bluuebunny/crossref_metadata_2025 huggingface dataset:
Shotgun proteomics for the discovery of protein biomarkers for cerebral amyloid angiopathy
Authors: Vervuurt Marc , Kuiperij H. Bea , de Kort Anna M. , Kersten Iris , Wessels Hans , Gloerich Jolein , Van Nostrand William E , Verbeek Marcel M.
Published: December 2023

Background

Oftentimes, the search for novel (protein) biomarkers starts in transgenic animal models, to minimize inter‐individual variation and confounding influences. In our search for novel biomarkers for cerebral amyloid angiopathy (CAA), we have executed shotgun proteomics analyses aimed at identifying novel biomarker candidates on the cerebrospinal fluid (CSF) of rodent models for CAA type I, and compared relative expression of proteins with wild‐type controls. Additionally, we have attempted to validate these candidates by comparing selected biomarker levels in CSF of human sporadic CAA patients (sCAA) compared to Alzheimer’s patients and control subjects.

Method

A Bruker TIMS‐ToF‐MS/MS instrument was used to analyze CSF samples of rTg‐DI and wild‐type rodent samples, following trypsin digestion. Protein identification was inferred from the Uniprot unreviewed rodent database using Bruker Daltonics Data Analysis. Identified biomarker candidates were additionally researched in human CAA and Alzheimer’s Dementia (AD) patients, and controls in CSF in independent validation attempts using targeted analyses including ELISA, or enzyme activity assays.

Result

Differential expression levels in rodents were discovered for cathepsins B (CatB; p < 0.001 and p = 0.05) and S (CatS; p < 0.001 and p = 0.06), and hexosaminidase B (HexB; p = 0.003 and p = 0.17) for uncorrected and corrected results respectively. Human CatB and CatS CSF levels measured by ELISA did not differ significantly between CAA, AD patients or controls (p = 0.77 and p = 0.09). Analytical sensitivity of the CatB and CatS activity assays was too low to quantify activity in human CSF, whereas total hexosaminidase (as a measure of HexB activity) and HexA activity analyses in human CSF did show (a trend) in significant decreases in CAA patients compared to controls (p = 0.07 and p = 0.05 respectively).

Conclusion

Biomarker candidates identified from untargeted protein screenings do not directly correspond to validation efforts in human biomarker studies. Increased HexB expression levels in rodents contrastingly appear to be reflected in decreased hexosaminidase activity in CSF in human CAA, but would need to be further validated in studies with greater power.

This study was funded in the NIH CAFÉ project (5R01NS104147‐02).
Eliciting evidence on linguistic perspectives for Subjective Cognitive Impairment, Mild Cognitive Impairment and Alzheimer’s Disease: A cross‐sectional study
Authors: Kaltsa Maria , Tsolaki Anthoula , Lazarou Ioulietta , Mittas Ilias , Papageorgiou Mairi , Papadopoulou Despina , Tsimpli Ianthi Maria , Tsangalidis Anastasios , Tsolaki Magda
Published: December 2023

Background

Most descriptions of the clinical and cognitive features of Alzheimer’s Disease (AD) highlight deficits mainly in memory ability, while the in‐depth understanding of the language deficits of people with AD remains limited with most data reported as heterogeneous (see Eyigoz et al., 2020; Kavé & Dassa, 2018). The overarching goal of DemLENS project (https://demlens.enl.auth.gr/) is to investigate the key linguistic characteristics of native speakers with cognitive impairment and the decline of language skills.

Method

The study integrates the clinical evaluation, the neuropsychological assessment and thorough linguistic profiling via language production data from 168 native speakers of Greek. Specifically, we examine the lexical, syntactic and content complexity of spoken language elicited through sentence repetition, single picture description, picture sequence narratives and personal narratives. We tested young healthy adults (yHC = 35), cognitively intact elder healthy adults (eHC = 31), speakers with Subjective Cognitive Decline (SCD = 32), speakers with Mild Cognitive Impairment (MCI = 33) and speakers with mild to moderate AD (AD = 38).

Result

The data analysis focuses on the annotated data at the microstructure level – e.g. POS, syntactic complexity, internal state terms – and at the macrostructure level – e.g. information content units, narration length and narration density and revealed that depending on the cognitive severity stage, language subsystems deteriorate at different stages in the progression of AD. Lexical access difficulties, reduced informational content (e.g. narration density: F
(4,164) = 6.514, p<.001; yHC,eHC>SCI,MCI>AD) and syntactic complexity of speakers’ production appear to drive linguistic decline. Note also that sentence repetition was shown to have high discriminatory value in the development of AD (e.g. accuracy index: F
(4,164) = 92.632, p<.001; yHC>eHC,SCI>MCI>AD (Figure 1).

Conclusion

Language performance exposes subtle early signs of progression to AD that can shed light on the early detection of cognitive decline, thus facilitating the clinical process. Consequently, a language‐based AD assessment is ecologically valid and one of the least intrusive ways to assess symptoms of AD.

References

Eyigoz, E., Mathur, S., Santamaria, M., Cecchi, G., & Naylor, M. (2020). Linguistic markers predict onset of Alzheimer’s disease. EClinicalMedicine, 28, 100583.

Kavé, G., & Dassa, A. (2018). Severity of Alzheimer’s disease and language features in picture descriptions. Aphasiology, 32(1), 27‐40.
Assessing a universal neocortical mask for Centiloid quantification
Authors: Bourgeat Pierrick , Dore Vincent , Rowe Christopher C , Benzinger Tammie L.S. , Tosun Duygu , Goyal Manu S. , LaMontagne Pamela J. , Jin Liang , Weiner Michael S. W. , Morris John C , Masters Colin L , Fripp Jurgen , Villemagne Victor L ,   the Alzheimer’s Disease Neuroimaging Initiative, OASIS3, and the AIBL research group
Published: December 2023

Background

The Centiloid (CL) project was developed to harmonise the quantification of Aβ‐PET scans to a unified scale. The CL neocortical mask was defined using 11C‐PiB, overlooking potential differences in regional distribution among Aβ tracers. We created a universal mask using an independent dataset of 5 Aβ tracers, and investigated its impact on inter‐tracer agreement, tracer variability and group separation.

Method

Using data from the ADOPIC study (AIBL, ADNI and OASIS3), age‐matched pairs of mild Alzheimer’s disease (AD) (MMSE = 20‐24;CL>25) and healthy controls (MMSE> = 28;CDR = 0;CL<15) were selected: 18F‐Florbetapir (FBP:147 pairs), 18F ‐Florbetaben (FBB:22 pairs), 18F ‐Flutemetamol (FLT:10 pairs), 18F ‐NAV (NAV:42 pairs), 11C‐PiB (PIB:63 pairs). The PET images were smoothed to a uniform 8mm resolution to reduce the influence of different scanner sharpness on the derived masks. The images were then spatially normalised using the SPM CL pipeline and transformed into SUVR (whole cerebellum). For each tracer, the mean AD‐HC difference image was computed and mirrored. The threshold for each difference image was optimised to maximise the overlap with the standard CL mask. The Universal mask was defined as the intersection of all 5 masks. It was then used to recalibrate each tracer into Centiloids. The Universal mask and associated transforms were evaluated on the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement and variance in the young controls (YC). They were also evaluated on the baseline ADOPIC dataset (N = 3565) with the effect‐size between HC/AD and HC/MCI.

Result

The overlap between each tracer specific mask was high (mean Dice = 0.82). The Universal mask was 26% smaller than the Standard one, but the overlap was high (Dice = 0.74). The Universal mask led to a small reduction in the variance of the YC in most tracers (‐3.4%) and a small increase in the R2 between each of the 11C‐PiB/18F‐tracer pairs (+0.24%). In ADOPIC, it led to a higher effect‐size between HC/AD (1.43 vs 1.42) and HC/MCI (0.71 vs 0.70).

Conclusion

The universal CL mask led to an increase in inter‐tracer agreement and group separation. Those increases were however relatively small indicating that the existing standard CL mask is suitable for the quantification of all Aβ tracers.
Neuroprotective Potential of Silymarin against Rotenone induced motor deficits in Wistar Rats
Authors: Agrawal Mohit , Chaudhary Hema , Singhal Manmohan
Published: December 2023

Background

Parkinson’s disease is a hypokinetic disorder characterized by selective loss of dopaminergic in substantia nigra pars compacta (SNPc) region of mid‐brain. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, neurons mitochondrial dysfunction and glutamate excitotoxicity etc. Silymarin was selected as an investigational drug, due to its numerous activities in current research, it possesses substantial antioxidant and neuroprotective functionalities and it has been reported to produce anti‐oxidant, anti‐inflammatory and neuromodulatory actions in previous studies.

Method

In the current study we have investigated the role of Silymarin against rotenone induced motor deficit and biochemical abnormalities in Wistar rats. Rats were treated with 1.5mg/kg rotenone subcutaneously for 35 days. Silymarin (50,100 and 200 mg/kg i.p.) was administered after 30 minutes of rotenone administration from day 7th to 35th day. Rotenone caused significant reduction in motor functions and body weight and produced elevation in striatal oxidative burden.

Result

The biochemical analysis revealed that there is reduction in the level of anti‐oxidants (GSH, Catalase, and SOD) in the animals following rotenone administration. Whereas Silymarin treated rats were stable and regained their body weight. In addition Silymarin significantly attenuated rotenone induced motor deficit and striatal oxidative stress

Conclusion

Outcomes of the current study suggest neuroprotective potential of Silymarin and its ability to correct movement disability and thus could prove to be useful candidate molecule in the management of motor disorders.
Perivascular spaces in the brain enlarge over time; A three‐year longitudinal study
Authors: Bernal Jose , Menze Inga , Yakupov Renat , Kaya Pinar , Aki Cagla , Pfister Malte , Geisendörfer Jonas , Peters Oliver , Priller Josef , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Wagner Michael , Ramirez Alfredo , Wolfsgruber Steffen , Kleineidam Luca , Jessen Frank , Schreiber Stefanie , Düzel Emrah , Ziegler Gabriel
Published: December 2023

Background

Perivascular spaces in the brain can become enlarged (ePVS); their temporal dynamics remain under increasing debate. We studied automatic ePVS measurements obtained from 870 subjects along the AD continuum over the course of three years.

Method

We measured centrum semiovale (CSO) and basal ganglia (BG) ePVS volumes computationally in the multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) (Table 1; 870 subjects; 51% female, mean age 70.85 (SD 6.16), up to 4 annual time points; 2487 sets of T1w and FLAIR). We segmented ePVS using a multiscale Hessian‐based filtering method leveraging T1w and FLAIR imaging and validated segmentation against clinical visual ratings. We studied local longitudinal changes via the sandwich estimator toolbox and linear mixed‐effect modelling and tested for effects of age, hypertension, clinical diagnosis, ApoE4 status, pTau181, and Aβ42/40 on ePVS trajectories.

Result

BG‐ePVS and CSO‐ePVS became more voluminous over time (Table 2 and Figure 1A‐C; BG: B = 0.04 [95%‐CI 0.03‐0.05], p<0.001; CSO: B = 0.02 [95%‐CI 0.00‐0.04], p<0.031).

The age of the patient at baseline determined the baseline volume of ePVS in the BG (B = 0.13 [95%‐CI 0.09‐0.17], p<0.001), but not in the CSO‐ePVS (p = 0.245).

WMH can form around ePVS (Figure 1D) and their progression was correlated with PVS enlargement (BG: B = 0.05 [95%‐CI 0.04‐0.07], p<0.001; CSO: B = 0.19 [95%‐CI 0.15‐0.22], p<0.001).

No other predictors contributed significantly to longitudinal ePVS changes.

Conclusion

Ageing is a major contributor to the volumetric expansion of ePVS over time. WMH and ePVS growth are associated, suggesting shared underlying pathological mechanisms.
Association of AD risk factors with plasma GFAP levels in a memory clinic population
Authors: Marizzoni Moira , Chevalier Claire , Paquis Arthur , Zetterberg Henrik , Blennow Kaj , Lathuiliere Aurelien , Ribaldi Federica , Wyss‐Dominguez Carine , Blouin Jean‐Louis , Abramowicz Marc , Pievani Michela , Garibotto Valentina , Frisoni Giovanni B
Published: December 2023

Background

Plasma glial fibrillary acidic protein (GFAP) is an emerging AD biomarker. We aimed to study how plasma GFAP correlated with age, clinical stage, sex, and the APOE4 status and whether amyloid pathology may mediate these associations.

Methods

Cohort of 330 individuals ranging from cognitively unimpaired to dementia due to AD from the Geneva Memory Center. Plasma GFAP was measured using Single molecule array (Simoa) technology. The effect of the variables of interest on plasma GFAP levels was assessed using linear regression models and partial eta squared (eta2
p). In a subset of 169 subject with amyloid PET, mediation analysis was performed to test the mediating effect of amyloid levels on the association between variable of interest and plasma GFAP.

Results

Age had the strongest effect on plasma GFAP levels (eta2
p = 0.39, p< 0.0001), followed by clinical stage (eta2
p = 0.10, p< 0.0001), sex (eta2
p = 0.06, p< 0.0001), and APOE4 (eta2
p = 0.02, p = 0.007). The effect of APOE4 status on plasma GFAP was fully mediated via the cortical amyloid uptake. The bootstrapped indirect effect was 0.09 (p< 0.0001) and the proportion of the effect of APOE4 status on GFAP that goes through the cortical amyloid uptake was 69%. No mediating effect by amyloid was found for age and sex.

Conclusion

These results show that in a memory clinic population, i) AD risk factors and severity affected plasma GFAP levels and, ii) the effect of APOE4 on GFAP is amyloid‐dependent whereas that of age and sex is amyloid‐independent. GFAP cut‐offs for the early diagnosis of AD should take age and sex into account.
Profiling amyloid‐β peptides as diagnostic biomarkers for cerebral amyloid angiopathy
Authors: van den Berg Emma , de Kort Anna M. , Kersten Iris , Brinkmalm Gunnar , Johansson Kjell , Marques Tainá M. , Jäkel Lieke , Gobom Johan , Stoops Erik , Portelius Erik , Gkanatsiou Eleni , Abdo Wilson F. , Rasing Ingeborg , Voigt Sabine , Koemans Emma A. , Kaushik Kanishk , Warren Andrew D. , Greenberg Steven M. , Terwindt Gisela M. , Wermer Marieke J.H. , Klijn Catharina J.M. , Schreuder Floris H.B.M. , Zetterberg Henrik , Blennow Kaj , Kuiperij H. Bea , Verbeek Marcel M.
Published: December 2023

Background

Amyloid‐β (Aβ) deposits are the main pathological hallmark of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD). Vascular deposits in CAA mainly consist of Aβ40, whereas Aβ42 is the predominant peptide in parenchymal plaques in AD. The diagnostic accuracy of other Aβ species in CAA remains understudied. We aimed to investigate the biomarker potential of various Aβ peptides for the differentiation of sporadic (sCAA) and hereditary Dutch‐type CAA (D‐CAA) from AD and controls.

Method

Cerebrospinal fluid (CSF) Aβ38, Aβ40, Aβ42, and Aβ43 levels were quantified by immunoassays in discovery (26 sCAA patients, 40 controls) and validation cohorts (40 sCAA patients, 40 AD patients, 37 controls), and D‐CAA patients (10 presymptomatic, 26 controls; 12 symptomatic, 28 controls). In a subset of samples (25 sCAA, 50 AD, 23 controls), we confirmed results using an extended panel of Aβ peptides (including Aβ34, Aβ37, and Aβ39, but not Aβ43) quantified by liquid chromatography mass spectrometry (LC‐MS). Area‐under‐the‐curve (AUC) was calculated using receiver operating characteristic curve to assess diagnostic accuracies.

Result

We found decreased levels of all Aβ peptides (quantified by immunoassays) in sCAA and D‐CAA compared with controls (Figures 1 and 2). All Aβ peptides, except Aβ43, were also decreased in sCAA compared with AD (Figure 1). LC‐MS verified the lower CSF levels of six Aβ peptides in sCAA compared with controls (Figure 3). All peptides, except Aβ42, were also decreased in sCAA compared with AD. Single peptide levels (using either method) differentiated sCAA from AD (immunoassays AUC 0.68‐0.88; LC‐MS AUC 0.51‐0.75) and controls (immunoassays AUC 0.61‐0.95; LC‐MS AUC 0.69‐0.85). Combinations of all Aβ peptides differentiated sCAA from AD patients (immunoassays AUC 0.93; LC‐MS AUC 0.84) and controls (immunoassays AUC 0.89‐0.98; LC‐MS AUC 0.91) with high accuracy.

Conclusion

CAA and AD each show a distinct disease‐specific profile of CSF Aβ peptides. All peptides shorter than Aβ42 were consistently decreased in sCAA, but not in AD, compared with controls. A panel of CSF Aβ peptides may diagnose CAA with high accuracy, and could have the potential to exclude patients with high load of CAA from anti‐Aβ therapies to avoid adverse events associated with CAA.
Can physical activity moderate the relation between systemic inflammation and cognitive performance in an elderly community dwelling population?
Authors: Fink Anne , Reinke Constantin , Aretz Benjamin , Doblhammer Gabriele
Published: December 2023

Background

Elevated levels of systemic inflammation have been shown to be associated with poorer outcomes in cognitive performance. However, regular vigorous physical activity is associated with improved cognitive performance. This study analyzes if regular physical activity may moderate the effect of systemic inflammation on cognition.

Method

We used the first two waves of the Dutch Lifelines cohort study (2006‐2015) of 19,985 individuals, who were 50 years or older at baseline. Cognitive performance was measured as psychomotor speed in wave 2 using the Cogstate Brief Battery, with higher scores corresponding to lower cognitive performance. As a biomarker of systemic inflammation, we used leukocyte count within the normal range of 4 to 10×109 cells per liter in EDTA blood samples at baseline. First, we performed linear regression models to examine the effect of inflammation and vigorous physical activity on cognition, adjusting for cognitive task accuracy, age, sex, education, and various comorbidities associated with cognitive impairment. Second, an interaction effect was used to analyze the potential moderation of physical activity.

Result

After adjusting for cognitive task accuracy, age, sex, and education, higher levels in leukocyte count were significantly associated with worse cognitive outcome (b = 0.020,p = 0.036). This effect attenuated when controlling for physical activity and comorbidities (b = 0.011,p = 0.257). Vigorous physical activity was highly significantly associated with better cognitive performance (b = ‐0.126,p<0.001). Analysis of the interaction between leukocyte count and physical activity showed a borderline significant slope for physically active subjects (b = 0.029,p = 0.093) and no effect for physically inactive subjects (b = 0.003,p = 0.782). When comparing predicted psychomotor speed scores for physically active and inactive individuals, we found significantly better cognitive outcomes for active individuals with leukocyte counts between 4 and 7×109 cells per liter, while individuals with leukocyte counts between 7 and 10×109 cells per liter did not differ significantly by physical activity.

Conclusion

In individuals with leukocyte levels up to 7×109 cells per liter, indicating low levels of inflammation, we found a protective effect of physical activity on cognition. Because physical activity had no effect in individuals with higher leukocyte levels (albeit within the normal range), physical activity appears to have preventive rather than intervening effects on cognitive performance.
Metabolic cross‐talk between astrocytes and neurons: implications for Alzheimer’s disease
Authors: Magi Simona , Preziuso Alessandra , Piccirillo Silvia , Cerqueni Giorgia , Serfilippi Tiziano , Lariccia Vincenzo , Amoroso Salvatore
Published: December 2023

Background

Converging evidence indicates that declining brain energetics contributes to the initiation and progression of neurodegenerative disorders, including Alzheimer’s disease (AD). Upstream events often characterizing AD include hypometabolism of glucose and oxygen in the brain, which may cause mitochondrial dysfunction, energetic failure, and oxidative stress (Moreira et al., 2010). Astrocytes, which have a main role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. By modulating the release of gliotransmitters (e.g. glutamate), they provide a fine control of neuronal metabolism and cell‐to‐cell communication, both of them involved in AD (Monterey et al., 2021). Impaired astrocytes metabolism may incite an inflammatory response that, in turn, negatively impacts neuronal viability.

Method

Primary rat cortical astrocytes were isolated from the cortex of Wistar rat pups. A metabolic stress was induced by using glyceraldehyde (GA) (Magi et al., 2021). We evaluated cell viability, the release of tumor necrosis factor alpha (TNFα) and the involvement of the nuclear factor‐kappa B (NF‐kB) pathway. In order to check the glutamate turnover, we analyzed the expression of GLAST and GLT1 and we evaluated the ATP content after glutamate exposure under physiological conditions. We also explored whether damaged astrocytes could elicit neuronal death in a co‐culture setting.

Result

Exposure to increasing concentrations of GA caused a concentration‐dependent cell injury in rat cortical astrocytes. GA (1mM) started to induce a significant cell damage after 24 h. After 48 h, GA exposure activated the NF‐kB pathway and the release of TNFα. GA treatment significantly increased GLAST and GLT1 levels after 48h. When injured astrocytes were co‐cultured with cortical neurons, neurons viability significantly decreased. Under physiological condition, glutamate significantly improved intracellular ATP levels after 4 and 8 hours of treatment, paving the way to the evaluation of its action in metabolic‐impaired setting, as induced by GA treatment.

Conclusion

Our results suggest that metabolically impaired astrocytes may damage neighboring neurons, suggesting astrocytes involvement in the pathophysiological development and progression of AD. Therefore, astrocytes can be considered a key therapeutic and neuroprotective target for future studies.
Fully automated ApoE4 assay in plasma and the estimation of the APOE polymorphism
Authors: Yuri Tatsushi , Sato Hideo , Nakazawa Takuya , Kamada Jo , Kaneko Atsushi , Aoyagi Katsumi , Nojima Hisashi
Published: December 2023

Background

Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Moreover, it has been reported that the APOE4 haplotype has a dose‐dependent association with an increased risk of amyloid‐related imaging abnormalities (ARIA) in individuals receiving disease‐modifying therapy (DMT) for AD. Therefore, the importance of APOE genotyping or phenotyping and its expanding clinical role in dementia field has been highlighted. Here, we developed fully automated chemiluminescence enzyme‐immunoassay (CLEIA) kits for ApoE4 and pan‐ApoE, and evaluated its diagnostic concordance with the APOE genotyping.

Method

ApoE4 and pan‐ApoE assays for fully automated platform, LUMIPULSE, are a two‐step sandwich CLEIA with a specific treatment process to extract the antigen from the lipid surface in plasma samples during the 1st immunoreaction. The turnaround time for each reaction is within 30 minutes. Healthy volunteers’ samples were used for the measurement of ApoE4 and pan‐ApoE with CLEIA or the PCR‐Restriction fragment length polymorphism (PCR‐RFLP) analysis for the APOE polymorphism. The study design was approved by the ethics committee at H.U. Group Holdings, Inc in the 2022 fiscal year (22‐012‐01).

Result

The ApoE4 kit specifically detected the ApoE4 concentration in plasma samples, and could distinguish ApoE polymorphism. Moreover, the polymorphism could be classified clearly by the ratio of ApoE4 and Pan‐ApoE amount in plasma.

Conclusion

The new CLEIA ApoE4 and pan‐ApoE assay robustly distinguishes among APOE4 carrier status in plasma. Assessing ApoE isoform by CLEIA may help not only clarify ApoE metabolism, but also ARIA risk.
Altered patterns of brain activity during a fMRI memory task in cognitively normal adults carrying the APOE ε4 allele
Authors: Corbo Daniele , Quattrini Giulia , Saglia Silvia , Agnelli Giancarlo , Mega Anna , Marizzoni Moira , D'Aprile Ilari , Cattaneo Annamaria , Bortoletto Marta , Gasparotti Roberto , Pievani Michela
Published: December 2023

Background

The ε4 allele of the Apolipoprotein E gene (APOE) is a well‐established risk factor for Alzheimer’s disease (AD), ε4 carriers showing earlier onset and more severe memory impairment than non‐carriers. Neuroimaging evidence suggests that APOEε4 may modulate neural activity in AD since early stages. The purpose of this study was to determine whether APOEε4 influences brain activity in the memory circuit in older cognitively unimpaired individuals.

Method

Thirty cognitively unimpaired participants (n = 10 APOEε4 heterozygous carriers, age = 65± 5 years, 50% females, MMSE score = 29±1; n = 20 APOEε4 non‐carriers, age = 68±5 years, 35% females, MMSE score = 30±1) were recruited and underwent multidomain (i.e., memory, visuospatial abilities, language, attention) neuropsychological exams and functional MRI scan during an associative memory task, which consisted of two phases: (i) encoding of face‐name associations; (ii) recognition of the name associated to each face. Image preprocessing and voxel‐wise comparisons were conducted using the Statistical Parametric Mapping (SPM, v12). Clusters were considered significant at an uncorrected threshold of p<0.001.

Result

Participants were comparable for demographic and cognitive features (p>0.10) and performed similarly on the in‐scanner face‐name association memory task (p>0.10). Compared to ε4 non‐carriers, carriers showed (i) greater activation during the encoding task in the left temporo‐occipital cortex/fusiform gyrus, (ii) greater activation during the recognition task in the middle temporal gyrus/temporo‐occipital cortex bilaterally and in the right cerebellum, and (iii) lower activation during the recognition task in the medial supplementary motor area.

Conclusion

These preliminary results confirm that the APOE ε4 allele is associated with a different pattern of brain functional activity during an associative memory task in cognitively unimpaired older. Given the similar cognitive performance between groups, higher activation in temporo‐occipital regions might reflect a compensatory process in regions vulnerable to AD pathology.
Digital biomarker co‐design with people with preclinical or prodromal dementia
Authors: Köhler Stefanie , Teipel Stefan
Published: December 2023

Background

Language markers can serve screening and early detection in Alzheimer’s disease (AD). Using artificial intelligence (AI) approaches enables automated assessment and analysis of speech biomarkes using chatbot technology. Reliable digital speech biomarkers require an easy‐to‐use chatbot which is adopted to the users’ needs. Currently, chatbots often are unsuitable for people with cognitive impairment and rather frustrating for their users. Here, we implemented a user centred design approach to iteratively evaluate usability of a chatbot system for automated speech assessments for people with prodromal or preclinical dementia.

Method

Within the study PROSPECT‐AD, participants (n = 53 by January 2023, 300 planned) are automatically called for six times every three months by our chatbot “Mili”. Each call takes about 15 minutes and consists of three cognitive tasks (Wordlist, Semantic Verbal Fluency, Story Telling). We applied a six stage usability check to improve Mili iteratively (see Figure 1). For deeper insights, we conduct semi‐structured interviews (n = 20). During the interviews, we focus on affinity for technology, usability, and participants’ attitude towards chatbots and artificial intelligence in medicine.

Results

To date, Mili has completed 54 assessments (see Figure 2). Drop‐outs (11.3%) occcur around the first assessment. Reasons were e.g., lack of accessibility of participants, excessive demands through cognitive tasks or through Mili. Participants reported problems due to Mili’s high speaking pace and hangs of Mili. Additionally, Mili struggled in automatically retrieving appointments and missed calling. All problems were quickly resolved. The speaking pace was reduced and the time‐out time extented by 2 seconds. Results of the system usability scale revealed a high user‐friendliness of the calls (see Table 1). Participants (n = 6) evaluated the calls as quick to learn and easy to use. Two participants wished for more technical support for the calls. Two participants felt uncomfortable in using Mili.

Conclusion

Our results revealed a high usability and feasibility of the automated phone calls by Mili. Due to close colaboration, problems with Mili were solved qickly and further drop‐outs prevented. This underlines the benefit of close cooperation between participants, scientists, and IT specialists. Interviews are needed for further improvement of Mili and to understand uncertainty with Mili.
Remote Caring Guidelines: An innovative protocol for dementia caregivers
Authors: Manola Panayiota , Makri Marina , Tsolaki Magda
Published: December 2023

Various technological innovations have emerged which allow for remote caring of people with dementia by their informal caregivers. Lack of access and social isolation have negatively impacted people with dementia and caregivers experience intensification of stress and burden. Currently, there is no widely accepted dementia protocol on remote care for caregivers. A partnership of five European institutions which specialise in mental health and dementia is preparing a protocol based on non‐formal education (NFE) which aims at training caregivers to provide better support and enhanced care even when physical presence is not possible. The NFE is designed to educate the caregivers on five major topics; recognising the symptoms of dementia, dementia prevention, potential activities for early and advanced dementia aimed at improving social interaction and the mental/physical wellbeing of people with dementia and on how to create support groups. Three piloting activities involving a minimum of 75 participants, caregivers of people with dementia, and ten case studies of successful support groups will be conducted in order to assess and refine the NFE. It is expected that; the social interaction between people suffering from dementia and their caregivers will be improved by using innovative devices and will allow for enhanced caring and assistance conditions for caregivers and the stigma which surrounds people will be diminished through the creation of support groups and the extensive use of new technologies. These findings will have a strong impact on the provision of everyday dementia care from informal caregivers and may lead to a more future‐proof dementia care. Moreover, upon the successful implementation of the protocol in dementia caregivers, the protocol could be adapted to serve as a protocol for mental and physical health caregiving.
Synergistic interaction between Cu overload and Aβ peptide promotes pro‐inflammatory response of microglia
Authors: Zubillaga Marlene , Calaf Xenia Abadin , Colell Anna , Bellini María José , Arnal Nathalie
Published: December 2023

Background

Changes in copper (Cu) homeostasis have been consistently linked to Alzheimer’s disease (AD). Cu can bind to amyloid beta (Ab) and enhance neurotoxicity through the generation of reactive oxygen species.Furthermore, Cu possesses both pro‐ and anti‐inflammatory properties mediated by its proximity to amyloid plaques. A key pro‐inflammatory pathway reported induced in AD is the NLRP3 inflammasome that leads to the activation of inflammatory caspases, mainly caspase‐1, and the processing of interleukin‐1b (IL‐1b) into its active form. This work aimed to assess the synergistic interaction between Cu overload and the Aβ‐induced inflammatory response on microglia and evaluate the underlying mechanisms.

Method

Using immortalized mouse microglia (SIM‐A9) exposed to 1 uM Ab and subtoxic doses of Cu (50, 100 and 200 uM) for 24 h, we assessed ROS by fluorometry using Dihydroethidium (DHE), expression levels of inflammasome‐related proteins by western blot and RT‐PCR selfie, and phagocytosis of microglia by confocal microscopy using fluorescent microbeads (1µm). To assess inflammasome assembly, cells were transfected with the pLEX‐MSC‐ASC‐GFP vector and ASC speckle formation was analyzed by confocal microscopy.

Results

Cu treatment induced IL‐1b and Nlrp3 expression, which was further enhanced when combined with Aβ. While untreated cells showed homogeneously distributed ASCs in the cytosol, we found “speckles” of ASCs in those treated with Cu and Cu plus Aβ, in the vicinity of the nucleus, indicating involvement of the inflammasome. Cu treatment increased total cholesterol (Cho) and mitochondrial Cho levels and was accompanied by a significant decrease in mitochondrial GSH levels. Accordingly, ROS levels increased significantly with the combination of Cu and Aβ. Oxidative stress was prevented by glutathione ester (GSHee) treatment and the use of mitochondrial antioxidant agents (MitoTEMPO and MitoQ). In parallel, we analyzed microglia phagocytosis by confocal microscopy. Microbead uptake was significantly impaired after Cu overload but was partially restored by pretreatment with GSHee, which recovered mitochondrial GSH and reduced oxidative stress

Conclusion

High Cu levels regulate the microglial response to Aβ by boosting mitochondrial oxidative stress, resulting in inflammasome activation with the release of pro‐inflammatory cytokines such as IL‐1b) and decreased phagocytic capacity, which may contribute to the accumulation and formation of Aβ deposits.
The molar ratio between PAI‐1 and BDNF is increased in Alzheimer’s disease patients with full dementia and negatively correlates with MMSE score
Authors: Angelucci Francesco , Veverova Katerina , Katonova Alzbeta , Jurasova Vanesa , Vyhnalek Martin , Andel Ross , Hort Jakub , Sheardova Katerina
Published: December 2023

Background

In a previous study, we demonstrated that the enzyme plasminogen activator inhibitor‐1 (PAI‐1), which inhibits plasmin synthesis in the central nervous system (CNS), is increased in the serum of patients with Alzheimer’s disease (AD). In addition to reducing the accumulation of Ab, plasmin in the CNS regulates the synthesis of the trophic factor brain‐derived neurotrophic factor (BDNF) which appears to be altered in the brain of patients with AD. We investigated whether BDNF serum levels in AD and amnestic mild cognitive impairment (aMCI) patients are altered compared to cognitively healthy controls. Moreover, we examined the PAI‐1/BDNF ratio in these patient groups and correlated with cognitive scores as measured by Mini‐Mental State Examination (MMSE).

Method

40 AD, 40 aMCI and 10 healthy controls were recruited. Venous blood was collected and BDNF serum concentration were quantified by sandwich ELISAs. Comparisons among the experimental groups (AD dementia, aMCI patients, and cognitively healthy controls) on BDNF serum levels were performed using univariate analyses of variance (ANOVA). Pearson correlation coefficients were calculated to explore relationships between biochemical and clinical data. The level of statistical significance was set at p<0.05.

Result

The results showed that BDNF serum levels are decreased in AD as compared to aMCI patients (p < .05). In addition, there was a positive correlation between PAI‐1 and BDNF serum levels (r = .190, p < .05). Furthermore, PAI‐1/BDNF ratio was significantly increased in AD patients as compared to aMCI (p < .001) and controls (p < .001). Lastly, PAI‐1/BDNF ratio negatively correlated with MMSE score (r = ‐.508, p < .001).

Conclusion

These data suggest that in AD a reduction of plasmin caused by PAI‐1 may negatively affect the production of BDNF and promote disease progression. Our results also demonstrate that the PAI‐1/BDNF ratio is increased in AD patients compared with aMCI and controls. They also suggest that this ratio could be used as a marker of AD in a state of overt cognitive impairment, as supported by the strong negative correlation between PAI‐1/BDNF ratio and MMSE.
Single‐nuclei spatiotemporal transcriptomics reveal an APOE4‐associated specific oligodendrocyte signature
Authors: Qin Wei , Xu Lingzhi , Li Bingqiu , Wei Yiping , Jia Jianping
Published: December 2023

Background

The APOE4 gene is a strong risk factor for Alzheimer’s disease (AD). However, an understanding of the APOE4 genotype‐associated cellular and molecular processes in the brains remains unclear.

Method

To clarify the APOE4‐related pathogenic pathways in AD, we performed single‐nuclei RNA‐sequencing and spatial enhanced resolution omics sequencing on the brains of aging human APOE3‐knockin mice and APOE4 knock‐in mice. We also investigated the relationship between different cell types and AD‐related pathology in APOE knock‐in mice using immunostaining. We conducted amplification‐based single molecule in situ hybridization to validate the characteristics of the APOE4‐specific subcluster. To substantiate the APOE knock‐in mice analyses, we also re‐analyzed a published single‐nuclei RNA‐seq dataset containing postmortem prefrontal cortex tissue samples from patients with AD and controls.

Result

We identified seven distinct cell types in brains from APOE‐knockin mice, and observed oligodendrocytes with most unique differentially expressed genes (Figure 1). And we found significantly increased Alzheimer’s disease‐related pathologies (including intracellular beta‐amyloid and phosphorylated tau) in oligodendrocytes in the hippocampus of APOE4‐KI mice compared to APOE3‐KI mice. Furthermore, an APOE4‐specific oligodendrocyte subcluster was identified. This subcluster had a dysregulated autophagy flux signature, which may affect neuronal oxidative stress and synaptic function (Figure 2). Both excitatory and inhibitory neurons presented dysregulation of genes related to synapse plasticity. Additionally, the oligodendrocyte subcluster significantly correlated with neuronal loss, beta‐amyloid deposition and tau phosphorylation in the brain tissues examined. We also found a similar oligodendrocyte subcluster in post‐mortem brains from AD patients.

Conclusion

Altogether, this study suggests the specific oligodendrocyte subcluster is related to the susceptibility of APOE4 to AD, and targeting autophagy changes in oligodendrocyte may be a novel therapeutic intervention approach in APOE4 carriers.
Psychometric evaluation of the German version of the Mild Behavioural Impairment Checklist (MBI‐C)
Authors: Grothe Jessica , Luppa Melanie , Pabst Alexander , Röhr Susanne , Riedel‐Heller Steffi G.
Published: December 2023

Background

Neuropsychiatric symptoms (NPS) are common in pre‐dementia state and are associated with an increased risk of dementia. The concept of Mild Behavioral Impairment (MBI) addresses this circumstance. However, to date, instruments that measure MBI in a standardized method are lacking. Therefore, the Mild Behavioral Impairment Checklist (MBI‐C) was developed on the basis of the MBI diagnostic criteria. Our aim was to psychometrically evaluate the German version of the MBI‐C.

Method

We interviewed 86 dyads of individuals with either subjective cognitive impairment (SCD), mild cognitive impairment (MCI), or cognitively healthy individuals, paired each of them with a relative and test the reliability, validity and acceptance of the MBI‐C.

Result

The internal consistency of both MBI‐C versions were at a questionable to acceptable level (α = 0.64‐0.86) and the interrater reliability was good to excellent (patients: ICC = 0.94, CI [0.91–0.96]; informants: ICC = 0.86, CI [0.79–0.90]). Informant‐rated MBI‐C correlated strongly with the Neuropsychiatric Inventory (NPI) total score (r = 0.51; p ≤.001). All participants found the MBI‐C acceptable.

Conclusion

The German MBI‐C is an instrument to assess MBI in healthy individuals, individuals with SCD, and those with MCI. It has acceptable psychometric properties. Further studies should address a larger sample of individuals in a pre‐dementia state to confirm the findings of our study. Moreover, the factor structure should be investigated.
The progression from Mild Cognitive Impairment to dementia in a community older population from São Paulo, Brazil
Authors: Lopes Marcos A , Nassar Silvia M , Barcelos‐Ferreira Ricardo , Folquitto Jefferson C , Litvoc Julio
Published: December 2023

Background

Mild Cognitive Impairment (MCI) is a cognitive condition greatly studied around the world, considering its potential to precede dementia, but it is little investigated in Brazilian community population. This study aimed to estimate the progression from MCI to dementia in a community‐dwelling older population from São Paulo city, Brazil.

Method

A two‐phase prospective cohort study evaluated a representative cluster sample of 1,370 individuals aged 60 years old and over from three different socioeconomic levels. The diagnosis of dementia was made according to DSM IV criteria. MCI was assessed at baseline, using Mini Mental State Examination (MMSE), Fuld Object Memory Evaluation (FOME) and Bayer‐Activities of Daily Living scale (B‐ADL), and classified into three subtypes: amnestic MCI (FOME < 35 and B‐ADL scale ≤ 3.19); non‐amnestic MCI‐multiple domains (MMSE < cut‐offs according to four levels of education and FOME ≥ 35 and B‐ADL scale ≤ 3.19); non‐amnestic MCI‐specific domain (executive function)(FOME ≥ 35 and verbal fluency for animals <11 and B‐ADL scale ≤ 3.19).

Result

Among 489 subjects that completed the evaluation, 42 were diagnosed with dementia. Considering the population completely evaluated, at baseline 76, 87 and 35 subjects were classified as amnestic‐MCI, non‐amnestic MCI‐multiple domains and non‐amnestic MCI‐specific domain (executive function), respectively. The rates of conversion to dementia from non‐amnestic‐multiple domains and non‐amnestic MCI‐specific domain (executive function), compared to non‐MCI, were 6.9%% (vs 5.1%) and 2.9% (vs 5.7%), respectively (no significative difference between groups). The rate of conversion to dementia from amnestic‐MCI was 23.7% (vs 5.7%)(p <0.001; OR: 5.1, 95%CI: 2.6‐10.1); specifically for amnestic‐MCI with depressive syndrome, it was 66.7% (vs 5.1%)(p <0.001; OR: 37.0, 95%CI: 6.3‐214.2).

Conclusion

The findings reinforced the role of amnestic‐MCI in the progression to dementia and Alzheimer’s Disease and exhibited an additional effect of depression on this process.
The eye as a window to the brain: hyperspectral retinal imaging as a biomarker for Alzheimer’s disease
Authors: Dahdouh‐Guebas Yasmin , Kulenovic Hana , Christinaki Eirini , Van Eijgen Jan , Lemmens Sophie , Ceccarini Jenny , Rousseau Frederic , Schymkowitz Joost , Vandenbulcke Mathieu , Vandenberghe Wim , Vandenberghe Rik , De Strooper Bart , Jayapala Murali , Blaschko Matthew , Moons Lieve , Stalmans Ingeborg , De Groef Lies
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder that is the leading cause of dementia, affecting more than 50 million people worldwide. In the search for new biomarkers, increasing attention has been dedicated to the retina. As part of the central nervous system, the retina manifests many of the characteristic pathological processes that occur in the AD brain. Moreover, it can be imaged at low‐cost and non‐invasively at high resolution, and therefore it may be used for AD diagnosis and monitoring. In this context, emerging evidence suggests the potential of in vivo hyperspectral retinal imaging (HSRI) as a potential biomarker for brain amyloid‐β accumulation. Therefore, this project aims at studying HSRI as a novel biomarker that could lead to inexpensive population screening, thereby removing one of the principal bottlenecks to therapeutic advances in AD.

Method

In this study, we seek to define the molecular basis, sensitivity, and specificity of the HSRI signal of AD, and whether it can distinguish AD from other dementias in a translational pre‐clinical and clinical research project. We perform HSRI of synthetic protein aggregates, and different cell and mouse models of neurodegenerative proteinopathies, and correlate these data with molecular biology assays, to study the molecular basis and pathological correlates of HSRI signals. In a parallel clinical study, we assess the correlation between amyloid status and HSRI and evaluate whether the diagnostic power of HSRI can be increased via a multimodal imaging approach.

Result

Our preliminary results demonstrate that HSRI can be used to quantify retinal amyloid in AD animal models and post‐mortem tissues as well as discriminate between AD patients and controls, with improvement in classification accuracy by including optical coherence tomography (OCT) data.

Conclusion

This research study covers out‐of‐the‐box thinking to transform the detection of AD. It collects evidence of the specificity and molecular basis of HSRI which is essential for its rational clinical use as an AD imaging biomarker.
Genetic Drivers of Atypical Alzheimer’s Disease Neuropathologic Change
Authors: Lee Eddie B
Published: December 2023

Background

Quantitative differences in neurofibrillary tangle density are not well captured by more global measures such as Braak staging. Indeed, amongst cases with high Alzheimer’s disease neuropathologic change (ADNC), quantitative differences in the distribution of neurofibrillary tangle density is associated with atypical, non‐amnestic clinical presentations. We sought here to study the effect of TREM2 and APOE risk genotypes on neuropathologically and clinically defined atypical Alzheimer’s disease.

Methods

TREM2 variant versus wild‐type autopsy cases with an intermediate to high level of ADNC were identified from the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Archived clinical records were used to classify cases into typical versus atypical AD. Neuropathologic classification of cases into typical versus atypical AD was based on quantification of neurofibrillary tangle density using PHF1 stained sections from neocortical and hippocampal regions. Morphology from Iba1 stained sections was used to quantify microglial reactivity.

Results

31 AD cases with TREM2 risk genotypes were compared to wild‐type TREM2 AD cases (n = 119). TREM2 variants were associated with a significantly higher proportion of atypical AD clinical phenotypes including behavioral/dysexecutive variants, primary progressive aphasias, posterior cortical atrophy, and others (19.33% versus 48.39%, Fisher’s exact test p = 0.002). These clinical phenotypes were associated with a significantly higher proportion of TREM2 variant cases with neuropathologically defined atypical AD, namely hippocampal sparing AD (8.7% versus 28.57%, Fisher’s exact test p = 0.046). Moreover, the proportion of microglia with a dystrophic morphology correlated with neurofibrillary tangle density and not amyloid burden. Finally, to get a sense of the magnitude of this TREM2 association relative to other genetic risk factors, we observed a non‐significant trend towards the absence of the APOE E4 risk genotype being associated with hippocampal sparing AD.

Conclusions

This clinicopathologic correlation study suggests that TREM2 risk variants are associated with clinically and neuropathologically defined atypical AD. Given that both TREM2 and APOE affect microglial reactivity to amyloid, the observed tendency towards TREM2 variant cases exhibiting hippocampal sparing AD suggests that altered microglial reactivity to amyloid may change downstream tauopathy patterns leading to atypical AD clinical phenotypes.