirium. All patients underwent a 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) scan in hospital while unwell, and during delirium for the first group. Confounders on FDG‐PET such as structural brain lesions and medications that affect brain metabolism were excluded.Then we also compared the delirium FDG‐PET scans to a group with Alzheimer’s dementia.ResultPatients with delirium demonstrated a unique, novel pattern of brain hypometabolism that reflected symptoms of delirium. The affected areas included: bilateral thalami; right posterior cingulate cortex (PCC); right superior frontal, right infero‐lateral anterior temporal and left superior parietal cortices. The areas highly negatively correlated with delirium severity scores (Spearman’s rank correlation coefficients between ρ = ‐0.39 and ‐0.71; p values from 0.089 to 0.001) and performance on a range of relevant neuropsychological tests, for example thalami and Trail Making Test B (Spearman’s ρ = ‐0.52; p = 0.028). Direct comparison to AD scans significant thalamic hypometabolism (p<0.01) in delirium, but the PCC was not different.ConclusionIn patients with acute illness but without dementia, delirium is accompanied by regional cerebral hypometabolism in a distribution that is not consistent with any known pattern of dementia. While there is some overlap with AD, thalamic hypometabolism is atypical of AD and consistent with the clinical features of delirium.ReferencesNitchingham AR, Pereira JV‐B, Wegner EA, Oxenham V, Close J Caplan GA. Regional cerebral hypometabolism on 18F‐FDG PET/CT scan in delirium is independent of acute illness and dementia. Alzheimers & Dementia 2022; 1‐10.
Delirium Following Elective Arthroplasty Predicts Mild Cognitive Impairment (MCI) and Dementia Eight Years Later However This Is Not Independent of Pre‐Operative Neurodegenerative Biomarkers And Cognition
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , O'Brien Seamus , Heslegrave Amanda , Schott Jonathan M , Zetterberg Henrik , Veleva Elena , Laban Rhiannon , Cunningham Emma L 
Published: December 2023

AbstractBackgroundIn 2012‐2014, an observational cohort study of postoperative delirium (POD) in an elective arthroplasty population recruited 315 individuals aged over 65 without a diagnosis of dementia. This follow‐up study aims to determine what effect POD has on cognitive function eight years later.MethodPreoperatively, participants underwent cognitive assessments and sampling of blood and cerebrospinal fluid (CSF) which were analysed for amyloid‐beta (Aβ)40, Aβ42, glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and interleukin (IL)‐6.In 2021, n = 172 of n = 264 surviving participants completed virtual cognitive assessments and agreed to have their medical records reviewed. For those who had died (n = 50), death certificates were obtained to determine if the participant died with a diagnosis of dementia. Univariate analyses and binary logistic regression were undertaken to investigate factors associated with mild cognitive impairment (MCI)/dementia in this cohort at eight years (Table 1). In cases when MCI or dementia was suspected, an expert consensus panel reviewed medical notes, cognitive test scores and informant reports to determine if a participant had MCI or dementia.ResultOf the n = 222 participants, n = 30 had POD in 2012‐2014 and n = 22 had developed dementia or MCI. On univariate analyses, those who developed MCI/dementia at eight years were significantly older at the time of surgery (p = .02), had greater preoperative functional impairment (p = .02), and depression (p = .03) and performed worse on a number of cognitive tasks pre‐operatively (p<.05). Rates of POD were significantly greater in those who subsequently developed MCI/dementia (p = .03). In those who developed MCI/dementia, preoperative plasma and CSF measures of Aβ42 were significantly lower (p<.01), while CSF neurofilament light (NFL) and plasma IL‐6, GFAP and NFL were significantly higher (p<.05). On multivariate analyses, CSF Aβ42 (p = .02) and preoperative phonemic fluency (p = .01) remained significant predictors of MCI/dementia, while POD did not (Table 1).ConclusionThis study did not find an independent association between delirium following elective arthroplasty and the development of MCI/dementia eight years later. The results of our study indicate preoperative CSF Aβ42 and cognitive function predict longer‐term outcomes and that the association between delirium and subsequent MCI and dementia is not independent of these factors.
A Study of Factors Influencing Quality of Life among Community Dwelling Elderly in Korean Urban Community
Authors: Lee Kyoung Hwan 
Published: December 2023

AbstractBackgroundWe examined the factors influencing quality of life among community dwelling elderly in Busan city.MethodThe subjects of this research were 160 community‐dwelling elderly people without dementia and major depressive disorder. Korean version of World Health Organization Quality of Life assessment instrument‐Abbreviated form (WHOQOL‐BREF), Korean version of Short Geriatric Depression Scale (SGDS‐K) and Korean version of MiniMental State Examination (K‐MMSE) were administered for each subject. Low quality of life was defined as below 60 points of WHOQOL‐BREF.ResultThe high quality of life group showed higher score of MMSE, lower score of GDS‐K, higher educational level and married status. About a third of the subjects complained about low quality of life. In the low quality of life group, there were significant associations between quality of life and SGDS‐K (p<0.001), but there was no association with education (p = 0.708), marital status (p = 0.410), and K‐MMSE (p = 0.683).ConclusionDepressive disorders including minor depressive disorder and subsyndromal depression, might play a role in the quality of life rather than cognitive impairments in community‐dwelling elderly people. Therefore, the treatments for the depressive mood should be considered in dealing with low quality of life.
Measurement of amyloid beta in nasal secretions as a potential biomarker for Alzheimer’s disease
Authors: Choi Seong Hye , Lee Sang‐Myung , Cho Won Woo , Cho Sungbo , Minn Yang‐Ki 
Published: December 2023

AbstractBackgroundWe investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer’s disease using multichannel impedance analyzer (ToAD) and electrical‐immunosorbent assay (El‐ISA), and determined the predictive value of Aβ in nasal secretions for AD diagnosis.MethodNasal secretions were obtained from 84 participants with probable AD dementia (ADD), 83 with amnestic mild cognitive impairment (MCI), 22 with cognitive decline associated with other neurological disorders (OND), and 62 cognitively unimpaired (CU) participants. Aβ oligomers in nasal secretions were analyzed using ToAD / El‐ISA analytical systems. Capture antibodies in El‐ISA kits specifically capture Aβ oligomer in nasal secretion, and then detection probes for El‐ISA method bind with amyloid beta oligomer sequentially. Finally, unbound free detection probes in solution was electrochemically measured by ToAD analyzer for quantifying Aβ oligomers. Because this analytical method is based on the back‐titration, the change of electrical signal is inversely proportional with the concentration of detectable Aβ oligomers. Electrical signals finally expressed to Cantis AD Index (CAI, 0∼99) which normalized by standards for system calibration.ResultThe CAI was higher in the probable ADD group than in the CU group (p < 0.05). The accuracy of the CAI was fair in separating into the probable ADD and CU groups (AUC of the ROC curve = 0.665, 95% CI = 0.572‐0.758, SE = 0.047, p = 0.001). The accuracy of the CAI was fair in separating into the participants with positive amyloid PET scan and those with negative amyloid PET scan (area under curve [AUC] of the receiver operating characteristic [ROC] curve = 0.697, 95% confidence interval [CI] = 0.629‐0.766, SE = 0.035, p < 0.001). The CAI has a negative correlation with Mini‐Mental State Examination score and positive correlations with Clinical Dementia Rating scale‐Sum of Boxes and amyloid PET centiloid scale scores.ConclusionThese results demonstrate that the level of Aβ in nasal secretions increases in AD and the detection of Aβ in nasal secretions using ToAD / El‐ISA analytical systems may be possible in predicting ADD.
Clinical appications of EEG/MEG in AD: diagnosis, prognosis and treatment monitoring
Authors: Gouw Alida A 
Published: December 2023

AbstractBackgroundElectroencephalography (EEG) and magnetoencephalography (MEG) capture neuronal functioning directly, thereby providing an objective intermediate marker between pathological changes and cognitive symptoms in neurodegenerative diseases. Both techniques are highly suitable as tools in the context of memory clinics and their use for treatment monitoring is increasingly recognized.MethodWe will highlight recent developments important for the use of EEG / MEG as diagnostic and prognostic markers in dementia and as outcome measures in Alzheimer’s disease (AD) trials.ResultIn memory clinics, both visual and quantitative EEG / MEG are being used as supportive evidence in diagnostic challenges, especially when other pathology specific –likely more invasive‐ biomarkers are not available. Increasing numbers of papers using artificial intelligence to differentiate a specific dementia type from cognitively healthy subjects report fair to excellent accuracies that are especially high for dementia with Lewy Bodies (DLB). Multi‐class classification between six memory clinic diagnoses resulted in MEG‐based diagnostic profiles describing the probability estimates of each class. These diagnostic profiles provide an informative and intuitive tool for clinical use. In pre‐clinical stages of AD spectral changes are predictive of future cognitive decline, and in the mild cognitive impairment stage it differentiates between progression into dementia due to AD or DLB. As EEG / MEG are found to be sensitive to longitudinal changes, there is increasing interest in the use of EEG as outcome measures in clinical trials. Both spectral and functional connectivity measures showed a treatment effect in phase 2 pharmacological studies in early AD, giving objective support for (subtle) clinical effects of the drug on trial. The pursuit of discovering even more sensitive, robust and complementary measures lead to novel neurophysiological markers reflecting functional connectivity, signal variability and neuronal hyperexcitability.ConclusionEEG / MEG provide diagnostic and prognostic information applicable in memory clinics. The use of sensitive conventional and novel markers in (pharmacological) trials can support clinical treatment effects and have potential to reduce the size of trials.
Interneuron hyperexcitability in an APP/PS1 mouse model of Alzheimer’s disease
Authors: Hijazi Sara , van Heusden Fran C , Diachenko Marina , Nejat Mazyar Abdollahi , Smit August B. , Linkenkaer‐Hansen Klaus , van Kesteren Ronald E. 
Published: December 2023

AbstractBackgroundNeuronal hyperexcitability is commonly observed in Alzheimer’s disease (AD) patients and in mouse models of AD. What is not clear yet is whether hyperexcitability occurs in all neurons or whether certain types of neurons are selectively vulnerable towards developing a hyperexcitable phenotype.MethodElectrophysiological recordings were performed in hippocampal slices from APP/PS1 mice to measure intrinsic and network properties of excitatory pyramidal neurons and of inhibitory parvalbumin (PV)‐positive interneurons. Cell type‐specific chemogenetic interventions were used to selectively reverse the hyperexcitable phenotype of these neurons. The outcome of these interventions was measured using hippocampal slice physiology, local field potential (LFP) recordings and behavioral assessment.ResultThe intrinsic excitability of hippocampal PV interneurons was significantly higher in APP/PS1 mice at 3‐4 months of age whereas pyramidal neurons were not affected at this age. Increased excitability of PV interneurons coincided with impaired learning and memory in the Morris water maze. Reducing the activity of PV neurons using chemogenetics resulted in a complete and long‐lasting rescue of PV cell excitability, network properties and learning and memory. LFP recordings revealed changes in oscillatory power and excitation/inhibition balance that could be related to early PV cell hyperexcitability and may translate to novel EEG biomarkers to detect AD at an early stage in humans.ConclusionHyperexcitability of hippocampal PV interneurons is an early cellular phenotype in APP/PS1 mice that is causally related to neuronal network and memory impairments, whereas pyramidal cells only become hyperexcitable at later disease stages. These findings are relevant for AD as they may help to identify neuronal activity markers that are specific for early disease stages as well as cell type‐specific ion channels or receptors that can be targeted to treat AD in its earliest stage.
Determinants of successful cognitive aging over 15 years: a population‐based study
Authors: Ekström Ingrid , Josefsson Maria , Bäckman Lars , Laukka Erika J 
Published: December 2023

AbstractBackgroundAlthough aging is related to loss in cognitive function, some individuals maintain high levels of cognitive performance also in late life. However, studies mapping longitudinal cognitive trajectories are scarce and little is known about the factors that may promote successful cognitive aging (SCA). We sought to identify predictors of SCA, based on latent profiles derived from interindividual differences in rate of change across several cognitive domains.MethodWe followed 1,966 individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K) over 15 years (mean baseline age = 71.6 years; 62.9% female). Participants were free from dementia at baseline and had undergone at least two cognitive assessments during follow‐up. Cognition was assessed with a comprehensive battery, including tests of semantic memory, episodic recall and recognition, letter and verbal fluency, and executive function. We estimated level and change within each of the cognitive domains with linear mixed effect models, based on which we classified participants into successful, normal, or decline groups. These groups were used to derive profiles of overall cognitive change trajectories, through latent class analysis. We then investigated demographic, health, lifestyle, and genetic predictors of profile membership.ResultWe obtained three latent cognitive profiles. 31.6% of the sample was classified as successful, 50.6% as normal, and 17.8% as decliner. In multi‐adjusted multinomial logistic regression analysis, membership in the successful profile was predicted by female sex, higher education, and a faster walking speed (ps < 0.003). Current smoking, feelings of loneliness, and carrying the Apolipoprotein ԑ4‐allele were associated with a lower likelihood of being classified as successful (ps < 0.037). Higher age, diagnosis of diabetes or depression, and being an ԑ4‐carrier increased the likelihood of being classified into the decline profile (ps < 0.026).ConclusionWe identified several demographic, lifestyle, health, and genetic factors of SCA. Of note, these factors were different from those that predicted accelerated cognitive decline. Although some cognitive loss may be an inevitable part of aging, our results suggest certain modifiable factors (i.e. smoking and quality of social interactions) to be related to maintained cognitive function in older age.