bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of online therapy session data to develop behavioural markers for cognitive outcomes in non‐pharmacological intervention
Authors: Li Yong , Chan Antoni , Hsiao Janet , Choy Jacky Chak Pui , Ma Maggie , Wong Gloria HY
Published: December 2023

Background

Evidence‐based non‐pharmacological interventions such as group‐based cognitive stimulation therapy (CST) involve complex interpersonal interactions based on the putative mechanism of person‐centred engagement. Empirical evidence of the hypothesised mechanism of action is lacking. Behavioural markers such as eye movement patterns can be used to predict cognitive ability. The rapid development of online interventions during the pandemic has made behavioural information such as eye movement patterns during therapy more readily available for hypothesis testing on mechanisms.

Method

We retrieve behavioural data using random time sampling of virtual CST session from people with mild to moderate dementia. Intervention characteristics of interest are frequency and relevance of self‐identity stimuli presented during the therapy session. Behavioural markers of interest are visual attention, language output, and facial expression. For visual attention, we compare subject‐independent and subject‐dependent protocols of automatic gaze estimation, using private and public (MPIIFaceGaze) dataset for pre‐training.

Results

Person‐centredness of the intervention can be operationalised based on a pre‐intervention assessment of self‐identity roles and video annotation. For determination of eye movement pattern, pretraining findings using 45,000 public train images, 6,420 private train images, and 600 private test images showed an average angle error of 9.79 using subject‐independent protocol, versus 5.91 using subject‐dependent protocol.

Conclusion

Behaviours captured on computer cameras during online therapy sessions can be automatically estimated reliably, especially with subject‐dependent protocol for eye movement and gaze analyses. This is a proof of concept for further development of behavioural markers, with advantages of simultaneously observing multiple interacting participants without Hawthrone effect and distraction in the group therapy. Further protocol finetuning using a larger data set, and models incorporating hand‐coded markers of person‐centred engagement for outcome prediction will be the next steps.
Amyloid predicts longitudinal atrophy in non‐demented individuals: Results from the AMYPAD Prognostic & Natural History study
Authors: Pieperhoff Leonard , Lorenzini Luigi , Mastenbroek Sophie E , Shekari Mahnaz , Wink Alle Meije , Wolz Robin , Grootoonk Sylke , Overduin Bert , Alves Isadora Lopes , Ritchie Craig , Boada Mercè , Marquié Marta , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Martinez‐Lage Pablo , Payoux Pierre , Visser Pieter Jelle , Schöll Michael , Frisoni Giovanni B , Stephens Andrew W. , Buckley Chris J , Farrar Gill , Jessen Frank , Grau‐Rivera Oriol , Gispert Juan Domingo , García David Vállez , Collij Lyduine E. , Barkhof Frederik ,   the AMYPAD consortium
Published: December 2023

Background

While the association between tau deposition on PET and brain atrophy on MRI is well documented in the literature, the relation between amyloid deposition and neurodegeneration in the earliest stages of Alzheimer’s disease (AD) is less studied. We investigated this relationship in a large cohort of non‐demented individuals.

Method

We included 1355 participants from the AMYPAD Prognostic & Natural History study (PNHS) with available MRI and amyloid‐PET. Among those, 753 had longitudinal MRI, with a mean follow‐up time of 3.47 years (SD = 1.55). The FreeSurfer 7.0.1 longitudinal pipeline was used to measure gray matter (GM) thickness and volumes in 40 regions (Reuter et al., 2012; Desikan et al., 2006). From PET scans, cortical amyloid burden was assessed globally using the Centiloid (CL) method. MRI‐derived regional volumes and thickness were harmonized across sites with neuroCombat (Fortin et al., 2018); all variables were Z‐scored.

Linear mixed‐effect models were used to investigate the effect of amyloid burden at baseline and its interaction with time on regional volume and thickness measurements. Models were corrected for age, sex, and CDR. P‐values were FDR‐adjusted.

Result

Cohort characteristics are shown in Table 1. Decreasing cortical thickness and volumes were observed over time in most regions. At baseline, higher amyloid burden was related to smaller volumes of the hippocampus, amygdala, putamen, and lateral ventricles; and thinner entorhinal cortex, precuneus and posterior cingulate cortex. At follow‐up, subjects with higher baseline amyloid burden showed greater loss of volume and thickness in mainly temporal and parietal regions, as well as amygdala and hippocampal volume (Figure 1).

Conclusion

In the largely asymptomatic AMYPAD PNHS cohort, we show that amyloid burden at baseline is predictive of future neurodegeneration, especially affecting temporal volume and parietal thickness. Cortical thickness was slightly more sensitive towards amyloid burden at baseline, while loss of cortical volume was greater than loss of thickness.
Genome‐wide association meta‐analysis identifies a novel LRBA locus for brain age acceleration in two independent Korean Cohorts
Authors: Kim Bo‐Hyun , Nho Kwangsik , Huang Yen‐Ning , Risacher Shannon L , Kim Jun Pyo , Yi Dahyun , Byun Min Soo , Kim Hee Jin , Won Hong‐Hee , Saykin Andrew J. , Lee Dong Young , Seo Sang Won
Published: December 2023

Background

Aging is a key risk factor for Alzheimer’s disease (AD) and has a significant structural impact on the brain. Machine learning approaches have been developed to estimate the biological age of the brain from MRI scans. Here, we performed genome‐wide association (GWA) analysis of accelerated brain aging in two independent Korean AD cohorts.

Method

Participants included 1,738 Korean older adults from two independent cohorts that consisted of preclinical and clinical stages of AD (n = 1,209 from the K‐ROAD cohort (Korea‐Registries to Overcome and Accelerate Dementia Research Project) and n = 529 from the KBASE cohort (Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease)). Brain age was estimated from structural MRI scans using brainageR. Brain age acceleration (predicted brain age ‐ chronological age) was calculated for each participant. Genetic variants associated with brain age acceleration were assessed after accounting for age, sex, APOE e4 carrier status, and diagnosis. Meta‐analysis was performed using METAL, followed by transcriptomic analysis. Polygenic risk scores for brain age acceleration were calculated with PRS‐CS using GWAS meta‐analysis summary statistics, followed by molecular imaging analysis.

Result

GWA meta‐analysis identified six intronic SNPs in the LRBA (Lipopolysaccharide responsive Beige‐like Anchor) locus on chromosome 4 as significantly associated with brain age acceleration with the most significant signal at rs7699001 (Fig. 1; p<5´10−8). LRBA is highly expressed in the brain, especially in microglia. The LRBA gene is differentially expressed in AD compared to cognitively normal older adults. rs7699001 was associated with expression levels of the LRBA gene in tissue from several organs including brain. rs7690001 has been reported to be associated with inferior parietal cortical thickness in non‐Hispanic whites (p = 5´10−3). Polygenic risk scores of brain age acceleration in the K‐ROAD cohort were significantly associated with amyloid‐β deposition measured from amyloid PET scans (Fig. 2; p = 2.7´10−4).

Conclusion

LRBA is a novel genetic risk factor for brain aging in the Korean population with relevance for AD. The microglial LRBA protein may be involved in phagocytosis, which has been implicated in aging processes and AD progression. Replication in other populations and mechanistic follow‐up studies are warranted.

This work was supported by U01AG072177.
Micro‐RNA dysregulation in brains of Alzheimer’s disease mice models: A systematic review
Authors: Quintanilla‐Sanchez Carolina , Salcido‐Montenegro Alejandro , Nagaraj Siranjeevi , Leroy Karelle ,   Alzheimer and other tauopathies research group
Published: December 2023

Background

Several dysregulated miRNAs have been reported in Alzheimer’s disease mice models. However, not all may be relevant for human cases. Therefore, a compilation and evaluation of the evidence is required, before choosing miRNAs as biomarker candidates or treatment targets.

Method

The current review is being done following PRISMA guidelines. The search in MEDLINE yielded 3952 results. After “abstract and title screening”, 319 articles passed to “full text” screening. Currently, 139 studies are being reviewed, evaluating mice model, dysregulated miRNA, brain region, miRNA extraction and analysis method, and their predicted/proven targets. Only peer review articles of in vivo mice models are being included.

Result

This is an ongoing review and the first one of its nature. From a total of 90 different dysregulated miRNAs, 4 are the most consistent in the literature: miR‐146a, miR‐181, miR‐155 and miR‐200. The expression of miR‐146 is upregulated in the hippocampus of amyloid beta (5XFAD, APPswe/PS1L166P, APPswe/PSEN1dE9) and tau models (Tau22 and 3xTg‐AD for both of them). In general, this dysregulation is observed since early stages (3‐4 months) in transgenic mice, but also in 16.6 months‐old WT animals (1‐5). Parallelly, 2 studies confirmed increased levels of miR‐146 in the blood of MCI patients and in the hippocampus of AD patients (2,4). miR ‐155 is consistently upregulated in the hippocampus and cortex of APP and tau transgenic models, as well in AD patients (3,4,6). miR‐181a is overexpressed in the hippocampus of transgenic and old WT mice (2,7), whereas miR‐181c is downregulated in the APP/PS1 and SAMP8 mice (8,9). Finally, miR‐200 is downregulated in the hippocampus of 3‐9 months‐old APP/PS1 and SAMP8 mice (10,11), while an upregulation was observed in 10 months‐old Tg2576 mice (12). All of these studies validated their results with qRT‐PCR.

Conclusion

miR‐146, miR‐181a and miR‐155 are consistently upregulated, whereas miR‐181c and miR‐200 are downregulated in the brains of different transgenic and non transgenic AD mice models at different ages. This data suggest further studies of these candidates miRNAs, as they are validated in human samples as well. However, a more robust conclusion can be made after assessing all the reported miRNAs.
Subcutaneous (SC) lecanemab is predicted to achieve comparable efficacy and improved safety compared to lecanemab IV in early Alzheimer’s disease (AD)
Authors: Willis Brian A. , Penner Natasha , Rawal Sumit , Aluri Jagadeesh , Reyderman Larisa
Published: December 2023

Background

Lecanemab is an anti‐amyloid antibody that has been approved by the United States FDA for treatment of early AD under the accelerated approval pathway. Lecanemab 10 mg/kg every 2 weeks (Q2W) intravenously (IV) was shown in the CLARITY‐AD trial to slow the progression of AD. Pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrated that lecanemab average steady‐state concentrations (Cav,ss) are associated with amyloid plaque lowering and efficacy, while maximum steady‐state concentrations (Cmax,ss) are correlated with the incidence of amyloid‐related imaging abnormalities‐edema (ARIA‐E). SC lecanemab is being developed to improve patient convenience and safety profile by lowering the rate of ARIA‐E.

Method

Two single‐dose studies (NCT05045716 and NCT05533801) were conducted in healthy subjects to establish absolute bioavailability of a drug‐in‐vial (SC vial) formulation and to compare PK of SC vial and autoinjector (AI). In the first study, subjects were administered 10 mg/kg IV Q2W or 700 mg SC vial once‐weekly (QW) lecanemab (n = 30/arm). In the second study, subjects were administered 720 mg SC vial or 720 mg AI lecanemab (n = 80/arm). Serum lecanemab concentrations were measured for 50 days, and noncompartmental PK parameters were calculated.

Result

The absolute bioavailability of SC vial was 49.7% (90%CI:43.5‐56.8). Cmax following SC vial was 22.8% of IV (59.8 vs 262 µg/mL). AI had 20% higher AUC than SC vial (20900 vs 17400 µg.h/mL). PK modeling demonstrated that Cav,ss following 720 mg QW, administered by SC vial or AI, is similar to 10 mg/kg IV lecanemab. Cmax,ss following SC vial or AI will be approximately half that of IV. Based on these results, exposure‐response models predict similar amyloid plaque lowering and efficacy for IV, SC vial and AI. ARIA‐E rates are expected to be reduced with SC formulations (APOE4 carriers, IV:14.0%, SC Vial:4.8%, AI:5.6%; APOE4 noncarriers, IV:5.4%, SC Vial:1.7%, AI:2.0%).

Conclusion

720mg QW using SC vial or AI results in comparable Cav,ss to 10 mg/kg Q2W IV lecanemab and is expected to have similar amyloid plaque lowering and efficacy. SC lecanemab has the potential to substantially lower incidence of ARIA‐E compared to IV. Ongoing studies will confirm the safety and efficacy profiles of SC lecanemab.
Burden of caregiving to people living with dementia in low‐and middle‐income countries in Asia: a systematic review
Authors: Tran Anh Tuan
Published: December 2023

Background

Home‐based care is the primary type of care given to people with dementia in Asian countries due to cultural perceptions and the limited formal dementia care support. Long‐term caregiving can lead to a high caregiver burden, further strained by limited access to caregiver support in less developed countries. It is essential to assess the level of caregiver burden and its factors in such settings to understand the impact on caregivers’ well‐being and quality of life. Aim: To synthesize the evidence on the level of caregiving burden and its factors among caregivers of people with dementia (PWDs) in LMICs in Asia.

Methods

Systematic review was conducted based on the PRISMA protocol. 71 eligible studies were identified from MEDLINE (Ovid), EMBASE (Ovid), PsyINFO (Ovid), CINAHL Plus (EBSCOhost), Cochrane Collaboration, Web‐of‐Science, and Scopus and from 2000 to 19 August 2022. Each article’s methodological quality was assessed with an appraisal checklist developed by the JBI.

Results

A total of 71 studies (12,424 caregivers) were identified from 09 LMICs (China, India, Iran, Malaysia, Pakistan, Philippines, Thailand, Turkey, and Vietnam). The caregiver burden was assessed using 10 tools, the commonest being Zarit Burden Interview (ZBI, n = 41) and Caregiver Burden Interview (CBI, n = 17). The prevalence of caregiver burden using ZBI ranged from 9.47% in Thailand to 64.57% in India. The prevalence of the burden of caregiving ranged from 25.00% in Thailand and 68.66% in China, as assessed by CBI. There were various patient characteristics (including severity and duration of dementia, Mini‐mental State Examination (MMSE) score, BPSD severity etc.) and characteristics caregiver characteristics (age, gender, education level, employment status, income, religion) associated with the burden of caregiving. Social support, positive aspects of caregiving (PAC), resilience, and intrapersonal resources were some of the moderating factors associated with caregiver burden. A meta‐analysis is still being attempted based on the homogeneity of the results.

Conclusion

Caregivers of people living with dementia in LMICs in the Asian region have a high burden of caregiving. There should be targeted interventions to alleviate the caregiver burden and to improve the quality of life of carers of people living with dementia in such countries
Prediction of short‐term MCI‐to‐AD conversion using multi‐modal neuroimaging features, and demographics
Authors: Kim Regina EY , Lee Min‐Woo , Choe Yeong Sim , Yang Hyeonsik , Lee Ji Yeon , Yong Jung Hyeon , Kim Donghyeon , Lee Minho , Kang Dong Woo , Jeon So Yeon , Son Sang Joon , Lee Young‐Min , Lim Hyun Kook , Kim Hye Weon
Published: December 2023

Background

Multi‐modality data can achieve better classification and regression performance than the use of only the single modality data. For this reason, we observed the potential of multiple data for early dementia conversion.

Method

In this study, the conversion group was defined as cases where MCI patients converted to dementia between 2 and 4 years, and T1‐weighted, T2 FLAIR, and Amyloid PET images were acquired from 4 domestic hospitals and ADNI. 114 volume features, WMH volume, and Fazekas scale were acquired from T1, T2 FLAIR images, and SUVR was calculated from amyloid PET. In addition to image features, age, sex, MMSE, and ApoE genotype were used. The 206 cases dataset was divided in a stratified way into a training set (80%) and testing set (20%), keeping the sample percentage of each class in both sets. We wanted to check the performance of each model on our dataset. The models used for this purpose were Decision Tree (DT), Random Forest (RF), Support Vector Machine (SVM), Linear Regression Classifier (LR), Gradient Boosting Model (GBM), Extreme Gradient Boosting (XGB). We trained and tuned each model, set up a grid search through hyperparameters to select a model that generalized well. The metrics used to evaluate model performance were BA, SE, SP, and AUC.

Result

Table 2 and 3 present the obtained results of all ML models for the two‐class classification task using 10‐fold cross‐validation and testing. In the case of 10‐fold cross‐validation, the model with highest mean BA was the SV model with 0.927. However, in the case of testing, we can see in Table 3 that the model with the highest BA, SE, and SP obtained was the GBM model, which was 0.917, 0.900, and 0.933, respectively. When ensemble was performed using the top3 models, BA, SE, SP, and AUC of the ensemble model were 0.917, 0.900, 0.933, and 0.963, respectively.

Conclusion

Muti‐modal neuroimaging features with minimal demographic information showed reliable results in predicting the converters and non‐converters between 2 and 4 years. This study suggests it could be utilized for future clinical trials to provide a high‐risk group for dementia conversion in advance.
Tau PET positivity comparison with visual rating, using automate quantitative method
Authors: Choe Yeong Sim , Ha Seunggyun , Kim Regina EY , Lim Hyun Kook , Kim Hye Weon
Published: December 2023

Background

Alzheimer’s disease (AD) is highly related to brain amyloid and tau deposition. PET images evaluate these patterns of amyloid and tau proteinopathy noninvasively. Tau PET is less familiar than amyloid PET to clinicians and researchers, it may occur inter‐ and intra‐observer variability to determine abnormalities in visual rating. We purposed to find optimal thresholds of tau PET, compared with visual assessment, and suggest the most appropriate standard of tau PET assessment using the assist of automated quantitative analysis of PET.

Method

101 participants were enrolled in tau (18F‐flortaucipir), amyloid (18F‐flutemetamol) PET, and a three‐dimension T1‐weighted MR image study. Each regional SUVR was calculated using SCALE PET version 1.2 (Neurophet Inc., Seoul, Republic of Korea.). Each regions‐of‐interest (ROI)‐mean SUVR of reference region (whole cerebellum (CW) and cerebellar gray matter (CG)) and quantitative Tau PET positivity was compared with visual rating results of a nuclear medicine physician. We compared accuracy of tau PET positivity driven from 1) total Braak ROI, 2) a priori ROI, and 3) whole cerebral cortical mean SUVR above 1.65 (CW, CG) or 1.30 (CG).

Result

The highest accuracy was observed 0.832 with above 1.65 mean SUVR in a priori ROI using CG reference region. False negative (FN), where participants classified as negative with mean SUVR when visually positive (FN), was 26.7%. These FN participants were mostly identified as borderline patients who were categorized to Braak III/IV (3) or V/VI (24) in visual rating. All the participants classified as tau positive in the quantitative method were amyloid positive while 54.1% were in the tau negative group. Also, the patient group composed of AD and mild cognitive impairment (MCI) participants was 96.3% in positive, behalf 55.4% in negative group. Both visual rating and quantitative classification showed a significant difference between negative and positive groups (p <0.001).

Conclusion

Visual assessment may provide more sensitive outcome than quantitative estimation, i.e., mean SUVR. Our quantitative methods of tau PET showed high accuracy with visual assessment in the regions of early Braak stage, i.e., Braak I/II/III/IV. In the future, there needed to develop more sensitive cutoff values or quantitative methods for tauopathy deposition observation.
Protective Effects of AR1001 in Alzheimer’s Disease Models: Polypharmacological Mechanisms
Authors: Kang Byung Woo , Kumar Ashish , Song Dong‐Keun , Ha Jae‐Young , Choung Jai Jun
Published: December 2023

Background

Nitric oxide/cGMP/CREB signaling is critical for learning and memory processes and is disturbed by Abeta amyoid and in Alzheimer’s disease. AR1001 is an inhibitor of phosphodiesterase (PDE)‐5, which degrades specifically cGMP, thus having a potential to reverse AD pathology.

Method

For the in vivo study, AR1001 was intraperitoneally administered (4 mg/kg/day) to APP‐C105 mice for 4 weeks. Then after behavioral tests (Morris‐water maze and passive avoidance tests) were done, hippocampal levels of Abeta1‐42 and p‐Tau (S199/202) were determined. In the in vitro study using human neuroblastoma SH‐SY5Y cells and mouse hippocampal HT‐22 cells, the effects of AR1001 on Abeta1‐42‐induced cytotoxicity and intracellular signaling were examined.

Result

AR1001 markedly improved cognitive functions in both Morris‐water maze and passive avoidance tests and reduced hippocampal Abeta1‐42 and p‐Tau levels in the APP‐C105 mice. In the in vitro experiments, AR1001 inhibited Abeta1‐42‐induced cell death, mitochondrial membrane potential derangement, and apoptotic markers (cleaved caspase‐3 and cleaved PPAR) concentration‐dependently. AR1001 reversed Abeta1‐42‐induced decrease in phosphorylated CREB (p‐CREB), and NGF/BDNF expression. Further, AR1001 blocked Abeta1‐42‐induced pSer9‐GSK3beta decrease and p25/p35 increase. Interestingly, compared with sildenafil, vardenafil and tadalafil, AR1001 was more effective in inhibiting glucocorticoid receptor (GR) dimerization and Wnt antagonist Dickkopf‐1 (Dkk‐1) expression, and in enhancing Wnt3a expression.

Conclusion

AR1001 had protective effects both in vivo and in vitro models of AD. Furthermore, AR1001 showed more pronounced activity in the modulation of GR and Wnt signaling among the various PDE‐5 inhibitors. It is suggested that the multimodal activity of AR1001 contributes to the therapeutic effects of AR1001 observed in the phase 2 clinical trial in AD patients (NCT03625622).
Classification of Alzheimer’s disease and frontotemporal dementia using electroencephalography and deep‐learning based approach
Authors: Sim Heedong , Yang Seok‐Jo
Published: December 2023

Background

A dataset[1,2] of electroencephalography(EEG) of frontotemporal dementia(FTD), alzheimer`s disease(AD) patients and healthy control(HC) were classified using convolutional neural network(CNN) and evaluated its performances

Method

EEG dataset containing 88 subjects is downsampled and sliced into 10 seconds. Total dataset was divided into train, test and validation sets for each subject. CNN structure was used to extract temporal and spatial features from EEG and classify patients into 3 groups(FTD/AD/HC). Cross entropy loss was calculated to train the model using adam optimizer. Classification performances were measured to validate model such as accuracy, confusion matrix, AUC(area under curve), F1 Score.

Result

After training, validation accuracy was 95.35% and macro‐averaged AUC was 0.9962. F1 score was 0.9469 and the minimum validation accuracy measured among subjects was 57.14% in FTD group. For AD group average accuracy was 92.79%, and for FTD group average accuracy was 97.52%. Average accuracy of healthy control group was 95.26%.

Conclusion

We implemented CNN model that can classify EEG of dementia patients with very high performances without expert‐designed feature engineering process. These results imply that deep learning based approach is most promising for EEG‐based patient classification.
Brain connectivity underlying apathy in Alzheimer’s and Parkinson’s diseases
Authors: Gazes Yunglin , Lee Seonjoo , He Ziqian , Huey Edward D. , Heron Campbell J Le , Vanegas Nora
Published: December 2023

Background

Apathy, defined as a lack of motivation towards goal‐directed behavior, is a common neuropsychiatric symptom in Alzheimer’s (AD) and Parkinson’s (PD) disease. However, the mechanism underlying apathy is still unclear. Studies have postulated that the degeneration of frontal cortical and subcortical structures may play a major role in the mechanism of apathy. This study investigates whether associations between degeneration in structural and functional connectivity between frontal and subcortical regions contributes to the development of apathetic behavior and whether these associations differ by diseases.

Method

Forty‐four patients, 8 with AD, 14 amnestic mild cognitive impairment (aMCI), and 22 PD, received MRI brain scans, a decision‐making behavioral task, cognitive and psychosocial assessments including the dimensional apathy scale (DAS). We quantified functional connectivity and white matter tract integrity for a set of frontal and subcortical regions of interest, and examined the associations among fronto‐subcortical connectivity, behavioral measures, and the DAS. These associations were tested for patient group interactions.

Result

Combining AD and aMCI into one patient group, the AD/aMCI group showed worse apathy than PD in terms of the total, the executive, and the behavioral/cognitive subscores (see Table 1), while the DAS emotional subscore was not different between the two groups. For the decision‐making task, the proportion of trial acceptance was similar between the groups, but AD/aMCI had slower decision latency than PD. Group interaction with brain measures was observed in the association between DAS total score and the functional connectivity between the right pars triangularis in the inferior frontal gyrus and the caudate (See Figure 1; interaction effect: beta = ‐.367, p = .0422 FDR corrected). The white matter tract connecting the right pars triangularis to subcortical regions also showed a group interaction with DAS total score but at an uncorrected statistical level (Figure 2; beta = 3.61, p = .0454, uncorrected).

Conclusion

Our preliminary analyses exposed phenotypic differences in apathy profiles and decision‐making behavior between AD and PD. Furthermore, the observed functional and structural neurodegenerative changes associated with higher apathy severity may also differ between the two diseases. Future analyses in a larger cohort will examine distinct neurodegeneration patterns between the two diseases.
Vascular, Imaging and Cognition Association of China (VICA) Study: Rationale and Design
Authors: Cui Mei , Wang Yingzhe , Jin Zishuo , Wang Mingqi , Dong Qiang
Published: December 2023

Background

China has the highest number of patients with dementia in the world, and about 15‐30% of these cases are caused by vascular disease. Currently, the pathophysiological mechanism that cause vascular cognitive impairment (VCI) remain insufficiently understood. Therefore, early diagnosis and prognostic indicators of VCI are critically important for managing its onset and development To this end, several Chinese institutions have joined forces to establish “Vascular, Imaging and Cognition Association of China” (VICA) (Figure 1). The objective of VICA is to identify new targets for intervention and prompting intelligent graded and stratified treatment.

Method

VICA is the first large‐scale multi‐center VCI consortium in China. It consists of seven advanced centers and over two hundred primary hospitals across the country. Included VICA are three different populations at risk for VCI: (a) high vascular risk factors for dementia, (b) cerebral small vessel disease, and (c) acute ischemic stroke or transient ischemic attacks (TIA).

Result

All individuals will be enrolled and monitored for at least 1 year using serial neuropsychological assessment, neuroimaging and collection of multi‐omics data from biospecimens (e.g., blood, urine, feces). In addition, a small sample of patients will undergo PET scans to determine whether neurodegenerative pathology (such as amyloid or tau accumulation) contributes to the course of vascular dementia. The enrollment procedure of patients with stroke or TIA is shown in Figure 2.

Conclusion

The overall scientific aim of VICA is to guide early clinical diagnosis and early intervention of VCI based on the integration of multiple vascular risk factors, neuroimaging features and biomarkers. VICA represents a unique scientific resource that will help better understand the dynamics of cognitive change in different populations and identify new potential therapeutic targets for this condition.
Aß oligomers peak in early clinical stages of Alzheimer´s disease and proceed Tau pathology
Authors: Blömeke Lara , Rehn Fabian , Kraemer‐Schulien Victoria , Kutzsche Janine , Pils Marlene , Bujnicki Tuyen , Priller Josef , Schneider Anja , Wiltfang Jens , Jessen Frank , Düzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Wagner Michael , Bannach Oliver , Willbold Dieter , Peters Oliver
Published: December 2023

Background

Aß oligomers are synaptotoxic and may initiate neurodegeneration in early stages of Alzheimer´s disease (AD).

Method

526 patients and controls from the DELCODE cohort were clinically diagnosed and afterwards neurobiologically classified using the ATN‐system. Aß and Tau oligomers were determined using the sFIDA technology.

Result

Within the AD continuum highest oligomer levels in CSF were detected in amyloid positive SCD and MCI. Aß oligomers outnumber in A+T‐ when compared to normal biomarker profile (A‐T‐) or full‐blown AD pathology (A+T+). APOE ε4 was associated with elevated Aß oligomer levels. No differences in Tau oligomers were found.

Conclusion

The appearance of Aß oligomers in CSF is an early event within the AD continuum precedeing the maximum of Tau pathology. Targeting Aß oligomers by disease modifying treatment in early disease stages might be crucial and is supposed to have the highest therapeutical potential in AD.
Tau pathway‐based gene analysis in the Alzheimer’s disease continuum identifies CLU and FYN associated with tau deposition on PET in a Korean Cohort
Authors: Yi Dahyun , Nho Kwangsik , Byun Min Soo , Jung Gijung , Ahn Hyejin , Lee Yun‐Sang , Kim Jong‐Won , Park Jong‐Ho , Liu Shiwei , Huang Yen‐Ning , Saykin Andrew J. , Lee Dong Young
Published: December 2023

Background

Abnormal tau protein aggregation and spreading in the brain is closely linked to cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). The role of genetic variation in brain tau aggregation has not been fully elucidated. Here, we performed pathway‐based candidate gene association analysis to identify novel genes associated with brain tau deposition on PET in a well‐characterized Korean AD continuum Cohort.

Method

We analyzed data for 145 older adults (69 cognitively normal (CN), 38 mild cognitive impairment (MCI), and 38 AD) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE). We selected 15 candidate genes related to both tau pathways and AD, curated from existing pathway databases, literature mining, and genome‐wide association study findings. We performed gene‐based association analysis of tau deposition measured by 18F‐AV‐1451 PET scans using PLINK. In addition, we performed whole brain voxel‐wise association analysis of identified single nucleotide polymorphisms (SNPs) to investigate their topographic distributions of differences in tau deposition across the whole brain using SPM12. We examined the interaction of the identified SNPs with APOE ε4 carrier status.

Result

Gene‐based analysis identified CLU and FYN as significantly associated with tau deposition after adjusting for multiple testing. The most significant signals originated from rs149413552 in CLU and rs57650567 in FYN. A voxel‐wise analysis for the two SNPs showed that individuals carrying at least one minor allele demonstrated greater tau throughout the temporal, parietal, and frontal lobes than individuals having no minor alleles (Fig. 1). The two SNPs were associated with greater cortical atrophy of AD‐signature regions and worse global cognition. rs149413552 in CLU was also associated with longitudinal decline in global cognition and immediate verbal memory over two years. APOE ε4 and the two SNPs appeared to exert additive effects on tau levels (Fig. 2). An interaction between rs57650567 in FYN and APOE ε4 carrier status was observed (Fig. 2)

Conclusion

CLU and FYN may play a specific role in tau pathophysiology. These risk genes may prove useful for biomarker and therapeutic development. Larger and multiethnic studies are needed to confirm these findings and to determine generalizability across populations.
The effects of a 24‐weeks resistance exercise intervention on global brain amyloid beta levels: Preliminary results of AGUEDA randomized controlled trial
Authors: Solis‐Urra Patricio , Shekari Mahnaz , Olvera‐Rojas Marcos , Fernandez‐Gamez Beatriz , Bellon Dario , Martín‐Fuentes Isabel , Peña Cristian , Gispert Juan Domingo , Erickson Kirk I. , Esteban‐Cornejo Irene
Published: December 2023

Background

Amyloid‐beta (Aβ) plaques are considered the initiating pathological hallmark of Alzheimer’s disease (AD). While animal studies suggest that physical exercise may have the potential to clear Aβ, there is limited research on humans, particularly in relation to resistance exercise. The aim of this study was to investigate the effect of a 24‐week resistance exercise program on brain Aβ accumulation in cognitively normal older adults.

Method

The study included 79 cognitively normal older adults with valid baseline and follow‐up data who were randomly assigned to either a 24‐weeks resistance exercise program (n = 42) or a wait‐list control group (n = 37) as part of the AGUEDA trial (NCT05186090) (Table 1). Participants underwent T1‐weighted Magnetic resonance imaging and [18F]Florbetaben amyloid‐PET (positron emission tomography) scans at baseline and after a 24‐weeks follow‐up period. Amyloid burden was quantified using the Centiloid (CL) method. Changes in amyloid burden between the groups were analyzed using analysis of covariance on an intention‐to‐treat basis including baseline CL values as covariate

Result

At baseline, the CL for the entire sample was 7.27 ± 25.81, and the prevalence of amyloid positivity using a 12 CL cutoff was 21.5% (n = 17, 10 women), with no significant differences between exercise and control group (p = 0.120 and 0.399, respectively). The estimated marginal mean change after 6 months was 3.51 CL for the exercise group and 1.78 CL for the control group, with no significant differences between the groups (CL group difference: 1.73 ± 1.43 SE; z‐score = 0.032), 95% confidence interval (CI): ‐1.13 to 4.59, p = 0.233).

Conclusion

The 24‐weeks resistance exercise program did not alter global amyloid brain burden in cognitively normal older adults. Further research with longer exercise interventions and different a manipulation of exercise parameters is needed to elucidate the role of exercise on brain amyloid burden in cognitively normal older adults.
The volume of the accessory‐basal nucleus of the amygdala reduces with tau pathology in AD, but remains normal in non‐AD conditions
Authors: Salman Yasmine , Malotaux Vincent , Colmant Lise , Gérard Thomas , Huyghe Lara , Boyer Emilien , Quenon Lisa , Dricot Laurence , Ivanoiu Adrian , Lhommel Renaud , Kienlen‐Campard Pascal , Hanseeuw Bernard J
Published: December 2023

Background

In AD, tau pathology starts in the medial temporal lobe, including the amygdala‐hippocampal complex. The amygdala is composed of subnuclei that until recently could not be distinguished in‐vivo. This has recently been achieved and implemented in FreeSurfer 7. We aimed to investigate the relative atrophy of the amygdala subnuclei in AD and non‐AD disorders, and to evaluate the association with tauopathy.

Methods

We recruited 131 participants who underwent 3D‐T1 brain MRI and 18F‐MK6240 tau‐PET. Amyloid status (A‐/A+) was determined using plasmatic SiMOA assays or cerebrospinal fluid analyses. The participants were classified after neuropsychological evaluation as cognitively normal (CN) individuals (n = 23 A‐CN, n = 23 A+CN), prodromal AD (n = 48 A+MCI), AD dementia (n = 24 A+dementia), or non‐AD disorders (n = 13, A‐MCI/dementia). We tested differences in the global amygdala volume, and amygdala subnuclei volumes according to clinical diagnoses and visual tau‐PET Braak‐stages. We also assessed the relationship between subnuclei volumes, cognition, and tauopathy in the temporal lobe, covarying age, sex, and global amygdala volume.

Results

We observed that the global amygdala volume was reduced in the A+MCI group compared to CN (A+/A), and further reduced in AD dementia. In contrast, A+CN and A‐CN had similar volumes (Fig.1A). The global amygdala volume was reduced in Braak III‐IV compared to 0‐I‐II. Individuals with Braak V‐VI had similar amygdala volumes than Braak III‐IV (Fig.1B). After adjusting for the global amygdala volume, only the cortical, medial, and accessory‐basal nuclei volumes were significantly reduced in A+MCI (versus A‐CN). Furthermore, the accessory‐basal nucleus volume was reduced in A+MCI/dementia group (n = 72) compared to A‐MCI/dementia (which was not different from CN ((n = 46), Fig.2). Among A+ participants, temporal tau was negatively associated with the volume of the same three nuclei and the central nucleus, even after adjusting for the amygdala volume. These subnuclei volumes were associated with cognitive performance (Fig.3).

Conclusion

The atrophy of amygdala, especially the cortical, medial, and accessory‐basal nuclei, is observed in symptomatic AD, and is associated with temporal tau pathology. Whereas the volumes of the global amygdala and most subfields are also reduced in non‐AD disorders, the volume of the accessory‐basal nucleus was reduced only in symptomatic AD patients.
Identification of Distinct and Shared Biomarkers in Cerebral Small Vessel Disease (SVD) through Proteomic Profiling of Cerebrospinal Fluid
Authors: Hristovska Ines , Kumar Atul , Binette Alexa Pichet , van Westen Danielle , Janelidze Shorena , Stomrud Erik , Palmqvist Sebastian , Ossenkoppele Rik , Mattsson‐Carlgren Niklas , Vogel Jacob W , Hansson Oskar
Published: December 2023

Background

Cerebral small vessel disease (SVD) is a cerebrovascular condition associated with age that contributes to dementia, stroke, and other neurological disorders. White matter lesions (WML), microbleeds, and infarcts are hallmarks of SVD, but their molecular mechanisms are poorly understood. The aim of this study was to investigate the CSF proteomic changes underlying the pathogenesis of SVD subtypes.

Method

We analysed CSF samples of controls and SVD patients (295 with WML, 149 with microbleeds and 64 with infarcts, total 894 subjects) from the Swedish BioFINDER‐2 study using the Olink proteomics platform, measuring 1331 proteins. To evaluate differentially expressed proteins, we used generalized linear models, including age, sex and CSF dynamics as covariates. For cell type enrichment analysis, we used scRNA‐seq data (Allen Brain Map) obtained from the middle temporal gyrus.

Result

We identified >400 CSF proteins dysregulated (pFDR<0.05) in subjects with WML and >20 proteins dysregulated in subjects with microbleeds and infarcts compared to controls. Proteins involved in the regulation of the extracellular matrix, including MMP12 (β = 0.2, p<0.0001 for WML; β = 0.07, p = 0.012 for microbleeds; β = 0.078, p = 0.004 for infarcts) and SMOC2 (β = 0.08, p<0.0001 for WML; β = 0.08, p<0.0001 for microbleeds; β = 0.04, p = 0.03 for infarcts), were significantly upregulated in all SVDs. Others were unique to a specific manifestation of SVD, including CHIT1 for microbleeds (β = 0.15, p<0.0001), and S100A4 for WML (β = 0.16, p<0.0001). Upregulated proteins associated with microbleeds were over‐represented in microglial cells (p = 0.037), but proteins associated with WML and infarcts were enriched in vascular leptomeningeal cells (VLMC) (p<0.0001). In addition, the downregulated proteins in WML were significantly enriched in glutamatergic and GABAergic neurons (p<0.0001).

Conclusion

In this study, we revealed shared and distinct proteomic signatures of WML, microbleeds, and infarcts. We uncovered distinct cell type signatures among SVDs, which indicated that microglia might be important for the occurrence of microbleeds but vascular leptomeningeal cells for WML and infarcts. In summary, these findings offer new insights into the molecular mechanisms underlying SVDs.
Clinical correlates of Dopamine transporter imaging and EEG biomarkers in Dementia with Lewy bodies
Authors: Baik Kyoungwon , Jeon Seun , Ye Byoung Seok
Published: December 2023

Background

Diagnostic value of dopamine transporter (DAT) imaging and electroencephalography (EEG) biomarkers in Dementia with Lewy bodies (DLB) is well studied, but their relationships with clinical symptoms in DLB are not elusive. We investigated the association between DAT imaging and EEG biomarkers and clinical characteristics of DLB.

Method

We evaluated the 120 patients with DLB retrospectively. Quantitative analysis of DAT imaging was performed and uptakes for caudate, putamen, and ventral striatum (VST) were assessed. Frequency of posterior dominant rhythm and theta/beta ratio (TBR) were used as EEG biomarkers. Four core clinical features of DLB were assessed. Firstly, correlation analysis between biomarkers and clinical symptoms were assessed. Regression analyses with significantly correlated biomarkers as model variable were performed to investigate the association between clinical characteristics and biomarkers. Age, sex, and education were used as covariates.

Result

Parietal TBR (B = 0.498, P = 0.023) and putaminal DAT uptake (B = ‐0.609, P = 0.010) were related to the presence of fluctuation. The severity of visual hallucination was associated with the higher parietal TBR (B = 0.391, P = 0.045) and lower DAT uptake in putamen (B = ‐0.520, P = 0.010) and. Putaminal DAT uptake was related to the presence of REM sleep behavior disorder (B = ‐0.646, P = 0.010). Severity of parkinsonism was associated with the frontal TBR (B = 3.353, P < 0.001).

Conclusion

DAT imaging and EEG biomarkers were related to the clinical symptoms in DLB differently. In addition, TBR reflects characteristics of DLB better than posterior slow activity.
Eligibility in the INTERCEPT‐AD trial: visual amyloid classification for equivocal SUVrs in early Alzheimer’s disease
Authors: Poppe Tanya , Feaster Todd , Manber Richard , Skljarevski Vladimir , Fuin Niccolo , Siemers Eric R
Published: December 2023

Background

PET tracers enable the in‐vivo measurement of amyloid in the brain and have been incorporated in eligibility criteria for clinical trials. Automated quantitative image analysis enables the calculation of a standardised uptake value ratio (SUVr) which can enable a rapid amyloid classification without requiring a visual read. However, quantitative analysis may have an equivocal range where amyloid classification does require a visual read. The range of SUVrs that is equivocal is not well understood.

Method

Participants in the INTERCEPT‐AD trial of ACU193 (Siemers et al., J Prev Alzheimers Dis. 2023;10(1):19‐24) underwent an amyloid [18F] Florbetapir PET scan and T1‐weighted MRI scans. MRIs were segmented using the LEAP algorithm (Wolz et al., NeuroImage. 2010;49(2):1316‐1325), registered to the PET image, and the global cortical average (GCA) SUVr based on brain regions typically with high amyloid load in Alzheimer’s disease (Klunk et al., Alzheimers Dement. 2015;11(1):1‐15) was calculated, using the whole cerebellum as the reference region. SUVrs greater than 1.2 were classified as amyloid positive, SUVrs less than 1.0 were classified as amyloid negative, and SUVrs in the equivocal range were assessed by visual read by trained central radiologists.

Results

Of 194 participants who underwent screening, 188 had an SUVr available from automated analysis. Of these, 64 were within the equivocal range (SUVr 1.0 – 1.2) and had a visual read performed. For PET scans in the equivocal range, 53 (83%) were classified as amyloid negative and 11 (17%) were classified as amyloid positive by visual read. Within the equivocal range, there was no difference in SUVrs between the images classified by visual read as amyloid negative or positive.

Conclusion

SUVrs may be used as an objective quantitative amyloid classification method at values > 1.2 for trial inclusion; however, in the equivocal range, the GCA SUVr did not correspond with amyloid classification based on a visual read. Further study is required to investigate the equivocal range and the use of combined quantitative measures and visual reads.
The Potential of Dendrimers as Alzheimer’s Disease Nanotherapeutics – Evidence of Antiamyloidogenic Properties Against Aβ42
Authors: Moreira Débora A. , Santos Sofia D. , Leiro Victoria , Pêgo Ana P.
Published: December 2023

Background

Today, available therapies for Alzheimer’s disease (AD) fail to modify the disease progression for the major AD clinical stages [1]. Therefore, new therapeutic approaches are an urgent need. Within nanomedicine, the use of nanomaterials, and dendrimers in particular, pose as promising AD therapies [2]. Dendrimers are globular macromolecules, with a well‐defined and hyperbranched structure, controllable nanosize (<15 nm) and multivalent surface. Due to their intrinsic characteristics, they are first‐in‐class for drug delivery as they can act as efficient and multivalent carriers of different therapeutic molecules. In addition, dendrimers can be used as a drug per se. Different types of dendrimers display antioxidant, anti‐inflammatory, anti‐prion and anti‐amyloidogenic properties [2]. With that in mind, a proprietary family of dendrimers was explored to hamper Aβ (1‐42) peptide aggregation.

Method

The dendrimer was synthesized following a divergent strategy up to generation 3 and characterized by nuclear magnetic resonance and Fourier‐transform infrared spectroscopy. To analyse the dendrimer’s effect on fibrillation, the aggregation kinetics of the Aβ (1‐42) peptide was studied by thioflavin T (ThT) in the presence of different dendrimer concentrations. The aggregates’ morphology was assessed by transmission electron microscopy. The cytotoxicity of dendrimers was evaluated in SH‐SY5Y cells by metabolic assays (resazurin).

Result

The dendrimers showed to interfere with Aβ fibrillation in a concentration‐dependent manner. Their behaviour was similar to fibrillation inhibitors that can break fibrils as well [3]. When at a lower molar ratio than Aβ, dendrimers hampered fibrillation and small/nonfibrillar aggregates were present. For a higher molar ratio (dendrimer/peptide ratio >1), they promoted Aβ fibrillation as more fibrils were present. More importantly, they were shown non‐toxic for neuroblastoma cells.

Conclusion

In conclusion, these results show that these dendrimers can interfere with Aβ fibrillation. Future studies will be performed to understand the mechanism of action of this new family of dendrimers.