bluuebunny/crossref_metadata_2025 huggingface dataset:
Versatile MRI acquisition and processing protocol for population‐based neuroimaging
Authors: Koch Alexandra , Stirnberg Rüdiger , Estrada Santiago , Zeng Weiyi , Lohner Valerie , Shahid Mohammad , Ehses Philipp , Pracht Eberhard , Reuter Martin , Stoecker Tony , Breteler Monique M.B.
Published: December 2023

Background

Neuroimaging plays an essential role in epidemiological studies and a special focus is directed towards the employment of versatile MRI acquisition and processing. The proposed multi‐purpose MRI protocol was designed for large‐scale and long‐term population neuroimaging and includes structural, diffusion‐weighted, and functional MRI modalities. It directly links the acquisition of an extensive set of MRI contrasts with fully automated data processing pipelines and quality assurance of the MRI data and image‐derived phenotypes.

Method

The MRI acquisition protocol is largely based on in‐house developed MR sequences. With a total scan time below one hour per participant, it allows to acquire multiple MR contrasts at 3T with whole‐brain coverage and high isotropic image resolution, while keeping potential subject discomfort and motion artifacts at manageable levels. Designed to be kept constant, but also adaptive, the scan protocol separates into a core imaging protocol with MR contrasts of high relevance acquired for all study participants, and a free protocol to accommodate alternative promising MRI techniques in smaller sub‐populations. The analysis protocol handles large‐scale imaging data by means of fast and fully automated processing pipelines that incorporate state‐of‐the‐art image analysis tools and innovative machine learning methods, particularly using deep learning. Dedicated quality assessment (QA) includes visual rating and inspection for incidental findings on structural MRI and QA workflows tailored for each postprocessing pipeline to automatically identify problematic data based on the distribution of subject‐specific QA metrics with respect to the population average.

Result

The MRI protocol has been successfully applied in the Rhineland Study, a prospective cohort study in Bonn, Germany, with currently over 10,000 participants. Image‐derived phenotypes include: global and regional brain tissue volume, thickness and surface measures from multi‐modal structural MRI, global and regional microstructural measures based on diffusion‐weighted MRI, brain functional connectivity using resting‐state functional MRI, and volumes of subcutaneous and visceral adipose tissue based on a single‐breathhold abdominal MRI (Figure 1).

Conclusion

We present a versatile MRI protocol with acquisition and analysis methods that are generally applicable and not geared towards a specific disease or research question. Thus, this protocol may be of specific interest for many neuroimaging applications including population imaging studies.
Association of subjective and objective cognitive performance to self‐rated driving ability in older adults
Authors: Morrissey Sol , Jeffs Stephen , Gillings Rachel , Fisher‐Morris Mary , Manley Ed , Hornberger Michael
Published: December 2023

Background

Older drivers often self‐regulate their driving behaviours to avoid more challenging situations that may lead to increased driving risk. However, other research also indicates that many older adults overestimate their driving ability, and therefore may be at risk of road traffic incidents due to not self‐regulating accurately. Understanding how self‐rated driving relates with cognitive performance can uncover markers for at‐risk driving behaviours. The present study therefore aimed to establish how self‐rated driving ability within a healthy older adult cohort relates to subjective and objective cognitive performance.

Method

925 cognitively healthy individuals were recruited to take part in an online cohort study (age: 71.07, % female = 55.56). Participants completed questionnaires examining driving behaviour and subjective cognitive performance. Subjective cognition was measured by a questionnaire examining spatial ability and memory performance across the lifespan and within the past 3 months. A subjective cognitive change measure was established by subtracting lifetime cognition ratings from recent cognition ratings. Participants then completed a cognitive battery in domains associated with driving performance. Hierarchical regression modelling was conducted to establish how self‐rated driving ability was associated with subjective and objective cognitive performance after controlling for age and gender effects.

Result

Within subjective cognition, individuals who rated their spatial ability and memory performance higher also rated their driving ability higher, and greater subjective cognitive change within both memory and spatial ability was predictive of lower self‐rated driving ability. Within objective cognitive performance, individuals with faster reaction speeds and faster Trail Making Test‐B completion time rated their driving abilities higher. Interestingly, when included in the same regression model, only subjective cognitive measures were predictive of self‐rated driving ability.

Conclusion

Previous studies have found that self‐perceived driving ability is a more accurate indicator of self‐regulation behaviour than actual driving ability. Here, we show that subjective cognitive measures were more predictive of self‐rated driving ability than objective cognitive measures within a healthy older adult cohort. These findings add to the understanding in how cognition interacts with self‐regulation behaviour and provides an opportunity for comparison in self‐regulation driving behaviour within prodromal and clinical dementia.
Sleep and circadian measures at age 73 are related to brain macrostructure, microstructure, and amyloid pathology
Authors: King‐Robson Josh , Nicholas Jennifer M , James Sarah‐Naomi , Sudre Carole H , Lu Kirsty , Barnes Jo , Coath William , Richards Marcus , Cash David M , Warren Jason D , Schott Jonathan M
Published: December 2023

Background

Sleep disturbance is associated with an increased risk of developing Alzheimer’s disease, yet the relationship between sleep metrics and brain pathology remains poorly understood. Complementing ‘traditional’ metrics such as total sleep time (TST) and sleep efficiency (SE), the midpoint of sleep, interdaily stability and intradaily variability provide important insights into chronotype and circadian rest activity rhythms.

Methods

We used data from dementia‐free participants from the Insight 46 neuroscience sub‐study of the MRC National Survey of Health and Development (NSHD, British 1946 Birth Cohort). Hippocampal, whole brain, and white matter hyperintensity volume (WMHV), and amyloid status (positive/negative) were derived from volumetric T1 and FLAIR MRI, and 18F‐florbetapir amyloid‐PET at age 73. TST, SE, midpoint of sleep, interdaily stability, and intradaily variability were calculated from 6 nights of wrist actigraphy (Philips Actiwatch) at the same time point. Normal appearing white matter (NAWM) microstructure was assessed by diffusion weighted imaging at age 70. Mean z‐scores for each participant’s neurite density index (NDI) and orientation dispersion index (ODI) were generated relative to normal controls.

The relationship between sleep and imaging metrics was examined using generalised additive models to allow a flexible functional form for the sleep metrics. Where there was no evidence of a nonlinear effect, results are presented from linear regression (continuous outcomes) or logistic regression (binary outcomes). All analyses were controlled for TST, SE, age, gender, socioeconomic status, intracranial volume, and interval from imaging to actigraphy, in addition to blood pressure age 53, and body mass index for WMHV analyses.

Results

There was a significant nonlinear relationship between TST and both hippocampal and brain volume, with ∼ 7 hours sleep appearing optimal (Table 1, Figure 1). Increasing TST and decreasing SE were associated with decreased NDI. Unexpectedly, increased interdaily stability was associated with an increased risk of being amyloid positive (P = 0.003, Figure 2).

Conclusion

Sleep and circadian measures at age 73 were associated with brain microstructure, macrostructure, and amyloid pathology. Efficient sleep of around 7 hours is associated with optimal brain health. Ongoing longitudinal follow‐up will help to explore causality.
The AppNL‐G‐F/MAPT mouse model of Alzheimer’s Disease demonstrates increased levels of ptau217 in CSF, changes that correlate with increased cerebral p‐tau depositions
Authors: Schultz Nina , Andersson Emelie , Wennström Malin , Hansson Oskar
Published: December 2023

Background

Cerebrospinal fluid (CSF) biomarkers reflecting the neuropathological hallmarks of Alzheimer’s disease (AD) have during the two last decades been developed and are commonly used to diagnose patients with AD patients. Previous studies have shown that CSF p‐tau217 particularly well can separate AD patients from healthy controls and that CSF levels of ptau217 correlate significantly with the amyloid burden and tau pathology in the brain (determined by PET). However, more studies are needed to fully understand the temporal relationship between CSF p‐tau217 changes and the accumulation tau in the brain. In this current study, we aim to investigate these temporal associations by the use of a novel knock‐in mouse model, AppNL‐G‐F expressing all six isoforms of human MAPT.

Method

Cerebrospinal fluid (CSF) and brain tissue will be collected from 3‐22 months old AppNL‐G‐F /MAPT and MAPT knock‐in mice. A pilot study of a subset of mice at different ages has been performed where levels of CSF ptau217 were analyzed using Mesoscale Discovery developed by Eli Lilly and Company. Mouse brain sections were immunostained against Aß and ptau181/217/231 to determine the cerebral p‐tau distribution.

Result

In CSF from our AppNL‐G‐F /MAPT double knock‐in (dKi) mouse model, we found age‐related increases in ptau217 levels compared to MAPT Ki mice. These changes in CSF ptau217 were associated with an increase of cerebral accumulation of p‐tau positive inclusions in the cortex and hippocampus of these mice. Additionally, we also found temporal differences in co‐localization between Aß plaques and the investigated phosphorylation sites of tau.

Conclusion

Our preliminary results from the AppNL‐G‐F/MAPT double knock‐in model, show early alterations in CSF ptau217 levels, changes that correlate in time with cerebral p‐tau positive accumulation as well as formation of Aß plaques. These findings indicate that alterations in CSF and cerebral p‐tau occurs early in the disease, when Aß pathology is widespread but no tau tangles are present. Furthermore, our preliminary data suggest temporal differences in phosphorylation sites of tau associated with Aß pathology. Additional CSF analysis and immunostainings will be performed before the AAIC conference.
Synergetic microRNA delivery for therapeutic targeting in Alzheimer’s disease
Authors: Polzer Oliver , Randoe Rosa E , Snoeck Sarah , Verhaagen Joost , Lucassen Paul J. , Salta Evgenia , Fitzsimons Carlos
Published: December 2023

Background

Alzheimer’s disease (AD) is a complex multigenic disorder primarily defined by the presence of β‐amyloid‐containing plaques and Tau‐containing neurofibrillary tangles. To date, there is no available treatment and the failure of numerous single‐target clinical trials shifts more and more the focus to ‘multiple drugs – multiple targets’ pharmacological approaches. miRNAs are short non‐coding RNAs that control the expression of specific target genes, often within the same biological pathways. This makes miRNA‐based therapeutics uniquely suited for gene network‐based approaches, as they may regulate common sensitive hubs in biological pathways relevant for AD. Importantly, most gene transcripts are regulated by multiple miRNAs, leading to functional convergence and increased regulatory strength and accuracy. miR‐124 and miR‐132 are among the miRNAs dysregulated in human AD brain and may counteract AD pathology and memory deficits via common pathways in rodent models of AD. Here, we directly address the therapeutic potential of synergistic miR‐124/miR‐132 delivery in AD.

Method

We first evaluate the in vitro efficiency of miRNA‐carrying pAAV plasmids to overexpress mature miRNAs individually or combined using transfection in HEK293T cells. Second, delivery of the generated AAVs via stereotactic surgery is employed to assess their efficiency in vivo.

Result

Here we show preliminary data on the development of cell type‐specific AAVs for the combined delivery of two miRNAs, namely miR‐124 and miR‐132, in the mammalian brain. We demonstrate their efficiency in vitro as well as in vivo to label targeted cells and sufficiently increase miRNA levels.

Conclusion

Our approach provides a distinctive toolkit to enable precise cell targeting, dosing and toxicity control of a combinatorial miRNA carrying AAV system in the central nervous system.
Polyphenol intake beneficially associates with inflammation and cognitive performance, and is mediated by MRI‐derived features
Authors: Dryer‐Beers Elliot R , Matthews Paul M , Frost Gary S , Griffin Jennifer
Published: December 2023

Background

Early changes to cognitive performance and neurophysiological biomarkers offer insights into one’s future risk of developing Alzheimer’s disease or other dementias. Evidence suggests a link between polyphenol intake and reduced incidence of age‐associated cognitive decline and neurodegeneration. These relationships may be driven by the effect of dietary polyphenols on inflammation and degeneration of critical neurological structures and systems. These relationships are challenging to assess, as few cohorts allow cohesive assessment of polyphenol intake, systemic inflammation, neurophysiological measures and cognition.

Method

Polyphenol intake was assessed in two UK cohorts: The Airwave Health Monitoring Study and UK Biobank (UKB). Diet diary and questionnaire data were integrated with polyphenol composition data from Phenol‐Explorer to allow for testing of associations between polyphenol intake, blood biomarkers of inflammation, and cognitive performance. 9008 Airwave participants and 209,163 UKB participants were included in a cross‐sectional analysis. C‐reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation, and cognitive assessments included reaction time (milliseconds) and fluid intelligence (score /13). Neuroimaging assessments included grey matter volumes and white matter integrity, and were considered individually and using PCA.

Result

Linear regressions showed inverse associations between total polyphenol intake and CRP: β ‐0.00702 (Airwave) and β = ‐0.00672 (UKB), both P <0.001, as well as fibrinogen: β ‐0.00221; P = 0.038 (Airwave only), in addition to biomarker associations with polyphenols at the compound group level. Regarding cognition, linear regressions revealed beneficial associations between total intake and performance in fluid intelligence tests: β 0.00657; P = 0.009 (Airwave) and β 0.00715, P <0.001 (UKB), and reaction time β ‐0.0000977; P = 0.020 (UKB). Mediations of the polyphenol‐fluid intelligence relationship were detected for IDPs including grey matter volumes of hippocampal‐associated regions, and white matter integrity measured using ISOVF.

Conclusion

We described polyphenol intake in two large, contemporary UK cohorts, and discovered associations between higher intake and improved inflammatory markers and cognitive performance, as well as mediations of the polyphenol‐cognition relationship by physical neurological markers. This contributes to evidence supporting the health benefits of dietary polyphenols, clarifies the physiological pathways through which they may act, and highlights their relevance when considering preventative interventions for neurodegeneration.
Regional brain atrophy is associated with measures of impaired blood‐CSF barrier in patients with prodromal and overt dementia with Lewy bodies and Alzheimer’s disease dementia
Authors: Nedelska Zuzana , Uller Miroslav , Hanzalová Jitka , Jurasova Vanesa , Lerch Ondrej , Hort Jakub
Published: December 2023

Background

Alzheimer’s disease (ADdem) and Lewy body dementia (DLB) are characterized by cholinergic impairment and regional brain atrophy including the medial‐temporal and temporo‐parietal regions. In DLB, the overlapping AD pathology is associated with more prominent atrophy. However, other factors than AD pathology play role in brain atrophy and clinical impairmentl. The choroid plexus (CP), part of blood‐CSF barrier, is central in regulating inflammation and monitoring the CSF synthesis, composition, and circulation. However, association between measures of blood‐CSF barrier impairment and regional brain atrophy, and the effect of AD biomarkers in this association, remain unknown in prodromal and overt AD and DLB.

Method

We included 108 participants from the Czech Brain Aging Study (n = 30 prodromal AD, n = 24 ADdem, n = 10 prodromal DLB, n = 20 overt DLB, n = 24 cognitively unimpaired controls, CN) who underwent clinical/cognitive testing, brain MRI and CSF sampling. FreeSurfer automated algorithm and cholinergic basal forebrain ROIs were used to measure CP volumes and nucleus basalis of Meynert (NBM) and other regional cortical thickness and volumes. From CSF, the established AD biomarkers and an albumin quotient (QAlb), a proxy of blood‐CSF barrier impairment, were derived. Associations were measured using multivariate analysis of variance adjusted for age, sex; mediation analysis was used to assess effect of CSF AD biomarkers on associations between atrophy and blood‐CSF impairment.

Result

CP volume was significantly larger and NBM volume was smaller in both DLB and AD compared to CN, and the CP volume increased from prodromal to overt dementia stages. Larger CP volumes were associated with smaller NBM volumes in AD and DLB prodromal and overt stages. Larger CP volumes were associated with abnormal QAlb, and with more abnormal levels of AD biomarkers. More abnormal AD biomarker levels mediated the association between larger CP volumes, abnormal AlbQ and regional atrophy in AD and DLB.

Conclusion

Measures of impaired blood‐CSF barrier by enlarged CP and AlbQ are associated with more profound regional atrophy including cholinergic regions from prodromal to overt dementia stages. Whereas AD‐related pathology likely plays role in this, investigating the blood‐CSF barrier as a potential treatment target may be beneficial for AD and DLB patients.
Combining working memory and speech data in a digital app for early detection of cognitive impairment in primary care
Authors: Hilsabeck Robin C. , Keller Jeffrey N. , Henry Maya L. , Li J. Jessy , Pugalenthi Lokesh , Rathouz Paul , Toprac Paul , Chang Patrick , Chang Joshua , Schmitz Suzanne , Largent Avery , Foil Heather , Brouillette Robert , Lester‐Smith Rosemary A
Published: December 2023

Background

Cognitive screening to detect mild cognitive impairment (MCI) and dementia in primary care settings has proven to be a challenging task. The ideal solution would be a brief, low‐burden assessment tool appropriate for use with individuals from diverse educational and cultural backgrounds that requires limited time and expertise from primary care providers. The purpose of this project was to develop a digital cognitive screening app derived from widely used cognitive and speech tasks using machine learning techniques.

Method

Participants were 104 old adults, 53 who were cognitively normal (CN) and 51 who were cognitively impaired (CI). All participants completed a working memory task (WM), followed by four speech‐language tasks, followed by a second administration of WM (WM2) to investigate the added utility of practice effects. Participants also completed the Quick Mild Cognitive Impairment (Qmci) screen. Bayesian adaptive regression trees were used to test 11 models. All models contained sex, age, education, and marital status. One model contained WM and the WM2‐WM difference. Four models contained 26 acoustic and 34 linguistic variables derived from each of the four speech tasks, and four more models were identical, except with the two WM variables added. For comparison, two models with Qmci were fitted: one with and one without the two WM variables.

Result

Three models achieved cross‐validated classification accuracy of c≥0.90: WM by itself (estimated c = 0.91; Figure 1), WM and a personal narrative task (c = 0.94; Figure 2), and WM and a counting backwards task (c = 0.90). Models with picture description and procedural discourse tasks performed the worst. The QMCI‐only model yielded c = 0.91.

Conclusion

Combining WM, acoustic and linguistic variables involved in recounting personal memories, and the ability to benefit from prior exposure to a task discriminated CN from CI groups with a high degree of accuracy. This unique combination assesses key cognitive abilities known to be affected early in neurodegenerative diseases, executive functioning and memory, and includes both verbal and nonverbal tasks. Importantly, individuals with varying levels of cognitive functioning, including mild dementia, were able to use the app successfully, and the automated nature of the tool required minimal staff time or expertise.
A Novel Method for Detecting Protein Aggregates Using Plasmonic Sensing
Authors: Cheetham Matthew R , Lam Jeff YL , Rocchetti Sara , Baumberg Jeremy J , Klenerman David
Published: December 2023

Background

Amyloid‐beta (Aβ) protein aggregates have been implicated in the pathology of Alzheimer’s disease (AD). These aggregates are difficult to characterise due to their small size, requiring very sensitive techniques. Gold Nanoparticles (AuNPs) form plasmonic cavities when in close proximity to a gold surface. The cavity both enhances and scatters incident light, with a resonant wavelength strongly dependent on the size of the cavity. These plasmonic cavities were used to detect and size Aβ aggregates at ultra‐low concentration using darkfield spectroscopy.

Methods

AuNPs were coated with the Aβ specific 6E10 capture antibody, incubated with a synthetic aggregate sample, and centrifuged to isolate the AuNPs. They were then placed on a gold surface, and darkfield scattering spectra were obtained. The peak scattering wavelengths for each AuNP were used to produce a histogram of gap sizes, and thus the size distribution of detected protein aggregates.

Results

Significant differences were seen in resonant peak position between monomeric samples of Aβ and 24 hour aggregated samples. This allows for easy identification of protein monomer vs fibrillar aggregates. In the case of aggregates, some peaks in the darkfield scattering spectra also appeared strongly polarised, suggesting dimerisation of the AuNPs. This was not present for the case of monomeric sample.

Conclusions

With this novel technique it was possible to clearly distinguish between samples of Aβ monomer and aggregates. This approach can likely be expanded to find the range and proportion of aggregate sizes in serum samples to detect the onset of AD. The AuNP dimerisation when Aβ aggregates are present is also interesting, and may serve as further verification of the size or shape of these aggregates.
Serum Nf‐L and GFAP are associated with incident dementia and dementia mortality in older adults: The Cardiovascular Health Study
Authors: Cronjé Héléne Toinét , Liu Xiaojuan , Odden Michelle , Moseholm Kristine F , Seshadri Sudha , Satizabal Claudia L. , Lopez Oscar L. , Bis Joshua C , Djoussé Luc , Fohner Alison E , Psaty Bruce M. , Tracy Russell P. , Longstreth W.T. , Jensen Majken K , Mukamal Kenneth J
Published: December 2023

Background

Although circulating neurofilament light chain (Nf‐L) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk, their additive association, and their associations with dementia‐specific mortality have not been investigated. Overall, prospective community‐based studies of these biomarkers, particularly those representing individuals beyond their eighth decade, are lacking.

Method

We investigated 1,712 cognitively healthy participants of the Cardiovascular Health Study (1,042 women [61%], 218 Black [13%], median [IQR] baseline age = 77 [74–80] years). Cox regression models were used to test the associations of serum Nf‐L and GFAP, measured using single molecule array technology, with 19‐year incident dementia and dementia‐specific mortality risk. These primary outcomes were complemented by repeated Modified Mini‐Mental State Exam and the Digit Symbol Substitution Test scores which were used in linear mixed models to test the associations of Nf‐L and GFAP with cognitive decline over three years.

Result

More than half of the participants were diagnosed with incident dementia (N = 975) and 183 dementia‐specific deaths occurred during follow‐up. In covariate, and mutual Nf‐L/GFAP adjusted models, each standard deviation unit higher Nf‐L or GFAP associated with a hazard ratio (HR) of 1.14 (95% confidence interval, 1.03–1.26) and 1.12 (1.04–1.21) for incident dementia, and 1.37 (1.11–1.69) and 1.55 (1.31–1.83) for dementia‐specific mortality (Table 1). These associations were graded and additive, with the strongest associations observed when Nf‐L and GFAP levels were simultaneously elevated (Figure 1). Compared to those in the lowest tertiles of both markers, we observed an additive increase in risk among individuals with both Nf‐L and GFAP levels in the highest tertile [HR, 2.06 (1.60‐2.67) for incident dementia and 9.22 (4.48–18.9) for dementia‐specific mortality, Figure 1]. Nf‐L, but not GFAP, independently associated with faster cognitive decline over three years (Table 1).

Conclusion

Circulating Nf‐L and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.
Clock drawing: Does the digital era have an influence on analog clock drawing in our young generation
Authors: Fisher Tali , Ayoub Rawan , Yarovinsky Natalya , Hadad Rafi , Dadi Lee , Stanger Chen , Marinberg Adi , Tanne David , Aharon‐Peretz Judith , Ben‐Hayun Rachel
Published: December 2023

Background

The clock drawing test (CDT) is frequently used for the evaluation of people with cognitive impairment. It is particularly sensitive for tasks dependent on executive and visuospatial functions. The original CDT involves drawing a clock with numbers and hands on specific time. As during the last decades, digital clock use became more widespread, our aim in the present study was to evaluate whether the analog clock drawing test can still be useful as an assessment tool for dementia and cognitive decline.

Method

This retrospective study includes three groups: 1) The young group (N = 45, Age: M = 20.2, SD = 2.49) was recruited from IDF (Israel defense force) neurology clinic following headache complaints; 2) The MCI group (N = 28, Age: M = 73.21, SD = 7.24); 3) The Dementia due to Alzheimer’s Disease (AD) group (based on CSF biomarkers) (N = 30, Age: M = 71.27, SD = 9.81). Both groups 2 and 3 were recruited from the Cognition Institute at the Rambam Health Care Campus. All participants underwent the CDT, which was scored according to the Manos scale and compared to relevant norms based on age. One‐way ANOVA was performed to determine if CDT performance varies by group.

Results

AD group CDT scores were lower (M = 3.7, SD = 3.86) compared to the cognitively intact age matching norms (M = 9.57, SD = 0.9), t (244) = 8.522, p<0.0001 as expected. CDT score of the MCI group (M = 8.57, SD = 2.04) did not differ from cognitively unimpaired norms (M = 8.65, SD = 1.69). Surprisingly, The CDT scores of the young group were significantly lower (M = 8.31, SD = 2.22) than expected according to norms (M = 9.22, SD = 1.373), t(246) = 3.543, p = 0.0005. AD group performed significantly worse compared to the other two groups (M = 3.7, SD = 3.86) (F (3) = 20.654, p<0.001).

Conclusion

While the CDT scores in the elderly (MCI and AD) matched previously reported data, young individuals perform significantly worse. These findings may indicate that the CDT test is suitable for use in the elderly population as it is still able to detect cognitive impairment in dementia. However, young people find it difficult to perform, probably due to their limited exposure to analog clocks. These results raise questions regarding the relevance of the CDT during cognitive assessment in the future.
Heparan sulfate 3‐O‐sulfation and Tgfb1 involvement in Alzheimer’s disease related tau aggregation
Authors: Castillo‐Negrete Rafael , Merrick Heloise , Girard Ombeline , Huynh Minh Bao , Diener Martin , Jedlicka Peter , Papy‐Garcia Dulce
Published: December 2023

Background

Aging is the main risk factor for Alzheimer’s disease (AD) characterized by a cognitive decline related to a synaptic disfunction (Chen et al., 2019). In AD brains, tau abnormal phosphorylation coexists with heparan sulfates (HS), suggesting that HS could lead to the formation of neurofibrillary tangles (NFT) (Goedert et al., 1996). In vitro, the aggregation of tau is not possible in the absence of heparin, a highly sulfated HS carrying 3‐O‐sulfation (3S‐HS). 3S‐HS are the product of HS 3‐O Sulfotransferase (HS3ST) enzymes (Sepulveda‐Diaz et al., 2015). In AD, Heparan Sulfate‐Glucosamine 3‐Sulfotransferase 2 (HS3ST2) expression is higher in tauopathy vulnerable brain regions, such as the hippocampus and cortex (Huynh et al., 2019). Previously, we showed in a cellular model that HS3ST2 induces cell autonomous aggregation of tau (Huynh et al., 2022). However, the mechanism leading to an increased expression of HS3ST2, and therefore increase in 3S‐HS synthesis are unknown. Additionally, it is not known the effect of reducing the levels of HS3ST2 in tau oligomerization and aggregation in neurons.

Method

Primary hippocampal neurons (PHN) from the rTg4510 mice model were dissected and maintained in vitro for 20 days (DIV20). All treatments (ALK5inh, Tgfb1) and lentiviral transduction (Lv‐NonTarget, Lv‐shHs3st2) were done at day in vitro 15 (DIV15).

Result

In brain of aged individuals, transforming growth factor TGFB1 is upregulated, modulating gene expression (Doyle et al., 2010). SMAD4 transcription factor is activated upon the dimerization of TGFB receptor targeting specific genes (Martin‐Malpartida et al., 2017). SMAD4 contains genome wide recognition motifs that are present in the Hs3st2 promoter, suggesting a possible regulation. We showed that Hs3st2 is under regulation of Tgfb1 and blocking pSmad2/3 reduces its levels. Contrarily, Hs3st2 levels were increased by increasing pSmad2/3. The importance of Tgfb1 coregulation with Hs3st2 was assessed by blocking the expression of Hs3st2, leading to a decrease in tau oligomerization and aggregation. Finally, we found that the reduction of 3S‐HS enhances synaptic size, and presynaptic/postsynaptic connectivity.

Conclusion

Overall, we depicted the regulation of Hs3st2, and demonstrate its involvement in synaptic connectivity and tau aggregation, confirming the importance of 3S‐HS in the physiopathology of AD.
Impact of type 2 diabetes mellitus on brain volumes and cognitive performance
Authors: Restrepo Carolina , Khlif Mohamed Salah , Patel Sheila , Alsawaf Shahad , Bird Laura J. , Werden Emilio , Ekinci Elif , MacIsaac Richard , Burrell Louise , Brodtmann Amy
Published: December 2023

Background

Type 2 diabetes (T2DM) is recognised as a major contributor to cognitive decline. People with T2DM demonstrate abnormalities on MRI compared to control individuals. The aim of this analysis was to investigate differences in cognitive performance and brain volume between individuals with T2DM participating in the Diabetes‐and‐Dementia (D2) study and a group of healthy controls (HC) part of the Cognition And Neocortical Volume After Stroke (CANVAS) study.

Method

One hundred and fifty individuals with T2DM and 36 cognitively‐normal participants completed neuropsychological assessments and a 3T‐MRI scan. FreeSurfer was used to estimate total brain volume (TBV), mean cortical thickness and subcortical volumes, including the thalami and caudate nuclei. Averages between left and right volumes were calculated for subcortical structures. WMH volumes were estimated manually using FLAIR MRI. Five cognitive domains, including attention, visuospatial skills, memory, language and executive function were computed using z‐scores. These domains were used to compare cognitive performance between individuals with and without T2DM.

Demographic and clinical comparisons were completed in MATLAB using Two‐Sample t‐test (age), Fisher Exact test (education, sex, APOE‐e4), and Wilcoxon Rank Sum test (BMI). A linear regression model was used to compare cognitive performance between the two groups with correction for age, sex and education level (more/less than 12 years), as well as total intracranial volume for comparing brain volumes.

Result

Participants with T2DM were significantly younger, with a higher BMI, had reduced cortical thickness, significantly smaller TBV and smaller subcortical volumes including thalamic, brainstem, amygdala, accumbens area and choroid plexus. Individuals with T2DM exhibited a poorer cognitive performance on tests of language, memory, attention, and visuospatial skills compared to the HC group. There were no significant differences between the two groups in terms of sex, education level, APOE‐e4 carriage, WMH, hippocampal volume (see Table 1).

Conclusion

T2DM is associated with accelerated structural brain aging, manifesting as cerebral atrophy and poorer cognitive function.
Sequential grey matter atrophy related to Alzheimer’s disease in adults with Down’s syndrome
Authors: Bejanin Alexandre , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Montal Victor , Pegueroles Jordi , Carmona‐Iragui Maria , Aranha Mateus Rozalem , Vaqué‐Alcázar Lídia , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Rodríguez‐Baz Íñigo , Belbin Olivia , Alcolea Daniel , Blesa Rafael , Lleo Alberto , Fortea Juan
Published: December 2023

Background

Due to the triplication of the APP gene on chromosome 21, virtually all individuals with Down’s syndrome (DS) present AD neuropathological hallmarks by the age of 40, and have a lifetime risk of developing dementia >90%. However, whether DS follows a stereotypical pattern of AD atrophy has not been investigated. Here, we aimed at defining the sequential grey matter (GM) volume loss across the whole AD continuum in adults with DS.

Method

Cross‐sectional design. 248 adults with DS (n = 145 asymptomatic [preclinical], n = 93 prodromal/demented AD) and 181 euploid cognitively unimpaired (CU) individuals from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol (Table.1). T1‐weighted images were preprocessed using CAT12. GM volumes adjusted for demographics (age, sex) and nuisance variables (TIV, MRI scanner) were computed for each cortical region of the Hammer Atlas and for each DS participant, using the CU group as a reference. Adjusted volumes (W‐scores) were binarized using a threshold of ‐2.33 (corresponding to a regional volume <99th percentiles of the CU group) to examine the brain regions most frequently atrophied in DS compared to CU. Conditional probability analyses were additionally performed in DS to assess if a brain region was more likely to present with atrophy than another.

Result

Adults with DS most frequently showed atrophy in the medial temporal lobe, anterior cingulate, and temporo‐parietal regions. This pattern remains essentially similar when using a dynamic range of thresholds (Fig1.A) and across clinical AD stages (Fig1.B), even though the proportion of individuals showing atrophy increased with disease progression (Fig1.C). Interestingly, the anterior cingulate was the most frequently atrophied region in asymptomatic but not prodromal/demented DS. Conditional probability analyses revealed that the hippocampus, amygdala, and anterior cingulate have a significantly higher probability of showing GM loss before any other regions. A second cluster of tempo‐parietal regions appears more likely to show atrophy than most other regions.

Conclusion

In DS, GM atrophy appears to follow a stereotypical pattern that strongly resembles the one of sporadic AD. Brain developmental specificities (e.g., anterior cingulate) are coupled with AD‐like atrophy early in the disease and become less predominant with AD progression.
TRIAL21: A COHORT OF ADULTS WITH DOWN SYNDROME AT RISK OF DEVELOPING ALZHEIMER'S DISEASE
Authors: Rebillat Anne‐Sophie , Laffon De Mazieres Clarisse , Hiance‐Delahaye Anne , Baraton Caroline , Bourgerie Anne‐Sophie , Bourgeois Pauline , Clert Manon , Falquero Segolene , Martet Diane , Sacco Silvia , Vilaire Marie , Durand Sophie , Mircher Clotilde
Published: December 2023

Background

Trisomy 21, in addition to being the first cause of intellectual disability, confers a high risk of developing Alzheimer’s disease (AD). The APP (Amyloid Precursor Protein) gene is located on chromosome 21, leading to high levels of ß‐amyloid peptide. However, there is great variability in the age of onset of symptoms.

The objective of this study is to identify factors influencing the age of onset of the disease by following a cohort of adults with trisomy 21

Method

This is a prospective, single‐center, open‐label study. A total of 200 patients aged at least 35 years without a diagnosis of AD at baseline will be included.

Baseline visit includes a medical examination, a neuropsychological evaluation, a blood sample and a lumbar puncture (if possible). A brain MRI is performed within 3 months. A medical visit takes place at 12 months. The end‐of‐study visit at 24 months includes a medical examination, a neuropsychological evaluation and a blood sample. An annual follow‐up for 10 years in the care setting is provided.

Result

Between April 2019 and January 2023, 119 patients were included, including 55 women and 64 men. The average age was 48 years.

25 lumbar punctures and 90 brain MRI could be performed, as 86 visits at 12 months and 44 visits at 24 months.

Conclusion

Early changes related to AD are particularly difficult to detect in adults with Trisomy 21 because of their intellectual disability. The identification of progression factors of the disease is essential to allow an early diagnosis for an appropriate management
Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for the Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis,∖ and Salivary Lactoferrin in Alzheimer’s Disease
Authors: Nara Peter N
Published: December 2023

Background

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm‐induced “chronic” multi‐systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention.

Method

The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases.

Result

A better explanation is offered for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial virulence factors/protein/toxins. Related to this, the “Gingipains Hypothesis”, AD‐related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model.

Conclusion

Thus it is hoped this presentation can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.
Sex‐specific associations of cerebrospinal fluid YKL‐40 with white matter hyperintensities over a 7‐year follow‐up period
Authors: Peterson Amalia Jo , Zhang Panpan , Moore Elizabeth E. , Eaton James , Pechman Kimberly R. , Liu Dandan , Houston Michelle L , Davis L. Taylor , Gifford Katherine A. , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L.
Published: December 2023

Background

Women have a higher prevalence of Alzheimer’s disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults.

Method

Vanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction.

Result

In main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values>0.20) or longitudinal WMH progression (p‐values>0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values<0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003).

Conclusion

Higher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline.

Funding

IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082
Hub vulnerability and short path length to entorhinal cortex are associated with tau binding in Alzheimer’s disease: a combined MEG/PET study
Authors: Schoonhoven Deborah N , Millan Ana P , Coomans Emma M. , Yaqub Maqsood , van Nifterick Anne M , Visser Denise , Ossenkoppele Rik , Tuncel Hayel , van der Flier Wiesje M. , de Haan Willem , Scheltens Philip , Stam Cornelis J , van de Giessen Elsmarieke , Hillebrand Arjan , Gouw Alida A
Published: December 2023

Background

Brain network studies have revealed that highly connected ‘hub’ regions are particularly vulnerable to Alzheimer’s disease (AD) pathology. Additionally, the ‘‘transneuronal spread” hypothesis proposes that a toxic agent (tau) propagates along shortest paths through functionally connected neurons, driven by aberrant neuronal activity. We investigate whether network characteristics as determined using magnetoencephalography (MEG) are correlated to tau pathology in the different stages of AD.

Method

We analysed source‐reconstructed MEG data and dynamic 100‐minutes [18F]flortaucipir PET from 57 subjects positive for amyloid‐beta (Aβ)‐pathology (preclinical AD (n = 16)), mild cognitive impairment (MCI (n = 16)) and AD dementia (n = 25)). Cognitively healthy subjects without Aβ‐pathology were included as controls (n = 25). For each subject, we obtained a network based on the alpha band amplitude envelope correlation (AEC‐c, 8‐13Hz), and theta band phase lag index (PLI, 4‐8Hz), based on the Brainnettome atlas. For each node in the network, we obtained the following measures: weighted degree, degree, betweenness centrality, eccentricity (as measures of hubness); distance to left entorhinal cortex (measure of shortest path/transneuronal spread); hub disruption index for all previous hubness measures (selective hub damage) and [18F]flortaucipir BPND. Pearson’s correlations were calculated between group averages of network measures and tau‐PET binding (FDR‐corrected). Furthermore, we analysed whether network measures of the previous disease stage correlated with [18F]flortaucipir retention in the subsequent disease stage.

Result

Hub regions were predominantly found in the temporal areas (Fig‐1). Higher ‘hubness’ and shorter neuronal distance to epicentre were associated to higher tau binding in all stages of the AD continuum (Fig‐2a). Disproportional disruption to hub regions in the AEC‐c alpha band was associated with increased tau binding, but the opposite effect was found for the PLI theta band (Fig‐2b). Finally, high weighted degree, degree, and betweenness centrality in the preceding disease stage were correlated with increased tau binding in subsequent disease stages (Fig‐2c).

Conclusion

Hub regions and transneuronal spreading are key mechanisms in the propagation of tau pathology across the AD brain. Furthermore, hubs are particularly vulnerable to tau. The insight that high neuronal activity might play a causal role in Alzheimer’s disease can have implications for early detection and interventional strategies.