bluuebunny/crossref_metadata_2025 huggingface dataset:
Recruitment of caregivers of persons living with dementia for an Online Support Group Programme– Learnings from India
Authors: Vasanthra Cicil R , Thirumoorthy A , Antony Sojan , Muliyala Krishna Prasad , Rao Girish N , N Anu K , Sivakumar Palanimuthu Thangaraju
Published: December 2023

Background

Caregivers of persons living with dementia (CGPwD) tend to have limited access to dementia care‐oriented support group and relevant resources. The disparity in the ratio of mental health professionals available and the number of people with dementia plays a pivotal role in care and services. Support group interventions may not be available or accessible to the vast majority, more so in the Indian context. Hence, the need to test feasibility of providingsupport via using video‐conferencing software were explored.

Method

Family caregivers of those persons living with dementia who had accessed an out‐patient facility at a Geriatric Clinic as part of a tertiary care center between January 2020 – January 2023 was screened for recruitment into a single group quasi‐experimental study (n = 341). The responses of the family caregivers were noted down along with the experience of the mental health professionals involved in the process. Content analysis (Krippendorff, 2004, Neuendorf, 2002) was carried out using Atlas.ti.9 web version.

Result

The mean age of the CGPwD was 42.5 ± 8.5 years and the mean years spent in care‐giving was 4.02 ± 1.5 years; 42.8% of the persons living with dementia had a definitive diagnosis of Alzheimer’s Disease and majority were in the moderate stage of illness. One‐fourth of the caregivers showed interest to sign up for the support group with the first invitation. Of them, Spousal caregivers were noted to show more interest; followed by daughters‐in‐law. Apart from technological challenges, a good number of caregivers measured d that their loved one with dementia has “improved” due to decline in challenging behaviours.

Conclusion

Use of technology in psychosocial interventions is a relatively new concept in LAMIC countries such as India. Therefore, familiarization and orientation of such services may pave way to increase in demand for video‐conferencing based support groups at a larger level in the near future.
Recruitment data of the HAPPCAP‐AD (Human‐APPlication Combined Approach for Prevention of Alzheimer’s Disease): a feasibility study
Authors: Ganmore Ithamar , Ravona‐Springer Ramit , Livny Abigail , Niv Tal , Matatov Adar , Yore Iscka , Bem‐Moshe Ariela , Heymann Anthony , Beeri Michal S
Published: December 2023

Background

Physical inactivity, obesity, type 2 diabetes [T2D], hypertension, smoking, and depression, are six major modifiable risk factors for Alzheimer’s disease (AD). While several multi‐domain intervention studies have been completed, mostly in older adults, targeting one or more modifiable risk factor, results have been inconsistent. We designed novel, “real‐life”, feasibility study of a personalized 18‐months intervention for prevention of cognitive decline in middle‐aged individuals at very high AD risk due the presence of at least two modifiable risk factors plus parental family history of AD. Our aims are to explore: 1) The feasibility of our novel approach; 2) Whether our intervention improves AD risk factors and whether greater adherence is associated with larger improvement; and 3) Whether our intervention improves cognition.

Method

Study’s participants are 40‐65 years old cognitively normal offspring of individuals with AD. Participants must have at least two of the six major modifiable AD risk factors. Recruitment goal was 100 participants. Participants were randomized at a 2:1 ratio to the intervention:control arms of the study. The 18‐months intervention combines a smartphone application (app) with study team guidance through phone‐calls, which include advice for risk factors improvement, interactive follow‐up using an app, and feedback on risk factors management for its modification.

Result

Since study was launch in 2019, 500 individuals have completed an online eligibility questionnaire. We have achieved the recruitment goal, and 100 participants have been enrolled, with 67 in the intervention group and 33 in the control group. Groups are well‐matched for baseline demographics and AD risk factors (intervention vs control: age‐ 57.3[SE = 0.64]vs.57.0[SE = 0.99]; sex ‐ [% males]30%vs.33%; years of education‐ 17.7[SE = 0.77] vs.17.0[SE = 0.64]; BMI‐ 30.5[SE = 0.63]vs.29.6[SE = 0.59]; % physical inactivity ‐84vs.82; % T2D‐ 15vs.12; % hypertension‐ 27vs.30; % depression‐ 16vs.15; and MMSE‐ 29[SE = 0.17]vs. 29.2[SE = 0.16]; all p>0.05), except for percentage of smokers which was significantly higher in the intervention arm (12vs.3). Additional analyses will be ready by AAIC 2023.

Conclusion

Results of this study will provide feasibility data on the adherence to the human‐app approach, characteristics of those who adhere, on whether the approach improves risk factors, and will provide initial data on intervention efficacy for cognition.
Detection of PART in vivo using tau‐PET: preliminary findings using [18F]RO948
Authors: Leuzy Antoine , Binette Alexa Pichet , Janelidze Shorena , Strandberg Olof , Ossenkoppele Rik , Smith Ruben , Hansson Oskar
Published: December 2023

Background

Primary age‐related tauopathy (PART) is a neuropathological entity describing tau pathology in the entorhinal cortex and hippocampus in the absence of amyloid‐β (Aβ) plaques. Though cross‐sectional work using [18F]flortaucipir tau‐PET has shown an association between medial temporal lobe signal and worse cognitive performance, longitudinal studies are needed to examine whether medial temporal lobe tau is associated with cognitive decline and cortical tau accumulation in cognitively unimpaired (CU) individuals. We here aimed to investigate whether CU individuals who are Aβ‐negative and tau‐PET positive in the medial temporal lobe show cognitive decline and increases in CSF phosphorylated tau (P‐tau) or tau PET over time.

Methods

Using BioFINDER‐2, PART was defined as i) CU individuals (not fulfilling criteria for mild cognitive impairment of dementia), ii) age ≥ 60 years, iii) Aβ‐negative (Centiloids < 20 and negative CSF Aβ42/40), and iv) an [18F]RO948 tau‐PET standardized uptake value ratio (SUVR) >1.26 (cut‐off based on Gaussian mixture modelling in BioFINDER‐2, n = 1754) in a volume‐weighted ROI encompassing the entorhinal cortex and hippocampus. [18F]RO948 data was collected 70 to 90 min post‐injection with longitudinal follow‐up collected after ∼2.5 years (average 2.73 ± 1.14 years). Longitudinal P‐tau217 was measured using immunoprecipitation‐mass spectrometry (average 2.67 ± 1.12 years). Longitudinal cognitive measures (average 2.75 ± 0.94 years) included the MMSE and modified PACC. For both longitudinal [18F]RO948, CSF P‐tau217 and cognition, change was assessed using slopes derived from linear mixed models.

Results

38 individuals fulfilled inclusion criteria (Table 1). These individuals showed significant increases in [18F]RO948 SUVR in the entorhinal cortex/hippocampus (p<0.05, t‐test vs 0)—but not in the temporal cortex—and in CSF P‐tau217 (p<0.01, t‐test vs 0) over time (Figure 1A). This group also showed cognitive decline over time using the PACC (p<0.01, t‐test vs 0) but not the MMSE (Figure 1B). Additional analyses are ongoing using two additional tau‐PET tracers and additional CSF‐based P‐tau measures.

Conclusions

These preliminary findings using [18F]RO948 suggest that PART can be detected in vivo using tau‐PET and that Aβ‐negative CU individuals who are tau‐PET positive in the medial temporal lobe are at risk for focal tau accumulation and cognitive decline.
Targeted bisulfite sequencing analysis of Alzheimer’s disease candidate genes reveals differential methylation across neurofibrillary tangle burden in the prefrontal cortex.
Authors: Wheildon Greg , Smith Adam R. , Soanes Darren , Smith Rebecca G. , Moore Karen , O'Neill Paul , Morgan Kevin , Thomas Alan J , Love Seth , Francis Paul T , Mill Jonathan , Pishva Ehsan , Lunnon Katie
Published: December 2023

Background

Recent epigenome‐wide association studies (EWAS) identified several loci in specific genes showing robust and reproducible alterations in DNA methylation in Alzheimer’s disease (AD) brain samples. Standardly, assessing methylation in EWAS is done using microarrays, which target a limited number of sites in each gene. Here, we performed targeted bisulfite sequencing of candidate genes associated with AD to determine the exact extent of methylation changes across neurofibrillary tangle burden (NFT) within these loci.

Method

Prefrontal cortex brain samples from 58 individuals were grouped by Braak stage (control 0‐II; intermediate III‐IV; AD V‐VI). Following DNA extraction, 30 genomic regions were captured using Agilent SureSelect target baits. After next‐generation bisulfite sequencing, reads were aligned and the methylation status of cytosine residues called using the Bismark program. Differentially methylated positions (DMPs) were analyzed across the three groups. Furthermore, the presence of differentially methylated regions (DMRs), made up of several DMPs was assessed. Methylation levels in genomic features, such as promoters and gene bodies, of the target regions were also compared.

Result

Methylation levels were quantified for each group. Linear regression controlled for co‐variation before differences were examined using a one‐way ANOVA, with Tukey’s post‐hoc test. Sites in several genes showed stepwise increases in DNA methylation across the groups. Interestingly, amongst the most robust sites, differences in methylation in the intermediate group when compared to the control and AD samples were observed. DMRs were observed in the groups, as were methylation differences between promotors and gene bodies in several targeted regions.

Conclusion

This work provides further evidence that dysregulation of methylation is associated with pathological changes in AD prefrontal cortex. Differential methylation with intermediate NFT pathology, at sites showing no difference between control and AD samples, potentially indicates early pathological changes. As DNA methylation is reversible, this could present potential targets for pharmacological intervention.
Culture‐sensitive dementia diagnostics and care: a best practice for a diverse patient population
Authors: Lazaar Najoua , Franzen Sanne , van Bruchem‐Visser Rozemarijn L. , De Jong Frank Jan , Raso Francesco U S Mattace , Papma Janne M.
Published: December 2023

Background

The elderly population in Europe is becoming more diverse. In order to provide effective dementia diagnostics and care, healthcare professionals need to cater more to diversity in terms of culture, language, educational attainment or (health) literacy. Therefore, the implementation of culture‐sensitive diagnostic instruments and a shift in approach to adapt to this group is necessary within memory clinics. We preformed semi‐structured interviews to gather the knowledge and experience of healthcare professionals on the topic of culture‐sensitive dementia diagnostics and care. The findings are summarized in a best practice.

Method

For the best practice we used qualitative methods and preformed 14 semi‐structured interviews. We interviewed healthcare professionals that work with a diverse patient population within different memory clinics in the Netherlands. We investigated their definition of culture‐sensitive care, the specific adjustments made in the diagnostic trajectory and discussed organizational aspects related to culture‐sensitive care. These interviews were transcribed verbatim and analyzed using Atlas.ti.

Result

Several requirements for effective dementia diagnostics have been mentioned, such as working with experienced translators, the use of culture‐sensitive diagnostic instruments, and language specific information material. Other adjustments consider communication between healthcare professionals and patients. First, healthcare professionals put extra effort into estimating the level of (abstract) reasoning of patients. In this way the language used by the healthcare professional is adapted in order to optimize the communication. Second, there is more attention for nonverbal communication if patients have a different cultural background. Lastly, healthcare professionals take more time to provide care for a multicultural patient group.

Conclusion

Learnings and experiences from healthcare professionals working at memory clinics across the Netherlands give valuable insights. A best practice for culture‐sensitive dementia diagnostics and care may help with accurate dementia diagnosis and provide tools for healthcare professionals to cater to a diverse patient population.
Longitudinal morphometry of medial temporal lobe subregions in earlyAlzheimer’s disease
Authors: Baumeister Hannah , Gellersen Helena M , Kleineidam Luca , Wolfsgruber Steffen , Bürger Katharina , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Heneka Michael T. , Düzel Emrah , Jessen Frank , Berron David
Published: December 2023

Background

Structural MRI is frequently used to track Alzheimer’s disease (AD) progression in clinic, research, and pharmacological trials. It has been shown that established MRI‐derived measures lack diagnostic sensitivity particularly in early stages of AD. Here, we investigate if the utility of structural MRI for tracking early AD progression can be increased when focusing on subregions of the medial temporal lobe (MTL) which are known to exhibit earliest AD‐related neuropathological change.

Method

We used data from N = 143 participants enrolled in the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE). This included cognitively unimpaired participants who were either Aβ‐negative (CU Aβ‐; n = 67) or Aβ‐positive (CU Aβ+; n = 20), Aβ+ participants with subjective cognitive decline (SCD Aβ+; n = 38), and Aβ+ participants with MCI (MCI Aβ+; n = 18).

Participants underwent annual assessments up to three years after baseline, including MRI (2.19 ± 0.86 follow‐ups) and a neuropsychological testing (2.18 ± 0.83 follow‐ups). Segmentations of MTL subregions were generated using a longiudinal, template‐based implementation of the Automated Segmentation of Hippocampal Subfields (ASHS; Yushkevich et al., 2015, Hum Brain Mapp.) algorithm (Figure 1). Linear mixed models were fitted to derive volumetric slopes and to test their relationship with longitudinal changes in Preclinical Alzheimer Cognitive Composite (PACC‐5) scores.

Result

We observed significant volume losses across diagnostic groups with the MCI Aβ+ group exhibiting the fastest rates. Compared with the CU Aβ‐ group, there were accelerated volume losses in the subiculum and dentate gyrus in the SCD Aβ+ group and, additionally, in the entorhinal cortex and Brodmann areas 35 and 36 in the MCI Aβ+ group. There was also a trend towards faster volume losses in the entorhinal cortex in the CU Aβ+ group. Higher rates of MTL subregional volume losses, particularly in the cornu ammonis 1 subfield, were related to a faster decline on the PACC‐5 in the MCI Aβ+ group. This effect remained significant when controlling for baseline volumes.

Conclusion

Our findings highlight the viability of subregional MTL morphometry for tracking earliest neurodegeneration and related cognitive decline due to AD.
Performance of plasma pTau181 and pTau217 measured with fully automated LUMIPULSE G prototype immunoassays
Authors: Vanbrabant Jeroen , De Meyer Steffi , Van Loo Maxime , Lambrechts Charlotte , Accou Flore , Dekeyser Filip , Rubel Carrie E. , Czerkowicz Julie , Fraser Kyle , Graham Danielle , Inaoka Daigo , Aoyagi Katsumi , Vanmechelen Eugeen , Poesen Koen , Vandenberghe Rik , Stoops Erik
Published: December 2023

Background

There is a need for scalable, robust and precise Alzheimer’s Disease (AD) plasma phosphorylated Tau (pTau) biomarker tests to support clinical trials and clinical practice. This study evaluated the performance of novel plasma pTau181 and pTau217 assays developed on the LUMIPULSE G1200 automated immunoassay platform and compared them to Quanterix homebrew assays.

Method

Homebrew Quanterix Simoa assays for plasma pTau181 and pTau217 were transferred to the LUMIPULSE G instrument using recombinantly expressed versions of respectively α‐pTau181 mAb ADx252 and α‐pTau217 mAb RD‐084 (capture) both combined with an ALP‐conjugated Fab fragment digested from α‐N‐terminal Tau recombinant ADx204/RD‐073 (detector). Analytical performance evaluated specificity, LLOQ and precision. Performance in patient samples was evaluated using a prospective memory cohort of 42 biomarker confirmed AD patients in the prodromal or dementia stage as well as 35 healthy spouse controls. LUMIPULSE G results were compared with results from the Quanterix homebrew assays designed by ADx using the same antibody configuration.

Result

Robust LUMIPULSE G1200 measurements (mean intra‐run CV 3%) distinguished AD patients from spouse controls with an area under the curve (AUC) of 0.81 and 0.88 for pTau181 and pTau217, respectively. The Quanterix homebrew assays demonstrated higher AUC of 0.98 for pTau181 (pDeLong = 0.002) and of 0.95 for pTau217 (Figure 1A). Addition of age, sex and ApoE4 status to the LUMIPULSE G‐based models increased the performance of both pTau181 and pTau217 to predict AD diagnosis – relatively to univariate models ‐ with AUCs of respectively 0.91 and 0.95 (Figure 1B, both pDeLong < 0.05), approximating Simoa‐based pTau performance. PTau values measured on both platforms correlated significantly (p<0.0001) for pTau181 (r = 0.66) and pTau217 (r = 0.77).

Conclusion

The LUMIPULSE G platform is a scalable, automated, real‐time‐testing platform that is globally available. These data demonstrate that two assays on this platform, pTau181 and pTau217, are capable of distinguishing AD from controls in plasma. The sensitivity and specificity are slightly less on LUMIPULSE G when compared to an assay using the same antibodies developed on the Simoa instrument. Thus, additional experiments are required on the LUMIPULSE G to optimize analytical performance of these assays using an IVD‐grade automated system.
Sex‐specific metabolomics‐derived blood biomarkers of Alzheimer’s disease.
Authors: Clark Christopher , Laczko Endre , Rabl Miriam , Stojkovic Slavisa , Popp Julius
Published: December 2023

Background

Readily accessible diagnostic tools are crucial for early detection of Alzheimer’s disease (AD). Here, we sought to identify peripheral metabolism biomarkers predicting the presence of AD pathology.

Method

Untargeted liquid chromatography‐mass spectrometry was used to quantify 2286 serum metabolites in participants on a longitudinal memory clinic study. Unbiased between‐group analysis using Orthogonal Partial Least Squares Discriminant Analysis, Linear Discriminant analysis and Principal Component Analysis were performed to build a classifier for AD as indicated by CSF biomarkers. MetaboAnalyst was subsequently used for selection of the most relevant metabolites. Pathway enrichment was used to determine biological pathway alterations related to AD.

Result

No biomarker signature of AD was found in the whole cohort. Stratification according to sex allowed building a classifier for AD using 14 serum metabolites in males and 9 in females. Thirteen enriched pathways were identified, including arachidonic acid and tryptophan metabolism (Figure 1). The selected metabolites significantly improved the prediction of cognitive decline in females compared to a reference model (Figure 2, AUC 0.874 vs. 0.719).

Conclusion

Sex specific peripheral metabolism biomarker profiles are useful to predict cerebral AD pathology and cognitive decline, and detect related metabolic alterations. This highlights the need for personalised diagnostic and therapeutic approaches in AD.
Locus coeruleus integrity, cerebrovascular health, and plasma Alzheimer’s biomarkers in cognitive aging
Authors: Dutt Shubir , Bachman Shelby L , Li Yanrong , Yew Belinda , Jang Jung Yun , Ho Jean K , Nashiro Kaoru , Min Jungwon , Yoo Hyun Joo , Gaubert Aimee , Nguyen Amy , Blanken Anna E , Sible Isabel J , Marshall Anisa J , Kapoor Arunima , Alitin John Paul M , Hoang Kim , Shenasa Fatemah , Martini Alessandra Cadete , Head Elizabeth , Rodgers Kathleen E. , Shao Xingfeng , Wang Danny J.J. , Mather Mara , Nation Daniel A.
Published: December 2023

Background

The locus coeruleus (LC) innervates the cerebrovasculature and plays a critical role in optimally regulating cerebral blood flow. However, few studies have examined potential relationships between these systems in humans with widely available neuroimaging methods, and none have explored how relationships may change in the presence of growing Alzheimer’s disease (AD) pathology.

Method

Participants were 66 community‐dwelling older adults free of dementia (ages 55‐87) recruited at the University of Southern California. Pseudocontinuous arterial spin labeling (pCASL) MRI measured regional perfusion, and T1‐fast spin echo (T1‐FSE) MRI quantified rostral LC contrast, a well‐established measure of LC structural integrity. Subsets of participants underwent neuropsychological testing (n = 36) as well as fasting venipuncture to measure plasma AD biomarker concentrations of Aβ42/40 ratio (n = 56) and ptau181 (n = 35). Multiple linear regression models examined associations among regional perfusion, LC integrity, and cognition (episodic memory, attention, executive function). Moderation analyses included additional terms for plasma AD biomarker concentrations and plasma x LC interaction effects.

Result

Higher LC‐MRI contrast was linked to higher frontal (medial and lateral orbitofrontal) perfusion but lower limbic (amygdala and entorhinal) perfusion. Greater LC‐MRI contrast was also associated with better episodic memory recall and recognition but not measures of attention or executive function. Plasma Aβ42/40 ratio and ptau181 moderated LC‐perfusion relationships such that associations significantly weakened in the presence of greater pathology.

Conclusion

This is the first human study to directly investigate associations between LC integrity and perfusion in a well‐characterized sample with neuroimaging, cognitive, and AD biomarker data. LC integrity tracked episodic memory performance along with cerebral perfusion, while greater AD pathology in preclinical populations disrupted LC‐perfusion relationships, suggesting that growing amyloid and tau pathology may negatively impact the LC’s ability to optimally regulate cerebral blood flow. Taken together, our findings highlight the importance of tracking the LC over the AD disease course. Concurrent multimodal imaging of the LC and cerebrovascular function may have potential as a novel non‐invasive biomarker, and future studies should track its utility longitudinally and its relationship with disease severity and other disease markers (e.g., grey matter atrophy, amyloid/tau PET).
The disintegration of cognitive reserve: exploring the association between years of education, delirium, and baseline cognition in hospitalized older adults
Authors: Avelino‐Silva Thiago J , Campora Flavia , Curiati Jose A E , Jacob‐Filho Wilson
Published: December 2023

Background

Cognitive reserve helps maintain cognitive function in the face of accumulating brain pathology and potentially delays the onset of clinical dementia. However, there is a lack of research examining the role of cognitive reserve in delirium, particularly in the context of preexisting neurocognitive disorders. We aimed to investigate the interaction between years of education and baseline cognition in their association with delirium occurrence in hospitalized older adults.

Methods

Prospective cohort study including acutely ill patients aged ≥60 admitted to the geriatrics unit of a university hospital in Sao Paulo, Brazil (2009‐2020). Candidates underwent comprehensive geriatric assessments in the first 24 hours of hospitalization. Delirium occurrence was defined using the CAM, completed daily during the hospital stay. Baseline cognition was determined using the CDR and the CDR‐SB. Years of education were used as a proxy for cognitive reserve. We investigated the association between delirium occurrence and years of education using logistic regression models; we then completed interaction analyses exploring the effect of baseline cognition on that association.

Results

We included 3,863 participants (mean age = 80; female = 62%; mean years of education = 6). Overall, 1,346 (35%) participants experienced delirium during hospitalization. Additionally, 777 (20%) participants had normal baseline cognition (CDR = 0), 2,068 (54%) had mild cognitive impairment or mild dementia (CDR = 0.5‐1), and 1,018 (26%) had moderate or severe dementia, with a median CDR‐SB of 4. After adjusting for age and sex, we found that participants with ≥12 years of education were less likely to experience delirium (OR = 0.75, 95%, 95%CI = 0.59‐0.96, p = 0.022). However, we found that the association was significantly modified by baseline cognition (p = 0.024) (Figure 1) and that having more years of education was protective against delirium only in the absence of preexisting cognitive impairment (Figure 2).

Conclusion

More years of education were protective against delirium occurrence in hospitalized older adults, but only in the absence of preexisting cognitive impairment. Our results suggest that after the onset of clinical neurocognitive disorders, previous markers of cognitive reserve no longer contribute to a lower risk of delirium.
Strategy for absolute quantification of phospho‐Tau epitopes in cerebrospinal fluid by mass spectrometry
Authors: Gomes Bárbara Fernandes , Sauer Mathias , Weiner Sophia , Andreasson Ulf , Blennow Kaj , Zetterberg Henrik , Gobom Johan
Published: December 2023

Background

Mass spectrometry is used as reference method for protein quantification by measuring tryptic peptides derived from the target protein relative to a stable isotope‐labeled standard. Existing targeted mass spectrometric methods to measure total tau (tTau) and phosphorylated tau (pTau) species in cerebrospinal fluid (CSF) rely either on immunoaffinity enrichment of the protein or exploit the unusual property of tau being soluble in 2.5% perchloric acid (PA), to precipitate abundant sample proteins. Both strategies, however, carry risk of introducing bias: immunoaffinity enrichment relies on the specificity of the used antibodies, which may not have equal affinity for all of the large number of processed or modified forms of tau, and PA may partially precipitate some tau forms. To address this problem, we have developed an antibody‐ and PA‐free method to measure tau and pTau epitopes in CSF by targeted mass spectrometry.

Method

CSF samples (100 µl) from healthy individuals (HC) and Alzheimer’s disease (AD) patients were spiked with stable isotope‐labeled tau peptide standards containing the phospho‐epitopes pTau181, pTau231, pTau217, pTau205, and non‐phosphorylated Tau212‐221, and subjected to tryptic digestion. Desalted samples were fractionated by strong anion‐ and strong cation‐ exchange (SAX and SCX, respectively) solid phase extraction with step‐wise pH elution. The fractions were analyzed by parallel reaction monitoring on a nano‐flow LC‐MS on a Quadrupole‐Orbitrap hybrid mass spectrometer.

Result

Several tau peptides were detected with both SAX and SCX, including pTau181, pTau217, pTau205, and Tau212‐221. The reproducibility of the new assay was assessed, and its performance was compared with PA‐based sample preparation and immunoassays for tau and pTau in a pilot study of AD patients and controls.

Conclusion

The method described here allows for the detection of multiple tau/pTau peptides, while avoiding the need for selective protein isolation methods such as immunoaffinity enrichment or PA precipitation, thereby eliminating bias toward more/less soluble tau species.
Proteins involved in synapse organization are associated with longitudinal loss in gray matter network connectivity in prodromal AD
Authors: de Leeuw Diederick Martijn , Duits Flora H. , Vromen Eleonora M. , Dicks Ellen , Barkhof Frederik , Visser Pieter Jelle , Tijms Betty M.
Published: December 2023

Background

Lower gray matter connectivity measures are related to faster cognitive decline in prodromal Alzheimer’s Disease (AD). We investigated the biological underpinnings responsible for this loss of brain connections using cerebrospinal fluid (CSF) proteomics.

Method

Data from ADNI was used to select 82 individuals with MCI and abnormal CSF amyloid (mean age±SD 74±7) and 37 controls with normal amyloid levels (mean age±SD 75±5), for whom repeated MRI‐scans (median of 6 scans over 1.5 follow‐up years) and baseline CSF proteomic data (in total 306 proteins) were available. We used an automated pipeline (Tijms, Series et al. 2012) to construct gray matter networks from 3D‐T1 sequences and calculate connectivity density and gamma – measures previously found to be most strongly related to cognitive decline (Dicks, Vermunt et al. 2020). Linear mixed models were applied to test associations between baseline CSF protein levels and repeated connectivity metrics, controlling for intracranial volume, age and sex. Proteins that demonstrated significant associations (p<0.05) were identified and examined for their biological relevance according to Gene Ontology.

Result

Connectivity density declined over time with ‐0.8% per year (pMCI = 0.001; figure 1), which did not differ from controls (pdif = 0.15). Gamma declined faster in MCI than in controls (bMCI = ‐0.016 vs. bCN = ‐0.007, pdif <0.001; figure 1). Higher levels of 99/108 proteins were associated with faster decline in connectivity density (a.o. tau and neuroprentaxins). These proteins were involved in regulation of synapse organization (GO:0050807; pFDR = 7.00E‐07; figure 2). Higher levels of 9/108 proteins associated with less decline and were involved in chemotaxis (GO:0048247; pFDR = 1.40E‐02). Similarly, 25 out 30 proteins (83%) associated with alterations in gamma over time, showed associations of higher levels with less gamma decline and were also involved in chemotaxis (GO:0050926; pFDR = 9.42E‐05; figure 3). There were no protein‐connectivity relationships in controls.

Conclusion

Proteins involved in synapse organization were associated with faster decline in connectivity density over time in patients, while chemotaxis was associated with less decline. This suggests that synaptic degeneration may predict disease progression while immune responses may serve as a resilience mechanism in AD.
Neurological manifestation of post‐COVID‐19 conditions
Authors: Jung Young Hee H
Published: December 2023

Background

We aimed to investigate the factors associated with neurological manifestations of post‐ coronavirus disease 2019 (COVID‐19) conditions.

Method

We retrospectively collected data from 440 patients who visited our post‐COVID‐19 clinic more than 4 weeks after severe acute respiratory syndrome coronavirus 2 infection. We analyzed the prevalence of different neurological symptoms (brain fog, memory impairment, headache, and dizziness) and assessed the associated factors.

Result

Brain fog was the most common symptom, observed in 170 patients (38.6%), followed by headaches (137, 31.1%), dizziness (128, 29%), and memory impairment (104, 23.6%). Brain fog was associated with hyposmia or hypogeusia (OR = 2.67, P < 0.001), fatigue (OR = 1.79, P < 0.001), sleep problems (OR = 1.72, P = 0.043), and anxiety (OR = 1.13, P < 0.001). Memory impairment was associated with sleep problems (OR = 2.89, P < 0.001), fatigue (OR = 1.47, P<0.001), depression (OR = 1.07, P = 0.032), and age (OR = 1.02, P = 0.010). Headache and dizziness were associated with sleep problems (OR = 1.5, P < 0.001 vs. OR = 2.79, P < 0.001) and fatigue (OR = 2.38, P < 0.001 vs. OR = 1.43, P < 0.001), respectively. The incidence of brain fog (P < 0.001), memory impairment (P < 0.001), dizziness (P = 0.007), and headache (P = 0.045) accompanied by hyposmia and hypogeusia was higher in patients with the aforementioned symptoms than in those without.

Conclusion

This study suggests that there is a relationship between neurological symptoms and other clinical factors, such as fatigue, depression, anxiety, hyposmia, and hypogeusia.
Targeted proteomic search reveals new actors in the synaptic and lysosomal dysfunction in genetic FTD, a GENFI study.
Authors: Weiner Sophia , Malichova Frederika , Simrén Joel , Sauer Mathias , Swift Imogen J , Heller Carolin , Knowles Kathryn , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Blennow Kaj , Zetterberg Henrik , Rohrer Jonathan D. , Gobom Johan , Esteve Aitana Sogorb
Published: December 2023

Background

At present, there are limited fluid biomarkers which measure the underlying pathophysiology of frontotemporal dementia (FTD). Approximately a third of people with FTD have a genetic cause where the pathological basis is well understood. Studying fluid biomarkers in these genetic forms therefore allows greater insight into the relationship between the measure and the underlying disease mechanism. Based on prior work identifying synaptic and lysosomal dysfunction as common mechanisms across the different forms of FTD, we performed a targeted search of proteins related with synapses and the lysosomal pathway on an unbiased proteomic dataset generated from the GENetic FTD Initiative (GENFI) study.

Method

The dataset was obtained from a total of 248 cerebrospinal fluid samples (CSF) from the GENFI cohort including 109 presymptomatic (44 C9orf72, 39 GRN, 26 MAPT) and 63 symptomatic (34 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 76 mutation‐negative controls where Tandem Mass Tag (TMT) proteomics had been performed. We selected the clusters obtained from a Gene Ontology analysis that corresponded to the terms “synapse” and “lysosome” and generated a list of proteins related to each category. We then analysed the differences in each specific protein between genetic groups.

Result

A total of 42 of the synaptic proteins preselected were significantly changed in symptomatic MAPT mutation carriers, 70 in symptomatic GRN mutation carriers, and 92 in the symptomatic C9orf72 group. Among all of these, there were only 9 proteins that overlapped in the three genetic forms. This list included reelin, which was significantly decreased in each symptomatic group when compared to controls (MAPT p‐value = 0.0016, GRN = 0.0008, C9orf72 = 0.0064), and calretinin, which was significantly increased in symptomatic groups compared to controls (MAPT = 0.0260, GRN = 0.0000, C9orf72 = 0.0100). We then used the same approach to study lysosomal proteins, and found that 38 proteins were significantly changed in symptomatic MAPT, 31 in the symptomatic GRN group and 41 in symptomatic C9orf72 expansion carriers.

Conclusion

This study provides new insights into candidate markers to assess synaptic and lysosomal dysfunction in FTD.
Investigation of the choroid plexus implication in Alzheimer’s disease pathophysiology using human proteomics and mouse transcriptomics
Authors: Delvenne Aurore , Vandendriessche Charysse , Gobom Johan , Fagan Anne M. , Verhey Frans R.J. , Zetterberg Henrik , Visser Pieter Jelle , Vandenbroucke Roosmarijn E , Vos Stephanie J. B. ,   EMIF‐AD MBD study group
Published: December 2023

Background

The choroid plexus (CP) is responsible for the production of cerebrospinal fluid (CSF), transport of proteins to the CSF and clearance of proteins from the CSF. The CP becomes compromised during aging, which is exacerbated in AD. Nonetheless, the relation between CP and AD pathophysiology remains unclear. We aim to investigate the pathophysiology underlying the CP involvement in AD, utilizing human CSF proteomics and mouse CP transcriptomics.

Method

We included 526 individuals from EMIF‐AD MBD, St Louis Knight ADRC and Maastricht BB‐ACL studies. Based on CSF Aβ1‐42 (A, data‐driven cut‐offs), individuals were classified as controls (cognitively normal (CN) A‐, n = 171) or as amyloid‐positive (CN A+, n = 120; mild cognitive impairment (MCI) A+, n = 154; AD A+, n = 81). CSF proteomic data were generated using TMT spectrometry and protein concentrations were compared using ANOVA adjusted for age and sex. Transcriptomic was performed in CP tissue of APPNL‐G‐F (n = 17) and wild‐type C57BL/6J (n = 17) mice using Illumina RNA‐Seq and differential expression analysis was conducted. Next, Gene Ontology and Ingenuity Pathway analyses were performed. For proteomics, high expression of proteins in the CP was identified based on Allen Brain Atlas and the R package ABAEnrichment.

Result

In CN A+, 51 proteins were increased and 21 decreased relative to controls. Out of those increased proteins, 57% were enriched for expression in the CP (ABAEnrichment P<0.001, Figure 1) and were associated with lysosomes and the CLEAR pathway, extracellular matrix and coagulation. A similar pattern was observed for both MCI A+ and AD A+ compared to controls, with a significant percentage of increased proteins enriched for expression in the CP (22 to 30%), which are related to lysosomes and the CLEAR pathway, extracellular matrix and coagulation. In APPNL‐G‐F compared to wild‐type mice, CP transcriptomics revealed 313 upregulated and 198 downregulated genes (Figure 2). The upregulated genes were also associated with the lysosomes and the CLEAR pathway, as well as energy metabolism and lipids.

Conclusion

Human proteomics and mice transcriptomics studies suggest an association between amyloid pathology, CP functioning and lysosomes. Dysfunction of lysosomes in AD could relate to compromised clearing events. This is important for future research and AD treatment development.
Longitudinal decrements in the sensitivity of cueing in the Free and Cued Selective Reminding Test predict A+T+ status in cognitively unimpaired individuals
Authors: Sánchez‐Benavides Gonzalo , López‐Martos David , Suarez‐Calvet Marc , Milà‐Alomà Marta , Gispert Juan Domingo , Minguillon Carolina , Zetterberg Henrik , Blennow Kaj , Grau‐Rivera Oriol
Published: December 2023

Background

The Index of Sensitivity of Cueing (ISC) from the Free and Cued Selective Reminding Test (FCSRT) memory test evaluates the efficacy of the semantic cues to facilitate retrieval from stored information. Although the ISC has been extensively studied in individuals with prodromal Alzheimer’s disease (AD), its association with AD core pathology, amyloid‐β (A) and p‐tau (T), in cognitively unimpaired (CU) individuals remains unknown. The aim of the present study was to explore the cross‐sectional and longitudinal differences in ISC scores among cerebrospinal fluid (CSF)‐defined AT groups in CU individuals.

Methods

We studied 341 CU participants from the ALFA+ study with available baseline CSF and longitudinal data for the word‐FCSRT‐without‐immediate‐recall version after 3 years. The ISC was computed as: (“total recall”‐“free recall”)/(48‐“free recall”). We defined AT groups (A‐T‐, A+T‐, and A+T+) using baseline CSF levels (Table1) using the cut‐offs defined in Milà‐Alomà et al., 2020. We set independent ANCOVAs to explore the associations between AT status and cross‐sectional and longitudinal (delta) ISC and main FCSRT variables (Table 1). All models were adjusted for age, education and sex, and longitudinal analyses were further adjusted for inter‐visit time and baseline scores. Nominal and FDR‐adjusted p‐values are reported.

Results

No differences among AT groups were found for baseline FCSRT variables (Table 2). At nominal p‐value levels We observed differences in total recall (TR) and ISC both at visit2 and delta in association with AT status at nominal p‐value levels (Table2), but only the ISC change survived FDR corrections (pFDR = 0.03). Associations were driven by the A+T+ group (Figure1). No differences between A‐T‐ and A+T‐ were found (p>0.05). TR delta was still significant after adjusting for free recall (nominal p = 0.011), suggesting ISC as the main driver of TR decrements.

Conclusion

Decrements in sensitivity of cueing after 3 years, that in turn diminish FCSRT total recall, were related to concurrent CSF Aβ and p‐tau abnormal levels in CU individuals. No differences between AT groups were observed in free recall, in contrast with other studies using other FCSRT versions that include immediate recall during learning. Further research on secondary memory variables may elucidate the subtle changes related to early AD pathology.
White matter hyperintensities associate with pathological stages of neurodegenerative disease.
Authors: Jonkman Laura E. , Lin Chen‐Pei , Frigerio Irene , Noteboom Samantha , Bouwman Maud M.A. , Reijner Niels , Preziosa Paolo , Boon Baayla D.C. , Bouwman Femke H. , Rozemuller Annemieke J.M. , Steenwijk Martijn D. , Barkhof Frederik , Berg Wilma D.J.
Published: December 2023

Background

White matter hyper‐intensities (WMH) are observed on FLAIR MRI, increase with age and are more prominent in neurodegenerative diseases such as in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The aim of this study was to assess the association between WMH and neuropathological staging of amyloid‐beta, neurofibrillary tangles (NFT) and α‐synuclein (α‐syn).

Method

In‐situ 3T‐MRI 3DT1‐weighted and 3D‐FLAIR data were collected for 77 clinically defined and pathologically‐confirmed brain donors; 31 AD, 21 PD and PD dementia (PDD), and 25 controls. WMH were segmented on FLAIR using an in‐house developed multiview convolutional neural network, followed by manual checking, and volume was obtained with FSL. Fifteen brain regions were dissected at autopsy, immunostained and evaluated for neuropathological diagnosis, including Thal amyloid phase, CAA type, and Braak stages for NFT and α‐syn. Group differences were assessed with linear models (corrected for age, gender, post‐mortem delay), and associations with Spearman and Pearson partial correlations.

Result

Compared to controls, WMH load was higher in AD (p<0.001), specifically amnestic AD (p = 0.003) rather than non‐amnestic AD (p = 0.053), and higher in PD (p = 0.016), specifically non‐demented PD (p = 0.015) rather than PDD (p = 1.0). No difference in gender was observed (p = 0.38). Without the influence of pathology (in controls), WMH was associated with age (r = 0.49,p = 0.016).

In the whole cohort, WMH was associated with Fazekas score (r = 0.67; p<0.001), normalized brain volume (NBV; r = ‐0.31,p = 0.007), gray matter volume (NGMV; r = ‐0.36,p = 0.002), Thal phase (r = 0.24,p0.034), Braak NFT stage (r = 0.33,p = 0.004), and Braak α‐syn stage (r = 0.27, p0.018).

Across controls and AD, WMH associated with NBV (r = ‐0.39,p = 0.004), NGMV (r = ‐0.42,p = 0.002), left and right hippocampal volume (r = ‐0.36,p = 0.008 and r = ‐0.32,p = 0.022), Braak NFT (r = 0.41,p<0.001), Thal phase (r = 0.41,p = 0.002), and CAA (r = 0.34,p = 0.01). Amnestic and non‐amnestic AD showed similar results, except for CAA, which was associated with WMH in non‐amnestic AD only (r = 0.33,p = 0.04).

Across controls and PD(D), WMH associated with Braak NFT stage (r = 0.39,p = 0.008) and Braak α‐syn stage (r = 0.60,p<0.001), but not with MRI outcome measures. In this respect PD and PDD showed different results; in PD WMH associated with NGMV (r = ‐0.37,p = 0.031), in PDD with left and right hippocampal volume (r = ‐0.44,p = 0.014 and r = ‐0.44,p = 0.015).

Conclusion

WMH associate with pathological stages of AD and PD(D), and contributes to MRI atrophy.
Knowledge, Attitude, and Compliance with management of Patients with Selected Risk; Diabetes Mellitus & Hypertension On Dementia in Selected Primary Health Care Centres in Nigeria: An Impetus for Primary Prevention of Vascular Dementia
Authors: Nwinee Victor Boma , Ucheoma Allessandra Chinazo
Published: December 2023

Background

Dementia is clinical syndrome, characterized by a progressive and irreversible loss of cognitive function, has seen a rapid increase in Nigeria over the past 20 years1. As access to healthcare improves, more people are living into old age and becoming at risk of developing the condition. In Nigeria, 55% of the population primarily rely on primary care centers for their health needs2. Studies have shown that the prevalence of hypertension and diabetes in Nigeria is increasing, and these are listed as risk factors for dementia by the World Health Organization3. Despite this, there has been limited research on the knowledge and compliance to treatment among those at high risk for dementia, who are crucial for reducing its prevalence. This study focuses on two common risk factors in Nigeria, hypertension and Type 2 diabetes mellitus.

ETHICAL COMMITTEE APPROVAL: Obtained from the Human Research Ethical Committee of Lagos University Teaching Hospital, Nigeria.

STUDY POPULATION: People with vascular risk factors (Hypertension & Type 2 Diabetes Mellitus) attending primary care facilities in selected centers in Nigeria.

Inclusion criteria:

1. Patients 35 to < 65 years.

2. Patients with correct diagnosis of Hypertension

3. Patients with correct diagnosis of Diabetes Mellitus

4. Patients with at least basic primary school education

Exclusion criteria:

1. Patients who don’t pass the cognitive test.

2. Patients with neuropsychiatric conditions

3. Hypertension in pregnancy

Study design: A clinic‐based descriptive cross‐sectional study.

Materials

Mini mental State Exam tool prior to commencement of the questionnaire‐based interview. SPSS, structured interviewer‐based questionnaires.

RESEARCH ASSISTANTS: Medical graduates of the College of Medicine, University of Lagos, Nigeria, are the field‐enumerators for this study.

Results, Discussion & Conclusion

Ongoing study

FUNDING: Self‐funded

References

1. Adeloye D, Auta A, Ezejimofor M, Oyedokun A, Harhay MO, Rudan I, Chan KY. Prevalence of dementia in Nigeria: a systematic review of the evidence. J Glob Health Rep. 2019;3:e2019014. doi: 10.29392/joghr.3.e2019014. Epub 2019 Mar 27. PMID: 31528708; PMCID: PMC6746335.

2. Akinlua JT, Meakin R, Umar AM, Freemantle N. Current Prevalence Pattern of Hypertension in Nigeria: A Systematic Review. PLoS One. 2015 Oct 13;10(10):e0140021. https://doi.org/10.1371/journal.pone.0140021. PMID: 26461923; PMCID: PMC4603956.

3. World Health Organization. Dementia. September 2022 https://www.who.int/news‐room/fact‐sheets/detail/dementia. Accessed 15/12/2022