bluuebunny/crossref_metadata_2025 huggingface dataset:
Tau pathology relates to regional microstructural alterations of cerebral white matter in older adults with diverse cognitive spectrum
Authors: Kong Nayeong , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2023

Background

Growing evidences suggest that degeneration of cerebral white matter (WM) occurs in Alzheimer’s disease (AD) independently of cerebrovascular risks or injury. Previous studies using diffusion tensor imaging (DTI) have reported a loss of WM microstructural integrity in the corpus callosum (CC) and cingulum (CG) in AD dementia and mild cognitive impairment (MCI). However, only limited information is available for the relationship of in vivo AD‐specific pathologies including beta‐amyloid (Aβ) and tau accumulation with WM microstructal alterations. Thus, we aimed to examine the association between in vivo AD pathologies and microstructural integrity of the CC and CG through cross‐sectional and longitudinal approaches.

Method

A total of 170 (74 cognitively normal, 58 MCI, and 38 AD dementia) older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease cohort were included. All participants underwent comprehensive clinical assessment and multi‐modal brain imaging including [11C]‐Pittsburgh‐Compound‐B‐positron emission tomography (PET), 18F‐AV‐1451 PET, and DTI. The mean fractional anisotropy (FA) values were obtained for 2 regions of interests, the CC and CG on DTI. The data was analyzed using linear regression model adjusted for age, sex, APOE4 positivity, and vascular risk factor score. Regression‐based mediation analysis was also conducted to assess the mediation of tau for the relationship between Aβ and FA.

Result

In cross‐sectional analyses for baseline data, global tau deposition had a significant negative association with both CC and CG FA (β = ‐0.013, p = 0.004 and β = ‐0.011, p = 0.002), while global Aβ retention showed a negative association with only CG FA (β = ‐0.015, p = 0.004). Longitudinal analyses revealed that higher tau deposition at baseline was associated with both greater reduction of both CC and CG FA over 2 years (β = ‐0.010, p = 0.001 and β = ‐0.005, p = 0.046), whereas Aβ was associated with neither CC nor CG FA change over the period. Additional mediation analysis demonstrated that the cross‐sectional association between Aβ and CG FA was mediated by tau deposition, while there was no direct relationship between the two.

Conclusion

Our findings suggest that regional alterations of WM microstructural integrity in MCI and AD dementia, which occurs independently of vascular risks, are mainly related with tau pathology rather than amyloid pathology.
The relationship between executive dysfunction‐associated activities of daily living (ADL) and the pattern of Clinical Dementia Rating (CDR) in patients with vascular dementia and age‐matched patients with Alzheimer’s disease
Authors: Park Joon Hyuk , Yang Hyun‐Ju
Published: December 2023

Background

Clinical dementia rating (CDR) scale was originally developed to stage the severity of Alzheimer’s dementia (AD) but is now used globally regardless of types of dementia. This study aims to investigate the relationship between the characteristic pattern of CDR domains, neuropsychological findings, and activities of daily living (ADL) in patients with vascular dementia (VaD), compared with age‐matched patients with AD.

Method

Very mild to mild VaD and AD patients matched for age were recruited among the first visitors to a dementia clinic. All subjects were administered a standardized clinical interview, physical and neurological examinations, and laboratory tests including the brain MRI according to the protocol of the Korean version of the CERAD assessment battery.

Result

One hundred and five pairs of VaD and AD patients participated in this study. Although the adjusted scores on MMSE were similar between two groups and the performances on Boston naming, word list memory, word list recall, word list recognition, constructional recall test were better in VaD patients, the scores on global CDR, CDR sum of box (SOB), and ADL‐related CDR domains were higher in VaD patients than in AD patients (p<0.001). The poor performances on disability assessment for dementia scale, frontal assessment battery, executive clock drawing task, and Stroop tests were observed in VaD patients.

Conclusion

Despite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.
Comparison of two semi‐quantitative amyloid PET analysis methods with and without MRI in Alzheimer’s Disease Spectrum Disorder
Authors: Yang Dong Won , Lee Chonghwee , Cho Jung hee , Hong Yun Jeong , Shin Seong A
Published: December 2023

Background

Standardized uptake value ratio (SUVR) is a standard method for amyloid PET analysis. 3D T1 MRI imaging is required for accurate spatial normalization in SUVR measurement to overcome regional cortical atrophy in neurodegenerative disorders like Alzheimer’s disease spectrum disorders. The SUVR method without 3D MRI has recently been developed for clinical application. We compared two SUVR methods with and without 3D MRI for the semi‐quantitative analysis of global and regional amyloid loading in Alzheimer’s disease spectrum disorders.

Method

75 subjects (normal cognition 8, subjective cognitive decline 20, mild cognitive impairment 23, Alzheimer’s disease dementia 24) were selected in the single dementia clinic for the analysis. For the SUVR measurement with 3D T1 MRI, in‐house software with SPM8 and MATLAB was used. For the SUVR measurement without 3D T1 MRI, AI‐based automated PET quantitative analysis software (called ‘BTXBrain‐Amyloid‐Research’) was developed by Brightonix Imaging Inc. With the visual PET reading as a gold standard, we compared regional and global SUVR between groups. Intra‐class correlation coefficient(ICC) was used to test the validity of the two methods.

Result

Global SUVR was higher in amyloid PET positive SCD group (SUVR with MRI (1.205 V.S. 1.635), SUVR without MRI (1.210 V.S. 1.599)). The mean global SUVR with MRI and without MRI of 75 subjects were 1.400 (S.D. 0.264) and 1.390(S.D. 0.237). ICC of global SUVR between the two methods was 0.950, p = 0.0001. Regional SUVR ICC were 0.941 in the prefrontal cortex, 0.953 in the orbitofrontal cortex, 0.947 in the anterior cingulate, 0.844 in the posterior cingulate, 0.955 in the lateral parietal cortex, 0.962 in the precuneus, 0.959 in the lateral temporal cortex, and 0.94 in the occipital cortex. The area under the curve of ROC curve analysis of both two methods to diagnose amyloid PET positivity was 0.98 and 0.97.

Conclusion

AI‐based automated PET quantitative analysis software of Brightonix imaging without MRI was valid as an MRI‐based SUVR method in Alzheimer’s disease spectrum disorders with variable brain atrophy. Short processing time (30 ‐40 seconds) and reliable SUVR measurement without 3D MRI benefit the Alzheimer’s disease diagnosis in clinical practice.Grant from the Ministry of Health and Welfare, HI18C0530, Seoul R&BD Program(BT200151)
Neuroprotective effect of inosine against aluminium chloride (AlCl3) induced experimental dementia of Alzheimer type in Wistar Rats
Authors: Agrawal Mohit , Singhal Manmohan , Chaudhary Hema
Published: December 2023

Background

Alzheimer disease is a neurodegenerative disorder that is identified by the loss of memory, cognitive function and muscle coordination and various memory related task. Various studies throughout the decades have shown that oxidative stress plays one of the key role in initiating the Alzheimer Disease.

Method

As the oxidative stress is majorly caused by the reactive oxygen species it is proven in various studies that the antioxidants are quite effective against the ROS to induce the oxidative stress in the brain the AlCl3 chemical is used as it is proven that AlCl3 model for the inducing dementia is a neurotoxic metal that can cause neurodegeneration by oxidative stress. As the Inosine is one of the naturally occurring potent antioxidant it can be quite effective against the ROS and protecting the brain from the oxidative stress and could help in improving the various memory and motor dysfunctions

Result

In this study we have selected 36 Wistar rats divided in a 6 group each containing 6 rats each weighing 150gm‐200gm. Various behavioural analysis were conducted at every week which were, Morris Water Maze, Novel Object recognition Test, open field test and Actophotometer. And the day of 30th day the brain was isolated from the rats specifically the cortex and the hippocampus region of the brain for various biochemical estimations which are Lipid Peroxidation, Glutathione Reduction (GSH), Superoxide Dismutase and Nitrite Estimation in the Brain.

Conclusion

The present study suggests that Inosine show beneficial effects in treating Alzheimer diseases. Our data demonstrated that Inosine could be effective in the protection of toxicity induced by Aluminium chloride (AlCl3)
Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort
Authors: Lorenzini Luigi , Maranzano Alessio , Tranfa Mario , Collij Lyduine E. , Sudre Carole H , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Chetelat Gael , Waldman Adam , Wardlaw Joanna M , Fox Nick C , Ritchie Craig W , Scheltens Philip , Visser Pieter Jelle , Wink Alle Meije , Mutsaerts Henk‐Jan , Gispert Juan Domingo , Ingala Silvia , Barkhof Frederik
Published: December 2023

Background

The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.

Method

We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aβ1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aβ1‐42 and p‐Tau181, including an interaction between CSVD indices and Aβ1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.

Result

Higher FRS scores were associated with lower CSF Aβ1‐42 (β = ‐0.18; p<0.001) and higher P‐tau181 (β = 0.21; p<0.001). Aβ1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2).

We found stronger association between Aβ1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes.

Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aβ1‐42 (indirect effect: β = ‐0.03; p<0.001). Aβ1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aβ1‐42 on P‐tau181 levels (β = ‐0.14; p<0.001) and HCV (β = 0.06; p<0.05), and of P‐tau181 levels onto HCV (β = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: β = 0.36; p < 0.05) and HCV (indirect effect: β = ‐0.24; p < 0.05) through Aβ1‐42 was observed.

Conclusion

Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.
Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1
Authors: Bell Simon M , Wareing Hollie , Hamshaw Alexander , De Suman , New Elizabeth , Shaw Pamela , De Marco Matteo , Venneri Annalena , Blackburn Daniel J , Ferraiuolo Laura , Mortiboys Heather
Published: December 2023

Background

Astrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitters at neuronal synapses. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The homeostatic role the astrocyte provides for neurons leads to metabolic demands, meaning that abnormalities in the function of astrocyte mitochondria and glycolysis could affect this relationship. Changes to cellular metabolism are seen early in Alzheimer’s disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti‐amyloid treatments in AD.

Methods

In this project, we characterised mitochondrial and glycolytic dysfunction in astrocytes derived from patients with sporadic (n = 6) and familial (PSEN1, n = 3) AD, and associated controls (n = 9). Astrocytes were derived using direct reprogramming technology. Astrocyte metabolic outputs; ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene.

Results

In sAD astrocytes a 20% reduction (p = 0.05) and in fAD a 48% (p<0.01) reduction in total cellular ATP was seen. A 44% reduction (p<0.05), and 80% reduction in Mitochondrial spare capacity was seen in sAD and fAD respectively. Reactive oxygen species (ROS) where increased in both AD astrocyte types (p = 0.05). Mitochondrial complex I and II was significantly increased in sAD (p<0.05) but not in fAD. Astrocyte glycolytic reserve and extracellular lactate was significantly reduced when compared to controls in both sAD and fAD (p<0.05). We identified that astrocytes had a deficit in the glycolytic pathway enzyme hexokinase, and that correcting this deficit restored total cellular ATP levels, extracellular lactate and reduced ROS in sAD but not fAD astrocytes.

Conclusion

AD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These deficits are likely to impede metabolic support for neurons. These functional deficits can be improved by correcting hexokinase deficits. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD.
Classification of human tauopathy using blood: Detection of tau isoforms in patients’s blood with a magnetic bead‐based gap sensor
Authors: Kwon SunSang , Yun Mijin , Lee Soo Hyun
Published: December 2023

Background

Tau protein, which is deposited or phosphorylated in the brains of patients with neurodegenerative progression, has six isoforms that include or exclude N‐terminal exons 2 and 3 and Exon 10, which is a microtubule binding region. Especially, 3R‐ and 4R‐tau, which are distinguished by inclusion or exclusion of exon 10, are known to be balanced in normal adults. However, in case of tauopathy such as progressive supranuclear palsy, the balance is disrupted and 4R‐tau becomes dominant in the patient’s brain. In this regard, some tauopathies can be classified through comparison of tau isoforms in the blood or cerebrospinal fluid (CSF) of neurodegenerative patients.

Method

First, magnetic beads were coated with each antibody that specifically interact with 3R‐ or 4R‐tau protein, respectively. The prepared samples were reacted with patient’s blood samples from 1) healthy control (HC), 2) Alzheimer’s disease (AD), and 3) 4R‐tau dominant tauopathy (4RDT). Samples incubated with 3R‐ and 4R‐tau antibodies, respectively, were placed between two metal electrode arrays surrounded by the SU‐8 well structure and their impedance changes were measured by electrochemical method (Figure 1).

Result

In the case of HC and AD, 3R‐ and 4R‐tau are known to be in balance, but as a result of measuring the impedance change rate, it was found that the impedance change rate of 4R‐tau is larger than that of 3R‐tau. For the 4R‐tau, HC group exhibits a larger impedance change rate than the AD group (Figure 2). The 4RDT group is currently measuring. Based on reference (Acta Neuropathol., 131, 267 (2016)), the impedance change rate of 4R tau in blood will be large, while that of 3R tau is expected to be negligible.

Conclusion

We used a magnetic bead‐based gap sensor to detect/compare tau isoforms in blood samples collected from living patients. Although slightly different from the expectation, the HC group showed a larger impedance change rate than the AD group for the 4R‐tau. The 4RDT group data have not yet been included, but are expected to be similar to those from CSF, and blood measurements can be used to classify tauopathies.
Alternative splicing and characterisation of the tauopathy‐induced gene Growth Arrest DNA Damage Induced 45 alpha
Authors: Williamson Kirsten L , Pitera Aleksandra , O'Connor Vincent , Deinhardt Katrin
Published: December 2023

Background

The Gadd45 family are a set of 3 genes classically induced by DNA damage. They are also induced by wider stresses such as axonal injury, ischemia and degenerative diseases like ALS. Increased Gadd45 protein staining is observed in AD brains, however their association with pathogenic tau is unknown. The Gadd45 genes undergo alternative splicing to generate 8 functionally distinct proteins, whose significance in neuronal systems are poorly understood. We aim to investigate if the Gadd45 family are upregulated in tauopathies and whether this is accompanied by changes to mRNA splicing of these genes, with a view to understand whether these differentially affect cell health.

Method

Transgenic mice (rTg4510) over‐expressing and FTD‐associated mutant tau (TauP301L) were used to investigate tau‐associated upregulation of the Gadd45 genes. Subsequently, we analyse which splice variants are present in primary cortical neurons and express plasmid constructs of these variants to investigate their sub‐cellular localisation and function, using apoptotic cell death as a read‐out.

Result

Gadd45α, but not β or γ members of the same family, is upregulated in response to pathological tau. Untreated cortical neurones express a single isoform of the Gadd45α gene, however upon cellular stress 2 additional isoforms are induced. The identified variants show distinct sub‐cellular distribution, including changes to nuclear localisation and the development of punctate staining. Furthermore, these differentially affect apoptosis.

Conclusion

Gadd45α is selectively upregulated by tau pathology. The gene undergoes alternative splicing in murine neurones in response to cellular stress, and these variants show evidence for distinct functions. We will next investigate the association of these variants with pathological tau.

We thank the Alzheimer’s Society for funding this work.
Cellular and molecular mapping of human adult hippocampal neurogenesis in Alzheimer’s disease
Authors: Tosoni Giorgia , Penning Amber , Ayyildiz Dilara , Snoeck Sarah , Poovathingal Suresh Kumar , Davie Kristofer , Macnair Will , Bryois Julien , Salta Evgenia
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive, irreversible disorder accounting for 50‐70% of all dementia cases. Given the current lack of disease‐modifying therapies, systematic profiling of the cell type‐ and cell state‐specific molecular signatures of resilience and vulnerability to AD may reveal novel therapeutic avenues. Adult hippocampal neurogenesis (AHN) refers to the birth of new neurons in the neurogenic ‘niche’ of a hippocampal subregion, the dentate gyrus (DG). AHN drops sharply in AD, and positively correlates with ante‐mortem cognition. Our work and previous reports show that boosting AHN in AD mice restores AHN‐related memory. Hence, harnessing AHN in human AD brain may provide novel strategies to prevent or counteract dementia. Insights into the molecular and cellular regulatory networks maintaining homeostasis of the human neurogenic microenvironment are currently missing.

Method

Here, we employ single‐nucleus RNA sequencing technology in the human AHN niche to profile cell type specific molecular signatures of AHN and their changes during the course of AD pathology and in resilient brains.

Result

We developed a novel protocol for precise microdissection of the AHN niche in tissue sections of postmortem human brain, which yields high‐quality input material, enriched for niche‐resident cell populations. We employ in silico ‘dissection’ of cellular populations putatively including neurogenic cell types, and lineage trajectories to identify any (rare) bona fide progenitors.

Conclusion

Using previously published and our own datasets, we identify species‐conserved and human‐specific markers that could be used for more reliable identification of adult neurogenic populations and of their transcriptional alterations in AD and resilient brains.
Associations between self‐efficacy across adulthood and midlife cognitive function: Evidence from the National Child Development Study (NCDS)
Authors: John Amber , Bartrés‐Faz David , Stott Joshua
Published: December 2023

Background

Previous research has shown that self‐efficacy is associated with a range of health outcomes. However, little is known about relationships between self‐efficacy and cognition across the life‐course. The aims of this study were to test (1) whether trajectories of self‐efficacy from age 33 to 50 are associated with midlife cognitive function (age 50); and (2) whether self‐efficacy acts as a path through which the relationship between childhood factors and adult cognition operates.

Method

Data used were from the National Child Development Study, a longitudinal birth cohort of 17,415 people born during a single week of 1958. Measures of self‐efficacy were available at ages 33, 42, 46, and 50. Measures of immediate and delayed memory, verbal fluency, processing speed, and processing accuracy were available at age 50. Growth mixture models were run to identify longitudinal trajectories of self‐efficacy. Structural equation modes (SEMs) were run to test associations between different trajectories of self‐efficacy and adult cognitive function. Next, mediation models were used to test the direct, indirect and total effects of childhood factors on adult cognitive function, through accumulation of self‐efficacy.

Result

According to standard indices (AIC, BIC, LRT, class proportions, etc), a 5‐class trajectory model best fitted the data (Figure 1). SEM models showed that compared with persistently high self‐efficacy, being in any other trajectory was significantly associated with poorer immediate and delayed memory, verbal fluency and processing speed. Being in the moderate and decreasing self‐efficacy trajectory was significantly associated with poorer processing accuracy, compared with the high self‐efficacy group. Greater accumulation (number of time points with high self‐efficacy) over time was significantly associated with better cognitive function in all domains. Mediation models showed significant indirect effects of childhood cognition and education on immediate memory through the accumulation of self‐efficacy score, but not for sex or childhood socioeconomic position.

Conclusion

Results show that in this prospective birth cohort, persistently high self‐efficacy across early adulthood to midlife (age 33 to 50) was significantly associated with higher cognitive function in midlife. This may be one path through which associations between childhood factors (childhood cognition and education) and adult cognitive function may operate.
Head‐to‐head comparisons of cognitive screening tests administered in primary care centers
Authors: Tideman Pontus , Spotorno Nicola , Palmqvist Sebastian , Hansson Oskar
Published: December 2023

Background

Cognitive screening tests are often used in primary care to aid in the decision whether further investigation is needed. The most widely used tests, MMSE and the Clock Drawing Test (CDT), were developed more than 40 years ago and there is a need to update the primary care neuropsychological toolbox. The objective for this pilot study was to examine the diagnostic accuracy of AD for different cognitive tests administered at primary care centers.

Method

The BioFINDER Primary Care Study consecutively recruits patients with cognitive complaints (SCD, MCI, or mild dementia) at different primary care centers in Sweden. Cognitive tests are examined as well as plasma AD‐biomarkers. A test battery including MMSE, MoCA, CDT, Verbal fluency tests, TMT A and B, Symbol Digit Test, ADAS 10‐wordlist and Recall of Picture Test (RPT) are administered to all patients at their respective primary care center. Patients are then referred to a memory clinic where they undergo a full clinical work‐up (including neuropsychological assessment, lumbar puncture or Aβ‐PET, MRI and an examination by a physician specialized in dementia diseases) after which a diagnosis is made (blinded to the tests done in primary care). A clinical diagnosis of AD is supported by CSF or PET findings. The diagnosis of AD, either at the MCI or mild dementia stage, was here used as the dependent variable in logistic regression models with the different cognitive tests as predictors (adjusted for age, sex, education). Comparisons of AUC were performed using DeLong statistics.

Result

In this pilot study the first 276 recruited patients were analyzed (Table 1). Four tests, MMSE (AUC = 0.73, P <0.01), MoCA (AUC = 0.71, P <0.05), ADAS 10‐wordlist (AUC = 0.80, P <0.001) and RPT (AUC = 0.79, P <0.001), performed significantly better than the basic model (age, sex, education) in predicting a diagnosis of AD. Both the ADAS 10‐wordlist and RPT performed significantly better than MMSE (P <0.05). Adding the CDT to MMSE did not improve the AUC (0.73).

Conclusion

In a diverse population, as seen at primary care centers, brief tests of memory may provide better accuracy in detecting AD than standard of care tests as MMSE and MoCA.
Is QEEG an effective biomarker in predicting cognitive decline?
Authors: Medici Valentina , Cassini Paola , Rossi Michele , Pettinato Laura , Negro Giulia , Profka Xhulja , Rolandi Elena , Guaita Antonio , Ceroni Mauro , Poloni Tino Emanuele
Published: December 2023

Background

Alterations in EEG traces are observed in synaptic failure with a reduction in the background α rhythm and an increase in slow frequencies (θ‐δ). The aim of the study is to evaluate whether quantitative EEG (QEEG) can be a reliable biomarker of neuro‐cognitive disorders (NCD), able to identify patients with mild and major‐NCD, and to reflect the clinical course over time.

Method

63 donors from the Abbiategrasso Brain Bank were included in the study. According to our protocol, the subjects were evaluated longitudinally (2015‐21) through a multidimensional assessment, and divided into 3 groups age and sex matched (NOLD for normal old, mild‐NCD and major‐NCD). A selection of 12 donors was further divided into 3 groups based on the change of the clinical state over time (NOLD>NOLD; NOLD>mild‐NCD and mild‐NCD>major‐NCD). The QEEG analysis was performed considering the relative power distribution (RPD) of band frequency (β, α, θ, δ) and the peak frequency (PF), as synthetic index. The Kruskall Wallis test, with post hoc analysis, and change analysis through one‐way ANOVA were used for the comparison between groups. Kendall’s TAU was used for correlations.

Result

The RPD of the different frequency bands as well as the PF were significantly different in the NOLD, mild‐NCD and major‐NCD groups (p<0.001); α‐RPD and PF decreased, while θ and δ‐RPD increased. NOLDs and mild‐NCDs were always different from major‐NCDs (p<0.001), while NOLDs were statistically different from mild‐NCDs only for θ‐RPD (p = 0.019), b+a‐RPD (p = 0.028) and q+d‐RPD (p = 0.025). A strong correlation between PF and MMSE (p<0.001) was present. Change analysis demonstrated that PF was lower in the NOLD>mild‐NCD group compared to the NOLD>NOLD group (p = 0.049). Interestingly, PF did not present any correlation with depression using CES‐D score (Center Epidemiological Studies‐Depression).

Conclusion

The RPD is able to distinguish NOLDs from mild‐ and major‐NCDs. If determined from the initial stages of the disorder, PF may be a promising biomarker for mild‐NCD diagnosis discriminating initial cognitive impairment from depression, and it may be useful to follow the evolution of dementia. PF appears to be a synthetic and simple quantitative index, easily obtained from a standard digital EEG, and widely applicable.
Brain imaging endophenotypes by unsupervised deep learning
Authors: Zhi Degui
Published: December 2023

Background

Understanding the genetic architecture of brain structure and Alzheimer’s disease is challenging, partly due to difficulties in designing robust, non‐biased descriptors of the brain.

Method

We present approaches to derive robust brain imaging phenotypes using unsupervised deep representation learning. Training a 3‐D convolutional autoencoder model with reconstruction loss, we derived a vector representation (termed endophenotype) that captures rich morphological information of the brain. Further, we developed a perturbation‐based decoder interpretation approach that can highlight brain regions that are most relevant to individual endophenotypes.

Result

Using UK Biobank data, we trained the model using over 6,000 UK Biobank (UKBB) participants’ T1 or T2‐FLAIR (T2) brain MRIs. The model is used to derive 128 endophenotypes. The endophenotypes have a mean heritability of 0.3 and the GWAS of which have identified 43 independent loci in the held‐out UKBiobank dataset (discovery n = 22,962/replication n = 12,848), among which 13 loci have not been previously reported by the UK Biobank Big40 study.

Conclusion

Using UK Biobank data, we show that, compared to traditional brain image‐derived phenotypes (IDPs), our endophenotypes are more heritable and have higher power for genetic discovery.
Sex differences in the associations between the risk for late‐life Alzheimer’s disease, protective lifestyle factors and cognition in mid‐life: The PREVENT Dementia study.
Authors: Qi Qing , Deng Feng , Ritchie Karen , Muniz‐Terrera Graciela , Koychev Ivan , Malhotra Paresh A , O'Brien John T , Ritchie Craig W , Lawlor Brian , Naci Lorina
Published: December 2023

Background

It is now acknowledged that Alzheimer’s Disease (AD) processes are present decades before the symptoms manifest, but whether lifestyle activities can protect against these early AD processes in mid‐life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies (Deng et al., 2022; Heneghan et al., 2022) on the contribution of mid‐life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance.

Method

Cognitively unimpaired middle‐aged participants (40‐59 years; N = 461) completed cognitive and clinical assessments cross‐sectionally. Risk factors (Apolipoprotein E [APOE] ε4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were assessed and mid‐life activities were measured with the Lifetime of Experiences Questionnaire.

Result

Replicating our key previous findings, we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score (Figure 1a), (b) positively associated with stimulating lifestyle activities (Figure 1b), and (c) that females performed significantly better than males in episodic and relational memory (Figure 2a). The key novel finding of this study was that APOE ε4 genotype modulated the association between sex, lifestyle and cognition. Only for APOE ε4+ females, not APOE ε4‐, higher occupational attainment was associated with better episodic and relational memory (Figure 2c, 2d). Conversely, only for APOE ε4+ males, not APOE ε4‐, higher occupational attainment was associated with worse episodic and relational memory (Figure 2c, 2d).

Conclusion

These findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid‐life and support the targeting of modifiable lifestyle activities for the prevention of AD. Furthermore, these findings suggest an urgent need for targeted research on female‐specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health.
Usability experience of remote sleep monitoring in patients with neurodegenerative diseases
Authors: Biswas Bijetri , Gabb Victoria , Li Haoxuan , Morrison Hamish , Blackman Jonathan , Coulthard Elizabeth , Group Remember
Published: December 2023

Background

Sleep disturbances and neurodegenerative disease are prevalent in later life and may worsen life quality. Home sleep monitoring may help allow early recognition of disease progression and offer therapeutic intervention targets. In the Remote Evaluation of Sleep To enhance understanding of Early Dementia (RESTED) study, we explored feasibility and acceptability of digital technologies to characterise sleep in cognitive impaired individuals.

Method

Recruitment and data collection is ongoing as of January 2023. We included data from seven RESTED participants who completed an end‐of‐study interview which includes individuals with early Alzheimer’s Dementia (AD) or Lewy Body Dementia (LBD), the prodromal state of Mild Cognitive Impairment (MCI) due to AD or LBD, healthy older adults from memory clinics and databases at the North Bristol NHS Trust. A wrist‐worn actigraph monitored sleep and trial activities were triggered through a mobile application for 8 weeks. During one week in‐depth monitoring included EEG headband worn nightly, overnight oximetry, circadian saliva samples and daily short cognitive tests.

Results

Preliminary data from the interview were analysed using thematic analysis. Participants were asked questions to draw off The Capability, Opportunity, Motivation, Behaviour and Unified theory of acceptance and use of technology model. Overall, Participants were able to use the technologies either independently or with support from a carer or family member. Some participants found it difficult to wear the headband, and doing the cognitive test made them feel anxious and worried about their memory. Using technologies did not negatively impact their relationship with their partner. Carer motivation was a major determinant of data completeness. This study made them aware of the importance of sleep for brain health.

Conclusions

Future research should review the ergonomic design principles by considering the infrastructure to make them more suitable for the targeted population. Our work also demonstrates some challenges in conducting this category of user experience study in healthcare, including time investment from carers, adherence to the continued interview and retrospective biases. This user experience study in dementia suggests remote sleep monitoring is preferred, holds the potential to enhance well‐being, improve participant‐carer relationships, and may provide a means to feel empowered and acquire new skills.
Human iPSC‐microglia expressing TREM2 p.R47H risk variant for Alzheimer’s disease do not show a loss‐of‐function phenotype
Authors: Nonneman Annelies , Swijsen Sofie , Sebrechts Pieterjan , De Bondt An , Wyngaert Ilse Van Den , Bhattacharya Anindya , Ebneth Andreas
Published: December 2023

Background

The most common TREM2 variant associated with increased risk to develop Alzheimer’s disease (AD) is p.R47H. This variant has been classified as loss‐of‐function, mostly by comparing p.R47H with the common variant in TREM2 over‐expressing cell lines. Whether this holds true when TREM2 is expressed at physiological levels in a disease‐relevant cell type such as human microglia, has not been fully characterized.

Method

We established and thoroughly characterized human iPSC‐derived microglia endogenously expressing TREM2 to assess the effect of p.R47H on TREM2 cellular distribution, TREM2 signaling and microglial functioning. For this study microglia generated from a set of isogenic gene‐edited iPSC lines homozygous for TREM2 knockout (KO) and TREM2 p.R47H were evaluated and compared to microglia from the parental control iPSC line. In addition, microglia generated from iPSC lines obtained from several p.R47H carriers were compared to microglia from iPSC lines obtained from several healthy control non‐carriers. SNP genotyping confirmed the presence of R47H.

Result

The p.R47H and common variant TREM2 were present at similar levels at the cell surface of iPSC‐derived microglia, whereas no expression of TREM2 was detected in the TREM2 KO microglia. Microarray profiling indicated that the microglial transcriptome is very similar between the common variant and p.R47H yet distinct from TREM2 KO microglia. Biochemical evaluation of TREM2 signaling indicated no reduction in TREM2 downstream signaling activation in the p.R47H variant expressing microglia. Similarly, soluble TREM2 levels were increased in culture medium of p.R47H microglia. Finally, analysis of microglial functioning including phagocytosis of artificial and disease‐relevant substrates showed no difference between the p.R47H variant and the common variant, in contrast to TREM2 KO microglia.

Conclusion

We conclude that in cultured human iPSC‐derived microglia, the p.R47H variant shows no evidence of a loss‐of‐function mechanism. Future experiments will determine whether this is also the case in microglia in their natural brain environment. Our long‐term goal is to better understand TREM2 biology to support the development of novel therapeutics for AD and other neurodegenerative diseases characterized by TREM2‐mediated neuroinflammation.
The Prevalence and Impact of Vertebral Artery Hypoplasia on Cerebral Hemodynamics
Authors: Fico Brandon G. , Moir M. Erin , Loggie Nicole A. , Gaynor‐Metzinger Sarean Harmoni A. , Miller Kathleen B. , Norby Alex M. , Rivera‐Rivera Leonardo A. , Howery Anna J. , Rowley Howard A. , Johnson Kevin M. , Johnson Sterling C , Wieben Oliver , Barnes Jill N.
Published: December 2023

Background

Vertebral artery hypoplasia (VAH) is an anatomical variation that may be associated with lower cerebral blood flow. We demonstrated the prevalence of VAH to be approximately 26% in a pilot study of healthy adults (n = 39). The purpose of this study was to expand on these findings by determining the prevalence of VAH and its impact on cerebral hemodynamics in a larger sample size of middle‐aged and older adults.

Method

A total of 550 participants (66 ± 9 years; 346 females) underwent 4D flow MRI scans to evaluate the internal carotid arteries (ICA), vertebral arteries, and basilar artery. VAH+ (positive for VAH) was determined from the 4D flow MRI scans using both diameter (<2.5 mm) and flow (<47 mL/min).

Result

We identified 152 participants as VAH+ (prevalence of 28%). The prevalence of VAH+ was similar between females (n = 95; 27%) and males (n = 57; 28%). VAH predominantly occurred in the right vertebral artery (n = 102; 67%). As expected within VAH+ participants, the hypoplastic vertebral artery diameter was smaller (2.0±0.2 mm vs. 2.8±0.5 mm; p<0.001), blood flow was lower (29±10 ml/min vs. 100±44 ml/min; p<0.001), and pulsatility index was higher (1.8±0.6 a.u. vs. 1.3±0.3 a.u.; p<0.001) compared to the contralateral artery. There were no differences in ICA diameter (p = 0.875), blood flow (p = 0.553) or pulsatility index (p = 0.984) between VAH+ and no VAH. When evaluating the basilar artery, the diameter was smaller (2.7±0.4 mm vs. 2.8±0.4 mm; p = 0.037) with lower blood flow (105±35 ml/min vs. 116±37 ml/min; p<0.001) in VAH+ compared with no VAH. Males with VAH+ had higher basilar artery pulsatility index compared with males with no VAH (1.4±0.4 a.u. vs. 1.2±0.3 a.u.; p = 0.004), but this was not apparent in females (p = 0.544). When comparing global cerebral blood flow, there was a trend for lower flow in VAH+ compared with no VAH (p = 0.096).

Conclusion

We demonstrated VAH prevalence to be around 28%, with similar prevalence in both males and females. VAH was associated with impaired regional flow and with elevated basilar artery cerebral pulsatility in males.
The association of gait velocity and cognitive performance in a sample of older Chinese Americans: A pilot study
Authors: Yang Xiao , Spat‐Lemus Jessica , Xia Tianxu , Cai Dongming , Lai Randy , Neugroschl Judith A. , Aloysi Amy , Zhu Carolyn W , Sano Mary , Akrivos Jimmy , Huang QiYing , Zeng Xiaoyi , Liu Linghsi , Li Clara
Published: December 2023

Background

Gait velocity and cognition generally decline as individuals age. Studies have indicated that gait velocity can be used as a simple, novel, and relatively culture‐free cognitive assessment tool in older adults, particularly in domains of memory, attention, and executive function. There is limited research in this area with racial/ethnic minority groups. This study examined the association between performance on specific cognitive domains and gait velocity in older Chinese Americans – a growing, yet underrepresented group in US‐based research.

Method

71 Chinese American older adults (age 73.6 ± 6.9) with normal cognition (n = 27), mild cognitive impairment (n = 32), and early dementia (n = 12) were included in a pilot study at the Alzheimer’s Disease Research Center (ADRC) at Mount Sinai. Participants underwent a standard dementia evaluation in Mandarin/Cantonese, which included a clinical interview, medical exam, and neuropsychological testing. All participants self‐reported as Chinese Americans who were primarily Cantonese‐ or Mandarin‐speaking. Exclusion criteria included: not proficient in Cantonese/Mandarin, mobility impairment, as well as history of psychiatric disorder(s) and cerebrovascular accident. Diagnoses were assigned at a consensus conference. Exploratory factor analysis was conducted to determine cognitive domains encompassing the neuropsychological battery, which included tests of processing speed/attention, executive function, memory, and language/verbal fluency. Gait velocity was measured with a walking speed test measured in seconds. Multiple linear regression was used to examine the association between gait velocity and cognitive performance, while controlling for age, education, depression measured by Geriatric Depression Scale (GDS), and lifestyle/medical factors (e.g., tobacco/alcohol use, hypertension).

Result

Factor analysis demonstrated 4 principal neuropsychological factors: non‐contextual memory, contextual memory, processing speed, and language/verbal fluency. The regression model showed that lower scores on a test of non‐contextual memory was associated with slower gait velocity. Higher GDS scores were associated with slower gait velocity.

Conclusion

Consistent with previous studies with predominately non‐Hispanic White samples, we found an association between gait velocity and non‐contextual memory in older Chinese Americans. In contrast to the literature, no other cognitive domains were significant in this small sample. The finding provides preliminary data to support the use of gait velocity as a novel cognitive assessment in this historically underrepresented group.
Impaired KATP channel‐mediated electro‐metabolic signaling in capillary pericytes disrupts brain blood flow control in aging and Alzheimer’s disease
Authors: Hariharan Ashwini , Longden Thomas Andrew ,   Longden lab of neurovascular interactions in health and disease
Published: December 2023

Background

Aging is associated with a gradual decrease in cerebral blood flow and disruptions in neurovascular coupling, causing a mismatch of energy supply and demand that can precipitate neuronal dysfunction and cognitive decline. We have recently discovered that ATP‐sensitive K+ (KATP) channels in capillary thin‐strand pericytes act as metabolic sentinels that couple subtle changes in local glucose to electrical signals such that blood flow is rapidly adjusted in response to decreased availability of this critical energy substrate. Aging and Alzheimer’s disease (AD) are linked to an increase in caveolin, association with which can disrupt the ability of KATP channels to sense intracellular energy state by decreasing sensitivity to ADP. Here, we demonstrate than an interaction between caveolin and KATP channels in aging animals underlies the loss of electro‐metabolic blood flow control by brain pericyte KATP channels.

Method

Using a combination of advanced techniques such as in vivo two‐photon laser scanning microscopy to image hemodynamics, and electrophysiological recordings from isolated cortical thin‐strand pericytes, we determine the effect of aging and familial AD on brain blood flow control by pericyte KATP channels in young (2‐3 months old) and aged (12‐14 months old) 5xFAD mice. We investigate the interaction between caveolin and KATP channels, and whether disrupting caveolae can restore the energy sensing abilities of pericyte KATP channels in older mice.

Result

In young mice, inhibiting glucose import into the brain with a glucose transporter‐1 blocker (1 µM BAY‐876) activates pericyte KATP channels to dilate arterioles and capillaries, and increase blood flow. Remarkably, this effect is completely lost in older mice. Our data reveal a key interaction between caveolin and KATP channels underlies this dysfunction, and disrupting caveolae in older mice reinstates the ability of pericyte KATP channels to sense decreases in local glucose.

Conclusion

Thin‐strand pericytes protect neuronal health by coupling local energy substrate availability with hyperemia, and the disruption of this mechanism can contribute to the development of blood flow dysregulation observed in dementia. Our data unveil a role of caveolin in the loss of energy sensing by pericyte KATP channels, which can be leveraged to augment blood flow in aging individuals.