bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the preanalytical stability of Alzheimer’s disease plasma biomarkers: the impact of blood collection tubes supplemented with protease inhibitors
Authors: Chen Yijun , Zeng Xuemei , Lee Jihui , Sehrawat Anuradha , Lafferty Tara K , Boslett James J , Klunk William E , Pascoal Tharick A. , Villemagne Victor L , Cohen Ann D , Lopez Oscar L. , Yates Nathan , Karikari Thomas K
Published: January 2025

Background

The detection and monitoring of Alzheimer's disease (AD) biomarkers in plasma are crucial for early diagnosis and prognosis. However, the stability of plasma AD biomarkers can be compromised by the degradation caused by endogenous proteases present in blood. The efficacy of protease inhibitors in mitigating this degradation is yet to be established. This study evaluated the stability of five plasma AD biomarkers (GFAP, NFL, Aβ1‐40, Aβ1‐42, and pTau181) in plasma over time under room temperature (RT) conditions. Samples were collected concurrently into either standard K2EDTA or BD‐P100 tubes, with the latter being coated with protease inhibitors. Our objective was to assess the effectiveness of protease inhibitors in preserving the stability of plasma AD biomarkers in plasma.

Method

We evaluated two experimental approaches. In Approach 1, whole blood samples (n=16) from the same draw were collected into K2EDTA and BD‐P100 tubes and stored at RT for 0h and 24h. In Approach 2, plasma samples (n=19) were isolated from whole blood collected into BD‐P100 and K2EDTA tubes and immediately stored at RT for 0h, and 24h. The levels of plasma AD biomarkers were measured using immunoprecipitation with mass spectrometry (IP‐MS) and Single Molecule Array (SIMOA). The IP‐MS assay replicated a protocol (Nakamura et al., 2018) for Aβ1‐40 and Aβ1‐42 measurement.

Result

The IP‐MS assay indicated that the use of BD‐P100 tubes significantly reduced Aβ peptide degradation compared with the K2EDTA tube. In Approach 1, the IP‐MS Aβ signal decreased by 23‐34% for samples collected in K2EDTA tubes relative to 17‐18% for samples collected in BD‐P100 tubes. In Approach 2, the IP‐MS Aβ peptide signal decreased by 14‐16% for K2EDTA tubes, with a lower decrease of 3‐7% for BD‐P100 tubes. The SIMOA assays produced similar results for Aβ peptides. No significant variations were detected in time‐dependent pTau181, GFAP, and NFL levels for samples collected using both tubes.

Conclusion

The study showed that tubes supplemented with protease inhibitors significantly improve the preanalytical stability of Aβ1‐40 and Aβ1‐42 in plasma. These results have important implications for preanalytical procedures that are needed to enable widespread access and utilization of plasma biomarkers in resource‐limited settings.
Superiority of p‐tau217 among plasma biomarkers in diagnostic accuracy in non‐demented persons from the Geneva Memory Center cohort
Authors: Mendes Augusto J. , Ribaldi Federica , Lathuiliere Aurelien , Ashton Nicholas J. , Janelidze Shorena , Zetterberg Henrik , Scheffler Max , Assal Frederic , Garibotto Valentina , Blennow Kaj , Hansson Oskar , Frisoni Giovanni B.
Published: January 2025

Background

The identification of Alzheimer's disease (AD) pathology at an early stage utilizing plasma biomarkers has attracted significant interest due to its potential for improving global screening programs. Different forms of p‐tau measured in plasma, mainly p‐tau217, have demonstrated similar diagnostic accuracy when compared to traditional biomarkers. Moreover, plasma biomarkers associated with neuroinflammation and neurodegeneration, namely GFAP and NfL, respectively, have been found to be elevated in patients with amyloidosis and tau accumulation, even though these conditions are not exclusive to AD.

Method

Our goal was to see if there were any differences in plasma biomarkers between amyloid (A+) and tau (T+) positive groups based on PET scans and compare their diagnostic accuracy in a Geneva Memory Center non‐demented group. Plasma, amyloid‐PET, and tau‐PET were assessed in a total of 100 subjects (CU = 33; MCI = 67). Plasma biomarkers included were p‐tau217, p‐tau231, p‐tau181, GFAP, and NfL. The differences in each plasma biomarker among A+/T+ groups were tested using Kruskal‐Wallis tests. Additionally, we calculated the receiver operating characteristic (ROC) and underlying area under the curve (AUC) in A+ and T+.

Result

All plasma biomarkers revealed significant differences between A‐/T‐ and A+/T+ (p < 0.05), where p‐tau217 showed a higher effect size (δ = 0.98) in comparison with other biomarkers (δrange = 0.31 ‐ 0.67). Moreover, p‐tau217 was the only biomarker displaying significant differences between A‐/T‐ and A+/T‐ (p < 0.001; δ = 0.89). Lastly, p‐tau217 showed a higher AUC for detecting amyloid and tau (AUCaverage = 0.96) than other p‐tau forms (AUCaverage = 0.77) and GFAP/NfL (AUCaverage = 0.69).

Conclusion

Plasma p‐tau217 revealed superior performance in AD pathology detection when compared to other p‐tau forms and plasma biomarkers of neuroinflammation/neurodegeneration. Our results suggest the potential of p‐tau217 to identify AD pathology in a non‐demented population.
Correlation Between Cognitive Impairment in Early‐Stage Amyloid‐Positive Alzheimer's Disease and CA1 Hippocampal Subfield Volume Loss Using 7T MRI
Authors: Adeyemi Oluwatobi F , Mougin Olivier , Penny Gowland , Bowtell Richard , Mukaetova‐Ladinska Elizabeta , Hosseini Akram A. , Shah Jagrit
Published: January 2025

Background

Early diagnosis is crucial in Alzheimer's disease (AD) for optimal treatment outcomes. Neuropsychometric assessments, particularly using the Uniform Data Set Neuropsychological Battery (UDSNB3.0) [1], provide insights into cognitive domains in early stages of Alzheimer’s disease before significant hippocampal atrophy occurs. This study leverages 7T MRI, which offers superior spatial resolution, to investigate these correlates.

Method

Forty‐seven participants were recruited (24 AD patients and 23 matched healthy controls [HC]; age range: 40 ‐ 76 years). Participants selected for the study met the ATN criteria [2] for symptomatic Alzheimer's disease with CSF‐Amyloid positivity. Participants with significant hippocampal atrophy (i.e. MTA score of >2 on clinical MRI at 1.5/3T [3] were excluded. Imaging was carried out on a Philips Achieva 7T scanner equipped with a Nova Medical single‐channel transmit and 32‐channel receive (1Tx32Rx) head coil. The acquired images included PSIR sequences (TE/TR=3.1/6.9ms; FA=60°) with isotropic 0.55 mm resolution, as well as T2‐weighted FSE sequences (TE/TR=119/5900ms; FA=90°) with a resolution of 0.38x0.39x1.50 mm³.

Result

The reduction in the volume of CA1 hippocampal subfield in patients with AD significantly correlated with multiple cognitive domains, highlighting its central role in various aspects of cognitive function (see Table 1 and Figure 2). The change in volume was not significant for the whole brain showing that the hippocampus was changing particularly and not simply as part of general brain atrophy.

A significant linear correlation was evident between the volume of CA1 and the total MoCA score (R2 = 0.47; p=0.02), indicating a particularly strong correlation with the memory category with p<0.05. There were also significant correlations between CA1 and specific cognitive subdomains including executive function, attention, language, Orientation, Craft Story Immediate, Number Span Backward.

Conclusion

The observed result, indicating a robust correlation between the CA1 hippocampal subfield volume and various cognitive measures, in the early stages of Alzheimer's disease, provides valuable insights into the intricate relationship between neuroanatomy and cognitive function.
Neurobiological and clinical characteristics of amnestic patients with Lewy body pathology
Authors: Silva‐Rodríguez Jesús , Moscoso Alexis , Labrador‐Espinosa Miguel , Sanchez‐Juan Pascual , Schöll Michael , Grothe Michel J.
Published: January 2025

Background

While Lewy body (LB) pathology typically associates with a distinct clinical profile compared to Alzheimer’s disease (AD), early memory deficits are not uncommon and can confound clinical diagnosis of amnestic patients. Moreover, approximately 30‐60% of AD patients have concomitant LB pathology, which has been reported to affect the clinical phenotype and result in a more aggressive disease course. Recently developed α‐synuclein seed amplification assays (αSyn‐SAAs) have demonstrated high diagnostic accuracy for LB diseases, but the role of these novel biomarkers in the context of amnestic presentations typical for AD remains to be investigated in more detail.

Method

We studied 872 patients from the ADNI cohort with a baseline diagnosis of aMCI (N=661) or AD dementia (N=211), who had CSF and FDG‐PET data available. CSF samples were analyzed for peptide levels of Aβ1‐42 and p‐tau181, and αSyn positivity was evaluated using a novel αSyn‐SAA. Based on positive/negative results on the different biomarkers, subjects were grouped into “AD‐/LB‐” (A‐T‐αSyn‐, N=106), “AD+/LB‐” (A+T+αSyn‐, N=336), “AD+/LB+” (A+T+αSyn+, N=158) and “AD‐/LB+” ((A‐|T‐)αSyn+, N=68). We analyzed group differences in demographics, APOE4 positivity, neurodegeneration patterns (FDG‐PET), as well as baseline and longitudinal scores of global cognition (MMSE) and domain‐specific function (ADNI_MEM, ADNI_EXEC).

Result

At baseline, AD+/LB+ showed worse global cognition (MMSE: d=‐0.27, p=0.004) and memory performance than AD+/LB‐ (ADNI_MEM: d=‐0.26, p<0.006). AD‐/LB+ were less globally impaired (p<0.001) and characterized by a markedly more dysexecutive profile (d(MEM‐EXEC): p<0.002). AD+/LB+ progressed faster on all cognitive scores, but they did not develop a differential cognitive profile compared to AD+/LB‐ (Figure 1). APOE4 positivity was similar between AD+/LB+ and AD+/LB‐ (72% vs. 75%, p=0.28) but lower in AD‐/LB+ (28%, p<0.001). In FDG‐PET, AD+/LB+ was characterized by a temporo‐parietal hypometabolism pattern similar to that of AD+/LB‐ but with higher effect sizes (Fig‐2). By contrast, AD‐/LB+ showed a strikingly different posterior‐occipital pattern of hypometabolism.

Conclusion

LB co‐pathology in AD was associated with more severe neurodegeneration and faster cognitive decline, but an amnestic AD‐typical phenotype. By contrast, patients with relatively pure LB pathology were characterized by a more dysexecutive cognitive profile and a distinct hypometabolism pattern typically suggestive of LB disease.
The State of the Art in mobile Augmentative and Alternative Communication Devised for People with Dementia: Evaluation of Features and Functions
Authors: Muñoz Mariateresa (Teri) H , Okine Joana , Brown Ellen L , Ruggiano Nicole
Published: January 2025

Patients with dementia (PWD) often face challenges with daily activities due to communication challenges, which may lead to negative outcomes for those with dementia and their family caregivers alike. Augmentative and alternative communication (AAC) devices have demonstrated to be feasible in supporting communication among PWD (May et al., 2019) through text, graphics, and/or sound. Traditional AAC devices have been non‐electronic memory and communication aids (May et al., 2019). However, in recent years many primary caregivers of PWD are seeking out mobile applications to address this challenge using their smartphone or tablet. However, mobile applications addressing communication skills specifically for dementia care are scarce despite their potential to improve quality of life (Ambegaonkare et al., 2021; Brown et al., 2023). To better understand the current landscape of AAC mobile applications, this systematic review identified and evaluated the features and design of commercially‐available mobile applications. A total of 27 AAC apps were identified through searches on the Apple IOS store and Google Play, after excluding duplicates and apps that targeted primarily children. Four research team members were involved in cataloging features and evaluating the apps using a modified version of the Mobile App Rating Scale (Stoyanov et al., 2015). The price of apps varied, though many listed as being free or low‐cost often required higher‐priced subscriptions or licensing fees. All apps were compatible for English speakers, though several were available in multiple languages. It was found that the apps varied in their potential for engagement, functionality, aesthetics, and information. It was also found that many apps are limited in their potential to support caregiving activities (e.g., mealtime, dressing) for those with communication barriers related to cognitive impairment. Apps that are limited in their ability to customize the interface to the user’s preferences for daily care may impede person‐centered care practices for PWD. Implications for practice, policy, and research are discussed.
Do glial‐reactivity and cerebral blood flow modulate cerebral glucose metabolism in Alzheimer’s disease?
Authors: Nowell Joseph , Femminella Grazia Daniela , Ritchie Craig , Holmes Clive , Walker Zuzana , Ridha Basil H , Lawrence Robert M , McFarlane Brady , Archer Hilary , Coulthard Elizabeth , Underwood Benjamin R , Koranteng Paul , Karim Salman , Prasanna Aparna , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Holscher Christian , Harrison John E , Hinz Rainer , Tadros George , Passmore Anthony Peter , Ballard Clive G , Edison Paul
Published: January 2025

Background

Alzheimer’s disease is a devastating neurodegenerative disorder with a complex pathogenesis. One main pathological feature utilised in diagnosis is neurodegeneration or neuronal injury, which is reflected in reductions in cerebral glucose metabolism measured by [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). Here we evaluated the involvement of glial reactivity measured with magnetic resonance spectroscopy (MRS) and cerebral blood flow measured with arterial spin labelling (ASL) on [18F]FDG PET as a measure of cerebral glucose metabolism.

Method

123 people living with early Alzheimer’s disease who completed baseline evaluations on the evaluating liraglutide in Alzheimer’s disease trial were enrolled. Participants completed [18F]FDG PET scans with arterial input, T1 weighted MRI, single‐voxel 1HMRS, and pulsed ASL scans at Imperial College London Clinical Imaging Facility. The Totally Automatic Robust Quantitation in NMR (TARQUIN) package was used to process MRS scans and identify the concentration of myo‐inositol within the posterior cingulate cortex (PCC), a marker of glial activation. Oxford‐ASL was utilised to process ASL and quantify cerebral blood flow in the PCC. Finally, spectral analysis was performed on the [18F]FDG PET scans to assess the cerebral metabolic rate of glucose in the PCC.

Result

Pearson’s correlations were performed between the cerebral metabolic rate of glucose, cerebral blood flow and glial activity measured by the level of myo‐inositol in the PCC. Increased cerebral glucose metabolism was correlated with higher myo‐inositol in this sample of Alzheimer’s disease participants. In contrast, cerebral blood flow was not associated with cerebral glucose metabolism.

Conclusion

Here we demonstrate that increased glial reactivity contributes to [18F]FDG PET signal in the early stages of Alzheimer’s disease. In response to early neuronal injury, astrocytes and microglia may become activated and enhance regional rates of glucose consumption. Hence, the contribution from these cells in addition to neurons should be considered in interpreting [18F]FDG PET as a measure of cerebral glucose metabolism. Interestingly, cerebral blood flow did not influence glucose metabolism. Microglia and astrocyte reactivity may contribute to an increase the cerebral glucose metabolism while neuronal loss and synaptic function may contribute to lower glucose metabolism measured by [18F]FDG in the early stages of Alzheimer's disease.
A Clinical Decision‐Making Tool to Identify Red Flags for Remote Cognitive Assessment: An Expert Consensus Study from the Canadian Consortium on Neurodegeneration in Aging
Authors: Friedman Nathan , Itzhak Inbal , Desmarais Philippe , Fisk John D , Lee Linda , Henri‐Bhargava Alexandre , Pettersen Jacqueline , McLaughlin Paula M , Ismail Zahinoor , Khanassov Vladimir , Freedman Morris , Chertkow Howard , Camicioli Richard , O'Connell Megan E , Geddes Maiya R.
Published: January 2025

Background

Remote diagnostic assessment of cognitively impaired individuals offers numerous potential benefits including increased access to care. However, remote cognitive and behavioral assessment also has limitations, and may not be appropriate for certain patients. Currently, evidence‐based guidance on virtual assessment readiness is lacking. Our goal was to develop a clinical decision‐making tool that outlines an approach to determining a patient’s suitability for undergoing remote cognitive and behavioral diagnostic assessment by identifying ‘red flags’ for remote assessment. To address this goal, a multidisciplinary workgroup was convened under the auspices of the Canadian Consortium on Neurodegeneration in Aging (CCNA). This workgroup was composed of experts in remote assessment and included behavioral neurologists, neuropsychiatrists, neuropsychologists, social workers, geriatricians, persons with lived experience and family medicine specialists.

Methods

The Delphi process is an iterative, systematic, group consensus method, used here to determine the features of the patient, caregiver, clinician and context/situation, or ‘red flags’, indicating that a remote cognitive diagnostic assessment should be avoided. The process consisted of anonymized data collection in three rounds among the multidisciplinary expert workgroup, culminating in two rounds of iterative scoring of potential red flags based on three quality indicators that assessed a potential red flag’s effectiveness, reproducibility, and efficiency. Red flags that received an overall mean score above the pre‐determined consensus threshold on the final round were included in the final clinical decision‐making tool.

Result

In the first round, 11 respondents, with an average of 12.4 years of clinical experience, generated 67 unique potential red flags. In the second and third rounds, 8 and 9 respondents, respectively, scored the flags on the three quality indicators. Applying consensus criteria yielded 14 red flags that achieved consensus.

Conclusion

To enhance the translation and implementation of these findings, we developed a clinical decision‐making tool and infographic describing the final set of red flags in collaboration with the CCNA knowledge translation team. This infographic is designed to help clinicians determine a patient’s readiness to undergo remote cognitive assessment. This study directly impacts the clinical care of cognitively impaired individuals by providing clinical decision‐making guidance on a patient’s suitability for remote neurobehavioral assessment.
A Review of Dementia Patients in a Local Neuro‐cognitive Clinic
Authors: LAI King Son
Published: January 2025

Background

It is more ideal to manage dementia patients in memory clinics but not all of them are referred to such clinics. Also, the characteristics of these patients are less studied and local published data is limited. In 2004, the Neuro‐cognitive Clinic of Alice Ho Miu Ling Nethersole Hospital was established. Situated inside the Geriatric Day Hospital, this clinic receives full support from other allied health departments (e.g. physiotherapy and occupational therapy departments). It serves patients living in the district presenting with neuro‐cognitive problems, who are attended by geriatric specialists or higher trainees in geriatric medicine under specialists’ supervision.

Objective and Method

It is a retrospective study to analyse the characteristics of patients attending this clinic in the past 10 years and their changes in function over time. The demographic data, medical comorbidities, mobility status, functional level, neuro‐cognitive and neuro‐psychiatric functions of the patients at our clinic were reviewed and the changes over three years were analysed.

Results

Among the 320 patients of age 65 or above, over 60% were female. More than 90% of them presented with memory deficit as the chief complaint. Alzheimer’s disease (AD) was the commonest dementia subtype, representing nearly half of all the cases, and was followed by mixed dementia and vascular dementia. The mean MMSE score at initial presentation was 16.4. Hypertension, hyperlipidaemia, diabetes mellitus and history of cerebrovascular diseases (stroke) were common medical comorbidities. Nearly all patients had an initial radiological neuroimaging for evaluation, mostly computed tomography scan of the brain. While findings of small vessel disease, lacunar infarcts and periventricular ischaemia largely predominated in vascular dementia patients (83.0%), such findings were also found substantially in AD patients (50.3%) in contrast to cerebral atrophy (18.3%) and normal (25.5%). More than half of all patients were prescribed with anti‐dementia drugs. AD patients taken anti‐ dementia drugs showed a slower decline of MMSE score at three years than those without anti‐dementia drugs.

Conclusion

This study provided some important data on the characteristics of dementia patients in a local neuro‐cognitive clinic in various aspects, and many of them were comparable with other published international studies.
Comparison of plasma ALZpath p‐Tau217 with Lilly p‐Tau217 and p‐Tau181
Authors: Bali Divya , Janelidze Shorena , Salvadó Gemma , Serrano Geidy E , Beach Thomas G. , Jeromin Andreas , Hansson Oskar
Published: January 2025

Background

There is an urgent need for accurate and validated methods to measure plasma phosphorylated tau (p‐Tau) biomarkers in Alzheimer´s disease (AD). Here we compared the performance of newly developed plasma ALZpath p‐Tau217 assay to other established p‐Tau assays such as Lilly p‐Tau217 and Lilly p‐Tau181.

Method

We included 72 participants from the Arizona Study of Aging and Neurodegenerative Disorders cohort, where we analysed antemortem collected plasma samples with ALZpath p‐Tau217 as well as Lilly p‐Tau217 and p‐Tau181. The plasma biomarkers were compared with relevant post‐mortem neuropathological measures.

Result

We found that ALZpath p‐Tau217 correlated significantly with Lilly p‐Tau217 and Lilly p‐Tau181. ALZpath p‐Tau217, Lilly p‐Tau217 and Lilly p‐Tau181 were found to be significantly associated with plaque (ρ=0.58, ρ=0.78, ρ=0.65; p<0.001) and tangle (ρ=0.26, ρ=0.51, ρ=0.37; p<0.05) load, when adjusting for age, sex and time of interval between blood sampling and death (Table 1). All the three biomarkers were also found to be significantly associated with plaque load (r=0.53, r=0.73 and 0.59; p<0.001), when adjusting for tangle load. However, only Lilly p‐Tau217 was significantly associated with tau tangle load (r=0.32, p=0.007), when adjusting for plaques. The correlations of ALZpath p‐Tau217 and Lilly p‐Tau181 with plaque load were comparable but Lilly p‐Tau217 exhibited significantly higher correlations with plaques (ρdiff =0.20; p=0.015) and tangles (ρdiff =0.29; p=0.003) than ALZpath p‐Tau217. ALZpath p‐Tau217 and Lilly p‐Tau181 predicted the elevated levels of ADNC, tangle, and amyloid pathology with similar accuracy (AUCrange, 0.74‐0.79) but the AUC´s of Lilly p‐Tau217 were significantly higher in comparison to ALZpath p‐Tau217 (ADNC, AUCdiff=0.12, pdiff=0.021; Braak, AUCdiff=0.08, pdiff=0.021; CERAD, AUCdiff=0.11, pdiff=0.024) (Figure 1). When looking at the changes in biomarker levels for non‐AD pathologies, we found that only Lilly p‐Tau217 was significantly higher in participants with both AD and cerebral amyloid angiopathy (CAA) pathology in comparison to those with only AD and CAA pathology (Figure 2).

Conclusion

ALZpath p‐Tau217 exhibited similar performance as Lilly p‐Tau181, but in this cohort associations between ALZpath p‐Tau217 and the core measures of AD pathology were significantly lower in comparison with Lilly p‐tau217. These findings will need to be replicated in larger independent cohorts.
BDNF Val66Met influences the mediation of sex differences in VLM scores by plasma BDNF in a cohort enriched with risk for Alzheimer‘s disease
Authors: Edmunds Kyle J , Mamlouk Gabriella M , Lose Sarah R , Asthana Sanjay , Sager Mark A. , Stremlau Matthew , Johnson Sterling C. , van Praag Henriette , Okonkwo Ozioma C
Published: January 2025

Background

Brain‐derived neurotrophic factor (BDNF)—a key neurotrophin involved in synaptic plasticity, neurogenesis, and neuroprotection—has been shown to mediate sex differences in verbal learning and memory (VLM) ability, but it remains unclear whether this relationship is conditionally dependent upon carriage of the Val66Met polymorphism in the BDNF gene. This study investigates how BDNFVal66Met carriage influences the mediation of sex differences in VLM scores by plasma BDNF levels in a cohort enriched for AD risk.

Method

Cognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=198, age 63.8±6y, 66% women, 66% family history of AD, 38% apolipoprotein E4 (APOE‐ε4) carriers, 31% BDNFVal66Met carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from learning trials 3‐5 and the delayed recall test were aggregated as a VLM performance index. Plasma BDNF levels were measured using a Human BDNF Quantikine Immunoassay (R&D Systems). Striatified mediation analysis and bootstrapping were performed to test the conditional dependence of BDNF mediation on BDNFVal66Met carriage, and model covariates included age, APOE‐ε4 carriage, parental history of AD, education, hippocampal volume, and date difference between VLM and plasma data acquisition.

Result

Stratified mediation models showed a significant association between sex and VLM scores in BDNFVal66Met carriers [β=‐0.61; p=0.04], but no significant association between sex and BDNF levels [β=0.06; p=0.85]. By comparison, in BDNFVal66Val homozygotes, women had significantly higher BDNF levels [β=‐0.62; p<0.01] and VLM scores [β=‐0.77; p<0.01], and bootstrapping showed BDNF to be a significant partial mediator of the effect of sex on VLM [β=‐0.14; 95% CI: ‐.292, ‐.021].

Conclusion

This study indicates that BDNFVal66Met carriage may attenuate the mediating role of plasma BDNF expression on the relationship between sex and VLM scores.
Genetic characteristics of PUMCH dementia cohort
Authors: Dong Liling , Shang Li , Qiu Yuyue , Bao Jialu , Mao Chenhui , Chu Shanshan , Jin Wei , Peng Bin , Cui Liying , Gao Jing
Published: January 2025

Background

Dementia is prevalent over the world with unclear mechanism. Gene is supposed to play a vital role in the pathogenesis of dementia. However, the genetic basis of the majority of dementia patients is unknown.

Method

All the participants were from the dementia cohort of Peking Union Medical College Hospital (PUMCH). They all received history inquiry, cognitive evaluation, biochemical test, brain imaging and gene testing. According to the standards of American College of Medical Genetics and Genomics (ACMG), the pathogenic/likely pathogenic variants (PLPV) related to dementia were screened.

Result

2593 subjects were enrolled, including 1144 males and 1447 females. The average age was 66.8±12.1 years old. 56.3% (1461/2593) cases were early‐onset (age of onset < 65 years old), while 43.7% (1132/2593) cases were late onset. 66.4% (1722/2593) cases were APOE‐ε4 non‐carriers, and 33.6% (871/2593) cases were APOE‐ε4 carriers. 6.2% (162/2593) subjects carried the PLPV related to dementia. The NOTCH3 had the greatest mutation frequency (n=32, 1.2%), followed by the PSEN1 (n=21, 0.8%) and the CSF1R (n=13, 0.5%).

Conclusion

There is genetic diversity among the PUMCH dementia cohort, with a high mutation frequency of the NOTCH3.
Unraveling the Link Between SGLT2 Inhibition, Circulating Metabolites, and Alzheimer’s Dementia: A Mendelian Randomization Study
Authors: Yang Hao , Ning Yuye , Chen Meilin , Jia Jianping
Published: January 2025

Background

Individuals with type 2 diabetes mellitus (T2DM) face an increased risk of dementia. Recent discoveries indicate that SGLT2 inhibitors, a newer class of anti‐diabetic medication, exhibit beneficial metabolic effects beyond glucose control, offering a potential avenue for mitigating the risk of Alzheimer’s disease (AD). However, limited evidence exists regarding whether the use of SGLT2 inhibitors effectively reduces the risk of AD. Previous cohort studies encountered challenges related to potential reverse causality. Hence, our study aims to explore the impact of circulating metabolites mediating SGLT2 inhibition on AD through Mendelian randomization (MR).

Method

In this study, a two‐sample Mendelian randomization (MR) approach was employed to investigate the association between SGLT2 inhibition and AD. Genetic instruments for SGLT2 inhibition were identified based on variants associated with the expression of the SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis for T2DM validated the chosen genetic instruments. Furthermore, we explored the relationships between SGLT2 inhibition and different forms of AD (late‐onset and early‐onset AD). Two‐step MR was utilized to examine the mediation effects of circulating metabolites linking SGLT2 inhibition with AD.

Result

Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with a reduced risk of both T2DM (odds ratio [OR] = 0.36 [95% CI 0.31, 0.41], p < 0.001) and AD (0.48 [0.36, 0.63], p < 0.001). The causal relationship between SGLT2 and late‐onset and early‐onset AD was consistent (OR = 0.29 [0.14‐0.60], p = 0.001; 0.29 [0.09‐0.89], p = 0.03). Among the 123 circulating metabolites examined, citrate demonstrated significant associations with both SGLT2 inhibition and AD (0.81 [0.79, 0.83, p < 0.001]).

Conclusion

This study provides robust evidence supporting the association between SGLT2 inhibition and a reduced risk of AD. Notably, citrate levels may mediate this association, emphasizing the imperative for further investigation through randomized controlled trials.
Diagnostic Performance and Clinical Applications of a Commercial Alpha‐Synuclein Seed Amplification Assay in a Tertiary Care Memory Clinic
Authors: Porter Amanda , Lachner Christian , Tipton Philip W , Graff‐Radford Neill R , Day Gregory S
Published: January 2025

Background

SAAs represent a promising biomarker of Lewy Body disease (LBD), with high sensitivity (87.3%, 95%CI: 0.755‐0.947) and specificity (97.2%, 95%CI: 0.922‐0.994) for detection of patients in the Parkinson’s Progression Markers Initiative repository with positive DaT SPECT; and reasonable sensitivity (78.7%, 95%CI: 0.66‐0.88) and specificity (89.5%, 95%CI: 0.78‐0.96 referencing clinical diagnoses in participants included within national research repositories. However, test performance in heterogeneous clinical cohorts is unknown.

Method

Patients with typical (n=122) and rapid progressive dementia (n=76) consented to banking of CSF at the time of clinically‐indicated diagnostic lumbar puncture. Clinical data were deidentified and uploaded to a secure research database and clinical (etiologic) diagnoses established by two neurologists following independent review of available records. SAA (SYNTap™) were run on stored CSF by Amprion Diagnostics (San Diego, CA).

Result

Median participant age was 69.1 years (18.4‐86.1); 56.3% were female. CSF was sampled median 1.4 years (0‐10.3) after symptom onset. Pathological alpha‐synuclein was detected in 28/122 patients with typically progressive dementia (including 6/18 patients with presumed LBD; sensitivity 33%, specificity 79%) and 11/76 patients with rapid progressive dementia (including 3/9 patients with presumed LBD; sensitivity 33%, specificity 88%). “Positive” SAA was associated with tremor (OR=3.2, 95%CI: 1.3‐7.8), visual hallucinations (OR=6.14, 95%CI 1.6‐23.6), and REM behavior disorder (OR=3.7, 95%CI: 1.4‐9.5) in patients with typical but not rapid progressive dementia. Brain autopsies were completed in 17 patients: Lewy bodies were detected in 2/3 patients with positive SAA and no patients with negative SAA.

Conclusion

“Positive” SAA demonstrated reasonable specificity but low sensitivity for the diagnosis of LBD. Additional studies in heterogeneous cohorts with neuropathologic data are needed to optimize clinical applications of SAA.
Model‐based analysis of episodic memory retrieval in healthy aging and mild cognitive impairment
Authors: Hill Paul F , Garren Joshua D , Markham Donette C , Ekstrom Arne
Published: January 2025

Background

Episodic memory declines during healthy aging and is often reported as an early symptom of Alzheimer’s disease (AD). However, standardized assessments of memory performance are limited in their accuracy to predict progression of early‐stage AD pathology. The ‘all‐or‐none’ approach commonly used in neuropsychological assessment for quantifying memory performance might miss out on subtle variation in the fidelity or quality mnemonic representations retrieved from memory.

Methods

Thirty‐five cognitively healthy older adults and nine older adults with MCI completed five study‐test cycles of a continuous report item‐location memory task. A subsample of 21 healthy older adults performed the task while undergoing high‐resolution fMRI. During the study phase, participants viewed trial‐unique objects located around the perimeter of an invisible circle. During the test phase, old and new objects were presented in the center of the screen and participants were instructed to recall the original location of each object using a continuous analogue response dial to indicate their response. Trial‐wise distance error between the remembered and true location of each object were fit with a probabilistic mixture model to estimate two distinct memory processes that are often conflated by categorical response memory paradigms: the ability to accurately retrieve prior details from memory (i.e., retrieval success), and the fidelity of details successfully retrieved from memory (i.e., memory precision).

Results

Behavioral measures of retrieval accuracy and memory precision were significantly reduced in the MCI cohort relative to healthy older adults. Critically, we observed substantial individual differences in memory precision that were independent of retrieval success and performance on standardized assessments of verbal and visuospatial memory. Encoding‐related brain activity predictive of subsequent memory precision was evident in the left hippocampus along with robust bilateral effects in dorsomedial frontal and occipitotemporal cortices. Precision effects at retrieval were modest by comparison, yielding a single cluster in the left intraparietal sulcus.

Conclusions

Precision‐based measures of episodic memory appear to capture subtle changes in cognitive function during early stages of AD progression that cannot be readily accounted for by standardized assessments of verbal and visuospatial memory.
Temporal dynamic effects of cortical resilience proteins on trajectories of cognitive aging
Authors: Zammit Andrea R , Wang Tianhao , Yu Lei , Oveisgharan Shahram , Jager Philip L. De , Petyuk Vladislav A , Bennett David A. , Buchman Aron S
Published: January 2025

Background

In prior work we identified cortical resilience proteins associated with the linear trajectories of cognitive decline independent of the effects of neuropathology. Some of these proteins were associated with slower and some with faster cognitive decline. We tested the hypothesis that the temporal onset and duration of effects of cortical resilience proteins associated with cognitive trajectories may vary in aging adults.

Method

We used data from 1,088 older participants (31% males, mean age at death =89.7, SD = 6.4; mean education = 16.3 years, SD = 3.6) from two clinical‐pathologic studies. Participants completed a battery of 19 cognitive tests annually, underwent neuropathologic examination, and had targeted proteomic analysis performed in the dorsal lateral prefrontal cortex. To identify cortical resilience proteins, we first ran linear mixed effects models with cognitive decline as outcome, and the proteins as predictors, controlling for the effects of neuropathologic indices. To estimate the temporal effect of the identified resilience proteins on cognitive decline, we then ran functional mixed effects models, which allow i) individuals to have heterogeneous (linear and nonlinear) patterns of cognitive decline, and ii) the influence of predictors to vary flexibly over time.

Result

We identified 40 cortical resilience proteins which linear and nonlinear effects on cognitive decline spanned the entire studied trajectory of up to 25 years of follow‐up. We found that the effects of 17 proteins were significantly nonlinear: while 10 were associated with higher resilience, 7 were associated with lower resilience. The onset of effects of these proteins showed that i) the effects of higher resilience (slower rate of decline) proteins start up to 23 years before death, while the effects of the lower resilience (faster rate of decline) proteins are restricted within the last 7 years of life.

Conclusion

Multiple cortical proteins may underlie the resilience afforded by varied lifestyles and behaviors. Yet, the temporal window during which different proteins may provide cognitive resilience may vary. Different analytic techniques may be needed to elucidate the molecular mechanisms underlying cognitive resilience and their critical temporal window during later life.
Cognitive reserve is associated with the recruitment of compensatory brain networks in individuals at risk for Alzheimer’s disease
Authors: Lizarraga Aldana , Kassinopoulos Michalis , González‐de‐Echávarri José María , Huguet Jordi , Sánchez‐Benavides Gonzalo , Brugulat‐Serrat Anna , Suarez‐Calvet Marc , Milà‐Alomà Marta , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Gispert Juan Domingo , Cacciaglia Raffaele ,   ALFA study
Published: January 2025

Background

Cognitive Reserve (CR) refers to the brain's ability to maintain optimal cognitive function despite damage or pathology. The neural implementation of CR is a major research focus, and resting‐state functional connectivity (RSFC) has emerged as a promising imaging correlate of CR. We assessed RSFC as a function of two different proxy measures of CR and further assessed the impact of these brain networks on longitudinal cognitive performance in a sample of cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD).

Method

Analyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). We examined the impact of years of education (YOE) and global score of the Cognitive Reserve Questionnaire (CRQ) on the RSFC amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p<0.005, and adjusting or the effects of age, sex, and APOE status.

Result

Of the entire sample, 38.4% had positive CSF Aβ42/40 markers. YOE was related to an increased RSFC between regions of the salience network and the anterior default‐mode network (DMN). Increased negative RSFC was found as a function of YOE between primary visual areas and regions of the executive control as well as dorsal attention (Figure 1). In models adjusted by CSF biomarkers, the increased RSFC between the anterior DMN and salience regions predicted better PACC score over time and further modulated the association between CSF Aβ42/40 and longitudinal PACC (Figure 2). CRQ score was associated with a decreased RSFC between the posterior DMN and inferior temporal areas. These patterns of reduced RSFC significantly mediated the impact of CSF Aβ42/40 on longitudinal memory performance (Figure 3).

Conclusion

RSFC may provide insights into the mechanisms relating CR and cognitive resilience in preclinical AD. Further, the expression of RSFC patterns may serve as an outcome in intervention studies aiming to boost CR.
Brain metabolic alterations associated with cognitive resilience
Authors: Li Jun , Capuano Ana W. , Bennett David A. , Liang Liming , Arvanitakis Zoe , Grodstein Francine
Published: January 2025

Background

Cognitive resilience (CR) refers to the continuum from worse to better‐than‐expected cognition, given the degree of neuropathology. Understanding mechanisms underlying CR could inform discovery of novel targets for dementia prevention; however, specific metabolic pathways underlying CR are yet to be elucidated.

Methods

Our study included 484 deceased participants (mean age at death =91 years, 70.2% women) from the Religious Orders Study and Rush Memory and Aging Project. Metabolomics profiling was conducted at Metabolon Inc. by a chromatography–mass spectrometry in postmortem dorsolateral prefrontal cortex tissue, yielding 600 known metabolites quantified for analysis. Antemortem cognitive function was assessed annually by 17 neuropsychologic tests through death, and neuropathologies were evaluated in postmortem brain. CR was defined as the residual slope of cognitive decline after controlling for age at death, sex, education, and nine Alzheimer’s disease, other neurodegenerative, and cerebrovascular neuropathologies. We analyzed the associations between individual brain metabolites and CR score using linear regressions. We also constructed co‐regulatory networks for metabolites significantly related to CR, and identified key metabolites for CR within each network using recursive conditional analysis.

Results

We identified 72 metabolites whose levels in the prefrontal cortex were associated with CR (FDR<0.05), encompassing diverse biochemical categories including 33 amino acids and peptides, 21 lipids, 7 cofactors and vitamins, 6 carbohydrates/energy metabolites, and 5 others. Based on partial correlations, the 72 CR‐related metabolites were constructed into 6 co‐regulatory networks, each linked to specific biological functions including oxidative stress (key metabolites driving the associations were N‐acetylmethionine sulfoxide, ergothioneine, and carotene diol), synaptic function (led by myo‐inositol, glycerate, and docosahexaenoyl ethanolamide), neuroinflammation (led by 7‐hydroxycholesterol), cell signaling (led by inositol 1‐phosphate and gamma‐glutamylthreonine), phospholipid metabolism (led by glycerophosphorylcholine), and energy/glucose metabolism (led by UDP‐glucose and adenosine monophosphate). The eigenvectors of all 6 co‐functional networks were significantly associated with CR (FDR<0.05).

Conclusion

We identified brain metabolites implicated in oxidative stress and necroinflammation, synaptic function and cell signaling, and lipid/energy metabolism, associated with rates of cognitive decline after controlling for neuropathologies. These CR‐related metabolites may inform the discovery of novel targets for improving cognitive resilience to neuropathology.
How value‐based healthcare can improve the work of memory clinics
Authors: Schönberger Anna R. , Steinmetz Annika , Schild Ann‐Katrin , Hausner Lucrezia , Spielmann‐Benson Gloria , Frölich Lutz , Jessen Frank
Published: January 2025

Background

Value‐based healthcare (VBHC) is a novel concept derived from economic research which is recently implemented in various medical departments and facilities. Additionally to an improvement of patient care, it postulates a reduction of expenses by providing patients with what they really need. Value in this context is defined as outcomes achieved for patients relative to the required costs. In VBHC collecting patient‐reported outcome measures (PROM) and patient‐reported experience measures (PREM) is essential to clarify patients’ needs. According to the VBHC approach, a modification of patient care based on PROM and PREM achieves a higher value and more efficient treatment for patients.

We have implemented the VBHC approach at two German memory clinics to test its applicability in this novel setting. We expect to gain concrete aspects for improving the diagnostic process for patients, relatives, and employees.

Methods

In each memory clinic we interviewed 25 patient‐relative dyads with regard to PREM and PROM. In addition, we conducted an employee survey about current problems and potential suggestions for improvement. Based on these results, respective modifications of the diagnostic process took place in both memory clinics. Thereafter a second evaluation, interviewing another set of 25 dyads was carried out.

Results

In the first evaluation the majority of patients of both memory clinics quoted the length of the diagnostic process as main negative experience. The duration from the first visit to the final diagnosis took several months which was experienced as highly stressful for patients and their relatives. Hence, the diagnostic process was shortened to a duration of approx. 3‐4 weeks. In the second evaluation preliminary data indicate a significantly better experience of patients and family members with the diagnostic process (PREM) after modification. Other aspects reported by patients, relatives as well as employees offer additional perspectives for improvement.

Conclusions

This is the first study implementing the VBHC approach in a memory clinic setting. We found that VBHC can indeed improve patient care and may contribute in establishing a standardized and optimized procedure in the diagnostic processes.