bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression, Depression Treatments, and Risk of Incident Dementia: A Prospective Cohort Study of 354,313 Participants
Authors: Yang Liu , Yu Jin‐Tai
Published: January 2025

Background

To investigate the associations between courses of depression, the application of depression treatment, and the risk of incident dementia.

Method

In this prospective cohort study, 354,313 participants aged 50 to 70 years were recruited from the UK Biobank between 2006 and 2010, and were followed‐up until 2020, with a total of 4,212,929 person‐years. We initially studied the effect of depression on dementia incidence across four subgroups characterized by courses of depressive symptoms. Then, 46,820 participants with depression diagnose were further categorized into the treated and untreated groups. We compared the risks of dementia among different depression treatments groups in all participants that depressed as well as four courses of depressive symptoms by performing survival analyses.

Result

Depression was associated with a 51% higher risk of dementia, among which the increasing, chronically high and chronically low courses were associated with increased dementia risk while no association was found in the decreasing course. Compare to those who were depressed but untreated, receiving depression treatments corresponded to a hazard ratio of 0.7 (95% confidence interval = 0.62‐0.77). Among the three detrimental courses, treatments for increasing and chronically low symptoms of depression were associated with a 42% and 29% lower risk of dementia while the reduction effect for chronically high symptoms was insignificant.

Conclusion

The negative association between depression treatment and incident dementia was significant in the increasing and chronically low course, highlighting the necessity of timely interventional strategies before depression progress to a chronically severe state.
AD risk alleles elevate microglial cGAS‐associated senescence and neurodegeneration in tauopathy
Authors: Gan Li , Naguib Sarah
Published: January 2025

Background

The strongest genetic risk factors for AD include the e4 allele of APOE and the R47H point mutation in the TREM2 receptor. TREM2 is required for the induction of a disease‐associated microglia (DAM) signature and microglial neurodegenerative phenotype (MGnD) in response to disease pathology, signatures which both include APOE upregulation. There is currently limited information regarding how the TREM2‐APOE pathway ultimately contributes to AD risk, and downstream mechanisms of this pathway are unknown. The combination of AD risk factors R47H and APOE4 may help highlight the mechanisms worsening disease and contributing to increased risk in humans.

Method

There are noteworthy sex differences in AD incidence and pathology, such that a greater proportion of AD patients are women, and APOE4‐associated risk is stronger in women. We accordingly focused our studies on female mice to examine the effects of combining three substantial risk factors: R47H, APOE4, and female sex. We chose to use the P301S tauopathy model for this study because tau pathology more closely aligns with cognitive decline than Ab pathology in human patients

Result

Our study has found that the combination of APOE4 and R47H risk factors induces neurodegeneration in female tauopathy mice without significantly impacting hippocampal tau load. A previous study similarly found that R47H does not affect hippocampal tau load in the P301S model, suggesting that R47H risk is driven by disease‐enhancing microglial responses to tau, rather than by tau itself. Indeed, we find that APOE4‐R47H exacerbates microgliosis, amplifies microglial cGAS‐STING signaling and downstream IFN response pathways in a cell‐autonomous manner, and increases cGAS‐ and BAX‐dependent microglial senescence. Our study links the strongest AD risk factors, R47H, APOE4, and female sex, with microglial cGAS‐STING activation and associated senescence in a tauopathy model, highlighting these pathways as important therapeutic targets in the treatment of AD.

Conclusion

Taken together, cGAS‐STING and senescence pathways are known drivers of neurodegeneration, and our study further links upregulation of these pathways to the strongest AD risk factors. This evidence points to cGAS‐STING and senescence as vital pathological mechanisms in AD and important targets for future therapeutics.
‘Dependence’ as a meaningful patient‐focused outcome in Alzheimer’s disease: Qualitative concept elicitation and cognitive debriefing of the Dependence Scale in early symptomatic AD
Authors: Atkins Alexandra , Delbecque Laure , Elliott Emma , Heinrich Phoebe , Cano Stefan , Stern Yaakov
Published: January 2025

Background

‘Dependence’ has been proposed as a measurable health outcome reflecting the overall impact of disease progression in Alzheimer’s disease (AD). However, the meaning and relevance of ‘dependence’ in early symptomatic AD (MCI and mild AD dementia) have not been previously investigated. Aims of the current research were to (1) explore the concept of ‘dependence’ from the perspective of caregivers of patients with early symptomatic AD, (2) assess the content validity of the Dependence Scale (DS; Stern, 1994), a 13‐item scale evaluating patient dependence based on a caregiver interview, and (3) explore the relevance of newly incorporated DS rater guidance clarifying potential ambiguities in item phrasing.

Method

Concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted with caregivers of patients with confirmed diagnoses of Mild Cognitive Impairment (MCI; n = 7) or mild AD dementia (mild AD; n = 18) recruited in the US. The DS was debriefed with 19 caregivers. CE interviews explored the concept of dependence, including its meaning and relevance. Transcribed interviews were analyzed thematically, with structured codes used for CD.

Result

During CE most caregivers (n = 21) described ‘dependence’ in AD in terms of ability/lack of ability to complete tasks alone. Several (n = 16) discussed dependence in the context of concerns about leaving patients alone, citing perceived risks to physical safety or need for emotional support. Most concepts covered by the DS were discussed during interviews. During CD, some respondents (up to 42%) felt some item phrasing lacked clarity, particularly when a single response was needed to characterize functioning across multiple activities (e.g. shopping and chores); in all cases, rater guidance provides relevant clarification for use during standardized administration. Regarding content, 1 or more caregivers provided examples of patient difficulties assessed by 10 of the 13 items. Items assessing instrumental daily activities appeared most relevant, with most caregivers reporting clear examples.

Conclusion

Findings support patient dependence as a meaningful concept in AD and provide evidence supporting content validity of the DS. Most DS concepts were discussed during the interviews. Rater guidance is relevant and may mitigate the impact of perceived ambiguities in item phrasing.
Developing a machine learning stack model to forecast the progression of mild cognitive impairment to Alzheimer’s dementia, using the Australian Imaging, Biomarker & Lifestyle (AIBL) Study dataset
Authors: Chu Chenyin , Wang Yihan , Maruff Paul , Masters Colin L. , Goudey Benjamin , Jin Liang , Pan Yijun ,   The AIBL research group
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative condition, with considerable variation in disease progression from the mild cognitive impairment (MCI) stage. Predicting disease progression will support prognostic decisions and patient management. Here we designed a machine learning (ML) stack model, where a classifier was used to differentiate MCI progressors from non‐progressors (i.e. whether an individual with MCI progress to AD), and different regression models were then applied to each category to forecast their Mini‐Mental State Examination (MMSE) score after 3 years.

Method

Demographic and neuropsychological data from 2428 participants of the AIBL study was used for model construction and validation. The model was validated via a stratified 3‐fold cross‐validation approach. Support vector machine (SVM), gradian boosting (GB), random forest (RF) was experimented, and their performance were compared. MMSE score was a predicted variable indicating cognition.

Result

The performance of RF‐stack model was superior to SVM‐ and GB‐stack models. Largest area under the receiver operating characteristic curve (0.85) when RF‐stack model was employed (compared with SVM 0.79 and GB 0.70), signifying the highest accuracy in classify MCI progressors and non‐progressors. RF‐stack model achieved the best performance in predicting MMSE score after 3 years), evidenced by the smallest median mean average error (MAE) (RF 1.51, SVM 1.52, GB 2.51). The MAE indicated how much the predicted MMSE score deviated from the AIBL record. Representative prediction results from RF‐stack model for AIBL participants were presented in Table 1.

Conclusion

Our RF‐stack model relies on neuropsychological test scores and demographic data to predict the probability of an individual progressing from MCI to AD and accurately forecast the MMSE score after 3 years. This model achieved is comparable if not better prediction accuracy than the existing ML models using neuroimaging data. Further model optimization and validation using data collected from other longitudinal AD cohort studies are required.
Exploring the Potential Rescue Effects of SorCS1, a Novel Amyloid Beta Competitor, on Synaptic and Cognitive Defects in an Alzheimer’s Disease Model Mouse
Authors: Yi Nayoung
Published: January 2025

Background

Soluble Aβ oligomers (AβOs) induce synapse dysfunction, leading to cognitive impairment and memory deficits in Alzheimer’s disease (AD). Our laboratory and several research groups characterized neurexin family members' physiological roles, pivotal synaptic adhesion molecules for development, plasticity, and maintenance. Beyond their normal functions, we found neurexins binding to AβOs causes AβO‐induced neurexin dysregulation. Another group’s findings highlighted SorCS1’s role, regulating neurexin1β isoform (NRX1β) trafficking and surface expression. Our recent in vitro study showed SorCS1 competitively binds NRXβ, countering AβOs' effect, rescuing AβO‐induced NRXβ dysregulation and synaptic toxicity. NRXβ’s pivotal synaptic and brain function roles suggest SorCS1 mitigates AβO‐induced synaptic dysfunction and AD‐related deficits. We hypothesize SorCS1 stabilizes synaptic NRXβ by competitively inhibiting AβO‐NRXβ interaction.

Method

To explore SorCS1’s in vivo roles, we created a forebrain‐specific inducible SorCS1 transgenic mouse line, breeding it with 5xFAD, an AD mouse model overproducing AβOs. To achieve temporal and forebrain‐specific expression of SorCS1, SorCS1KI mice were crossed with CaMKIIa‐CreERT2 mice, allowing Cre recombinase expression upon tamoxifen treatment specifically in forebrain excitatory neurons. Through these crossings, we established four genetic groups: 1) non‐AD normal control(Male = 14, Female = 14, Total n = 28), 2) non‐AD with SorCS1 overexpression (OE) (Male = 12, Female = 15, Total n = 27), 3) AD model (Male = 11, Female = 12, Total = 23), 4) AD with SorCS1 OE rescue model (Male = 13, Female = 16, Total = 29). Structural, biochemical analyses such as immunoblot and immunohistochemistry, and behavioral tests (Morris water maze, Open field, Y‐maze) were conducted to determine SorCS1’s impact on synaptic impairment and memory deficits in AD mice.

Result

In mice overexpressing SorCS1 in the AD model (5xFAD), no significant differences were observed in long‐term spatial learning memory (assessed using the Morris water maze), locomotor activity, or anxiety levels (evaluated in the open field test) compared to the AD control group. However, SorCS1 overexpression notably improved weakened short‐term working memory (assessed via the y‐maze) in the AD mice. Furthermore, SorCS1 overexpression partially restored the expression levels of synaptic proteins, such as PSD95, GluA1, and β‐NRX in the cortex, as well as PSD95 and α‐NRX in the hippocampus within the crude synaptosome.

Conclusion

In vivo, the overexpression of SorCS1 rescues impaired levels of synaptic proteins and improves deficits in short‐term working memory.
Cognitive‐Behavioral Performance Pre‐ and Post‐Surgery in Parkinson’s Disease Patients Undergoing Deep Brain Stimulation
Authors: Fernandez Maria Cecilia , Giordano Ximena , Berrios Waleska , Barbieri Licina , Ciceri Agustina , Milicich Gaston Moreno , Cornejo Pablo Vera , Stefani Carla , Ciancaglini Lucia , Bestoso Jose , BAUSO Diego
Published: January 2025

Background

Parkinson’s Disease (PD) is known to cause cognitive and behavioral problems, especially in executive‐attentional areas. For some patients, medication is not effective, and surgery is considered a treatment option. However, changes in mood and cognition have been reported after surgical intervention in the subthalamic nucleus (STN) or the internal globus pallidus (GPi), but the literature is inconsistent. This study aims to examine PD patients' cognitive and behavioral performance before and after deep brain stimulation (DBS) surgery in a patient population from Argentina.

Method

Our study involved a retrospective analysis of 24 patients who underwent DBS surgery, half of whom received surgery in the STN area and the other half in the GPi. We evaluated cognitive function using neuropsychological tests and neuropsychiatric symptoms using the Beck Depression Inventory and Neuropsychiatric Inventory before and 1 year after the surgery. Variables of age, sex and years of education were evaluated and average values of each domain were calculated in the pre‐surgical test, to be later compared with values obtained in the post‐surgical evaluation, according to the brain nucleus operated on.

Result

The study included patients between the ages of 43 and 69 with an average education level of 10.5 years. After surgery, those who underwent STN intervention (83.3% male) showed improved executive‐attentional domains but a slight decline in visuospatial construction and semantic fluency. Behavioral improvements were observed, with a decrease in symptoms from 12.5% pre‐surgery to 2.33% post‐surgery, while mood worsened (37.5% vs. 41.7%), but not significantly. On the other hand, patients undergoing GPi intervention (83.3% male, 16.7% female) showed slight declines in memory, executive‐attentional functions, and semantic fluency but positive changes in mood‐behavioral aspects (0% and 11.1%, respectively).

Conclusion

We found that patients who underwent DBS experienced subtle changes in cognitive performance a year after surgery. While STN intervention showed improvement, those who underwent GPi intervention experienced a slight, nonsignificant decline. However, the study acknowledges that a larger sample size is needed for more substantial results.
Integrative Metabolomics and Whole Transcriptome Sequencing Reveal Role for TREM2 in Metabolism Homeostasis in Alzheimer’s Disease
Authors: Wang Meng , Qin Qi , Tang Yi
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells‐2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown.

Method

In the present study, we explored whether TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis with the help of an AD mouse model (APP/PS1). First, we performed untargeted metabolomics analysis of hippocampal tissues from APP/PS1 transgenic AD mice (APP/PS1‐TREM2 KO mice) and APP/PS1 transgenic AD mice (APP/PS1 mice), which revealed the changes of different metabolites after TREM2 knockdown. Next, we performed transcriptomic analysis to identify differentially expressed genes (DEGs). Finally, we used metabolomics and transcriptomics analysis to screen for genes associated with lipid metabolism.

Result

Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1‐TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1‐TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression.

Conclusion

TREM2 knockout was found to be associated with abnormalities in multiple metabolic pathways in AD mice, particularly lipid metabolism and glucose metabolism. Also, LPL is a novel gene that may affect lipid metabolism and sphingolipid metabolism in AD mice.
Alzheimer’s Disease (AD): Depression is associated with lower Mini‐Mental State Exam (MMSE) Scores
Authors: Komatsu Caroline
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) are core features of AD and depression is a common co‐morbidity in people with AD, affecting overall outcomes and decreasing quality of life.

Method

205 outpatients with the diagnosis of AD conforming criteria proposed by NINCDS‐ADRDA (2011), followed‐up at a public university hospital, had their Geriatrics Depression Scale – 15 (GDS ‐15) and MMSE scores evaluated.

Results

125 patients (60,97%) were diagnosed with depression and 80 patients (39,03%) were not diagnosed with depression. From the depression group, 20 patients (16%) presented severe cognitive impairment (MMSE < 10), 50 patients (40%) presented moderate cognitive impairment (MMSE = 10 – 20) and 55 patients (44%) presented mild cognitive impairment (MMSE > 20). From the non‐depression group, 10 patients (12,5%) presented severe cognitive impairment, 30 patients (37,5%) presented moderate cognitive impairment and 40 patients (50%) presented mild cognitive impairment. Both groups, depression and non‐depression, had on average the same educational level: 3,02 and 3,42 years, respectively.

Conclusion

In this sample of patients with AD, depression is associated with lower MMSE scores when compared to non‐depression group.
Adenosine receptor 1 signal mediates the high salt diet induced tau pathology and behavioral abnormalities by suppression of Cers1
Authors: Zhu Ling‐Qiang
Published: January 2025

Background

Adenosine receptor 1 (A1R) is the predominant subtype of adenosine receptors, primarily distributed in memory‐associated brain regions such as the cortex, hippocampus, and cerebellum. It actively participates in plasticity‐regulated synaptic transmission and is crucial for functions related to sleep, arousal, cognition, learning, and memory. In a recent study, we reported that an elevation in A1R signaling mediates aberrant neuron‐glial crosstalk in Alzheimer’s disease. However, the role of A1R signaling in mediating tau pathology and behavioral abnormalities induced by a high salt diet, an independent risk factor for dementia and cognitive impairment, remains unclear.

Method

We used western blot and qPCR to determine the expression of different protein and mRNAs. Morris water maze was used to examine learning and memory. Virus based shRNA delivery was used to silence the A1R and Cers1 expression

Result

Here, we first reported that the Mef2c/miR‐133a/A1R signaling pathway is activated in the hippocampus of mice treated with a high salt diet (HSD). This activation is accompanied by tau pathology and disruption of neuron‐glial crosstalk. Application of KW3902, a specific A1R antagonist, or silencing of A1R, rescued tau pathology, neuron‐derived astrocytic activation, and synaptic dysfunction in HSD mice. Furthermore, we identified that the inhibition of Cers1, resulting from the deficiency of the cAMP‐guided pathway, led to both PP2a suppression and Lcn2 release, potentially underpinning the toxic effects of A1R activation in HSD mice. Artificial overexpression of Cers1 not only ameliorated tau pathology and astrocytic activation but also alleviated synaptic and memory impairments in HSD mice.

Conclusion

Our study unveils a novel signaling pathway mediating high salt diet‐induced brain dysfunction and provides a new therapeutic target for related diseases.
Nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts
Authors: Zhou Weichen , Karan Kalpita R , Gu Wenjin , Klein Hans‐Ulrich , Sturm Gabriel , De Jager Philip L. , Bennett David A. , Hirano Michio , Picard Martin , Mills Ryan E
Published: January 2025

Background

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non‐human species and recently demonstrated to occur in rare instances from one human generation to the next.

Method

Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post‐mortem brain and blood samples from different individuals. Second, we tested the dynamic transfer of Numts using a repeated‐measures whole genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging.

Result

In the ROSMAP dataset, compared to circulating immune cells (n = 389), post‐mitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples we observed a 5.5‐fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. In the lifespan model, the longitudinal experiments revealed a gradual accumulation of one Numt every ∼13 days. Numtogenesis was independent of large‐scale genomic instability and unlikely driven cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient‐derived SURF1‐mutant cells exhibiting mtDNA instability accumulated Numts 4.7‐fold faster than healthy donors.

Conclusion

Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito‐nuclear horizontal gene transfer among human post‐mitotic tissues produces functionally‐relevant human Numts over timescales shorter than previously assumed.
Understanding the cellular responses to anti‐Abeta antibodies to gain insights into mechanisms of ARIA
Authors: Foley Kate E. , Weekman Erica M , Wilcock Donna M.
Published: January 2025

Anti‐amyloid immunotherapy holds great promise for our patients and their families as the first disease‐modifying therapy for the treatment of Alzheimer’s disease (AD) to be approved. Positive clinical trials for lecanamab and donanemab showed significant and rapid lowering of brain amyloid burden and a significant slowing of cognitive decline. Amyloid‐related imaging abnormalities (ARIA) in the form of vasogenic edema (ARIA‐E) and micro ‐ and macro‐ hemorrhages (ARIA‐H) remain the major obstacle to broad use of these agents. Significant cerebrovascular pathology precludes treatment due to enhanced risk of ARIA. In addition, it is known that ApoE4 carriers are at a significantly increased risk of ARIA incidence, with 25‐40% of homozygotes developing ARIA. Understanding the mechanisms underlying ARIA is of critical importance to increase safety and broaden the use of anti‐amyloid immunotherapy.

Using mouse models of amyloid deposition, we have performed systemic and intracranial anti‐beta‐amyloid antibody administration to study the potential mechanisms of both amyloid clearance and cerebrovascular disruptions that lead to ARIA. We have found that microglial activation is present along the vessels that are laden with cerebral amyloid angiopathy (CAA). Furthermore, coincident with microhemorrhage occurrence is increased expression and activity of matrix metalloproteinases (MMPs) MMP9 and MMP3. MMPs are known to degrade basement membranes and tight junction proteins that could lead to disruption of the blood‐brain barrier and, ultimately, edema and hemorrhage. in fact, it has long been understood that MMP9 plays a critical role in the hemorrhagic transformation of ischemic stroke. We have performed single‐cell transcriptomic analysis to examine the glial responses following a single anti‐amyloid immunotherapy and we find significant microglial population shifts and also enhanced signaling from microglia to perivascular macrophages, potentially implicating these cells as a key player in the development of ARIA.

Ultimately, discovering the mechanisms of ARIA will result in the development of safer, next‐generation antibody therapy that has reduced ARIA risk, and also could lead to the identification of adjunct treatments that can be co‐administered with the anti‐amyloid immunotherapy to prevent the occurrence of ARIA in those at risk.
The relationship between right and left hemisphere regional tau and proper name recall from Logical Memory story recall
Authors: Olson Hayley A , Langhough Rebecca E. , Bruno Davide , Hermann Bruce P , Basche Kristin E , Miess Beryl , Kaminski Noelle , Mandel Olivia , Christian Bradley T. , Johnson Sterling C. , Betthauser Tobey J. , Mueller Kimberly D
Published: January 2025

Background

Sensitive screening for early Alzheimer’s disease (AD)‐related cognitive decline are needed. Prior research links high beta‐amyloid (Aβ) levels to reduced proper name (PN) retrieval in individuals without cognitive impairment. We examined whether language‐related regional tau from PET associated with Logical Memory (LM) proper name recall, accounting for LM covariates.

Method

Participants included n = 396 from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) with Logical Memory (LM) story recall, amyloid PET ([11C]Pittsburgh Compound‐B, PiB), and [18F]‐MK‐6240 tau PET; all were unimpaired at LM baseline. Outcomes included z‐scores for LM delayed total score (“total‐LM”) and PN delayed LM subscore (“PN‐score”) from the visit most adjacent to PET‐tau imaging. Amyloid PET burden (visit adjacent to tau PET) was summarized as a global PIB DVR (PiB index, cerebellum GM reference region, graphical analysis). Left and right volume‐weighted MK‐6240 SUVR (inferior cerebellar GM reference regions) averages were calculated for regions previously associated with PN retrieval, including temporal pole, anterior temporal gyrus, anterior middle gyrus, and anterior inferior gyrus (“PN‐regional‐tau‐network”). We compared results from two ANCOVA models (L vs. R regional network as predictors) for each outcome (PN‐score, total‐LM). Covariates in each model included age at LM, sex, WRAT‐3 reading, and PiB index (to replicate prior analyses). To account for unexplained variance from global tau in entorhinal cortex, residuals from a regression of global tau on PN‐regional‐tau‐network were also included.

Result

Table 1 displays demographics overall and by tau status (T+/T‐). Overall mean age was 67 (SD = 7); n(%) = 80(20.2%) were T+. Left and right PN‐regional‐tau‐networks were significant predictors of PN‐score (β = ‐.06, R2 = .190, β = ‐.08, R2 = .192, respectively) and total‐LM (β = ‐.08, R2 = .201, β = ‐.09, R2 = .202, respectively; Table 2, Fig 1). In sensitivity analyses removing n = 23 participants with MCI or dementia, Right‐hemisphere PN‐regional‐tau (but not left) was still a significant predictor of PN‐score (β = ‐.06, R2 = .190), and L and R PN‐regional‐tau significantly predicted total‐LM (β = ‐.06, R2 = .134, β = ‐.07, R2 = .136, respectively).

Conclusion

Logical Memory story recall measures may be sensitive to tau burden in specific language regions; right hemisphere tau in the PN‐regional‐network may be particularly sensitive to early tau burden. Future directions include characterizing regional PET patterns and plasma‐biomarker‐related preclinical rates of change in these outcomes.
Deep Learning Model for Forecasting Propagation of Amyloidopathy in Alzheimer’s Disease
Authors: Jeong ByeongChang , Kim Daegyeom , Seo Surin , Lee Seung‐Hoon , Jeong Hyun‐Ghang , Han Cheol E ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Amyloid‐β accumulation is a pivotal factor in Alzheimer’s disease (AD) progression. As treatment for AD has not been successful yet, the most effective approach lies in early diagnosis and the subsequent delay of disease progression. Hence, this study introduces a deep learning model to predict amyloid‐β accumulation in the brain.

Method

We mathematically modeled the diffusion of amyloid‐β based on its biological traits, encompassing generation, clearance, and diffusion. We converted the model into a deep learning framework with multi‐layer perceptron (MLP) and graph convolutional neural network (GCN) (Kipf et al., 2016) to forecast the accumulation of the protein. We extracted the necessary information from various neuroimage data, including T1 structural magnetic resonance (MR) images, 18F‐Florbetapir positron emission tomography (PET) scans, and diffusion weighted MR images (DWI), to simulate the diffusion of the protein (Figure 1). We used longitudinal data of 146 subjects, incorporating 436 data points.

Result

The proposed model accurately predicted amyloid‐β after 2 years (Figure 2), showing a high correlation in the test dataset (median = 0.8273, IQR = [0.7708, 0.8692]), outperforming the previous model (average 0.58) (Kim et al., 2019). We examined generation and clearance terms, mapping top 30% ROIs onto the brain by averaging each term across subjects (Figure 3). The regions with early AD amyloid‐β accumulation are believed to be related to the default mode network and prefrontal network (Palmqvist et al., 2017) supported by Figure 3a. The effectiveness of amyloid‐β clearance may be influenced by brain activity (Mergenthaler et al., 2013; Ullah et al., 2023). Earlier studies reported diminished metabolism in specific regions during the early AD (Chételat et al., 2020; Kantarci et al., 2021). The proposed model identified high clearance regions (Figure 3b), aligning with regions showing normal metabolism.

Conclusion

We introduced a deep learning model that simulates the diffusion of amyloid‐β with strong predictive performance and interpretation. While parameters were optimized for the entire group, accuracy varied for some subjects. Also, further investigation is needed to interpret each term comprehensively. Despite the need for individual optimization and additional interpretative analysis, the model may contribute to the diagnosis of AD.
Efficacy and safety of computerized cognitive training combined with SSRIs for treating cognitive impairment among patients with late‐life depression: A 12‐week, randomized controlled study
Authors: Wang Xiao , Zhang Qinge
Published: January 2025

背景:Background

This randomized, open‐label study examined the therapeutic effects of computerized cognitive training (CCT) combined with selective serotonin reuptake inhibitors (SSRIs) on cognitive impairment among patients with late‐life depression (LLD).

方法: Method

Study data were collected from May 5, 2021, to April 21, 2023. Outpatients who met diagnostic criteria for major depressive disorder according to the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) criteria (HAMD‐17) ≥ 18 and a total score on the MOCA) <26 were randomly assigned to receive up to 12 weeks of CCT and SSRIs treatment (n = 57) or SSRIs and Control treatment (n = 61). The primary outcome was the change in Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) scores from baseline to week 12 between the two groups. Mixed model repeated measures (MMRM) analysis was performed on modified intention‐to‐treat (mITT) and completer populations.

结果: Result

The full analysis set (FAS) included 118 patients (CCT and SSRIs group, n = 57; SSRIs and Control group, n = 61). Over the 12‐week study period, the reduction in the ADAS‐cog total score was significant (P < 0.001) in both groups, while MMRM analysis revealed a significantly greater reduction in cognitive function (ADAS‐cog total scores) from baseline to posttreatment in the CCT and SSRIs group than in the SSRI and Control group [(F (1,115) = 13.65, least‐squares mean difference [95% CI]: −2.77 [−3.73, −1.81], p<0.001)]. There were significantly greater improvements in depression symptoms (measured by the HAMD‐17) in the CCT and SSRIs group than in the control group [MMRM, estimated mean difference (SE) between groups −3.59 [−5.02, −2.15], p < 0.001]. The least‐squares mean changes in the HAMA scores and NPI scores between baseline and week 8 were greater in the CCT and SSRIs group than in the control group (all P < 0.05). The most frequent adverse events (AEs) in both groups were dry mouth, somnolence, and constipation. There was no significant difference in the incidence of adverse events between the two groups.

结论:Conclusion

CCT combined with SSRIs was efficacious and well tolerated in LLD patients with cognitive impairment.
Everyday life episodic memory change and limbic quantitative PI‐2620 tau PET in participants with mild cognitive impairment and mild dementia
Authors: Booncharoen Kittithatch , Hiransuthikul Akarin , Thanapornsangsuth Poosanu , Thanprasertsuk Sekh , Sukprakun Chanan , Tepmongkol Supatporn , Phanthumchinda Kammant , Likitjaroen Yuttachai
Published: January 2025

Background

Episodic memory change is among the earliest symptoms of Alzheimer’s disease (AD). Accumulation of neurofibrillary tangles in limbic regions serves as a key indicator of the initial tau abnormality. This study aimed to investigate the correlations between episodic memory change and quantitative tau deposition specifically in Braak stage 3‐4 Limbic regions among participants with mild cognitive impairment (MCI) and mild dementia.

Method

Participants diagnosed with MCI and mild dementia were recruited from the memory clinic at King Chulalongkorn Memorial Hospital, Thailand. Episodic memory change was assessed using the Episodic Memory Change Score (EMCS), an informant‐based interviewing score designed to measure the severity of daily life episodic memory changes over the past 10 years, with a higher score indicating more pronounced memory impairment (Table 1). Participants underwent amyloid (Florbetaben) and tau (PI‐2620) positron emission tomography (PET) scans. amyloid PET results were defined as either amyloid‐negative (A‐) or amyloid‐positive (A+). Quantitative tau deposition was measured using the Standardized Uptake Value Ratio (SUVR). Correlations between EMCS and Braak stage 3‐4 tau SUVR were performed using Pearson’s correlation base on amyloid status (A+ and A‐).

Result

Among the 50 enrolled participants (median [interquartile range] age 72 [65‐77] years), 37 (74%) exhibited Alzheimer’s pathological changes (A+). Table 2 presents the correlation analysis between the EMCS and tau SUVR across different Braak stages. In Braak stage 3, higher EMCS significantly correlated with higher tau SUVR in A+ participants (r = 0.35, p = 0.03), but not in A‐ participants (r = 0.03, p = 0.92). In Braak stage 4, a correlation was noted, but did not reach statistical significance, between higher EMCS and increased tau SUVR in A+ participants (r = 0.20, p = 0.23) (Figure 1).

Conclusion

In participants with Alzheimer’s pathologic change, we found a significant correlation between episodic memory impairment and tau abnormality in Braak stage 3 regions, which encompass critical elements of the Papez circuit. The results suggest that EMCS could serve as a practical and easily accessible tool for early detection of tau PET positivity in A+ individuals, offering a straightforward approach for identifying Alzheimer’s‐related tau changes in a timely manner.
Sensitive methods to define subtle memory decline capture intra‐individual hippocampal atrophy and increased cortical volumes in preclinical Alzheimer’s
Authors: López‐Martos David , Cacciaglia Raffaele , Suárez‐Calvet Marc , Milà‐Alomà Marta , Minguillon Carolina , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo ,   for the ALFA study
Published: January 2025

Background

Objective Subtle Cognitive Decline (obj‐SCD) can be identified through standardized neuropsychological tests and may precede the development of Mild Cognitive Impairment (MCI). Nevertheless, current clinical and research criteria lack a standardized protocol for identifying obj‐SCD. This study introduces cutting‐edge sensitive methods to characterize obj‐SCD, defined through Alzheimer’s disease (AD) biomarker‐based longitudinal cognitive performance in episodic memory. Neurocognitive characterization of obj‐SCD is supported by Voxel‐Based Morphometry (VBM) analyses, examining longitudinal changes in Grey Matter volume (GMv) at the preclinical stage of the Alzheimer’s continuum.

Method

Three hundred cognitively unimpaired (CU) individuals (mean age: 60, SD: 4.76) from the ALFA+ cohort study (three‐year follow‐up) were included. AT(N) profiles were defined at baseline with Cerebrospinal Fluid (CSF) biomarkers. AD biomarker‐based reliable change indices adjusted for practice effect (A‐T‐[N]‐ longitudinal performance as reference) were computed for the assessment of episodic memory (Free‐Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale‐IV). Considering the relationship between the number of neuropsychological measures and the base rate of impaired scores, obj‐SCD was defined as longitudinal biomarker‐based performance below ‐1.645 SD (<5th percentile) in at least 3/11 variables. Magnetic Resonance Imaging scans were performed with 3T‐scanner and a high‐resolution 3D T1‐weighted sequence (voxel‐size: 0.75mm3). Intra‐individual changes in GMv were voxel‐wise computed using longitudinal scans, smoothed at 8mm3. The associations between obj‐SCD and GMv changes were analyzed with VBM linear regression models, selecting a voxel‐wise statistical threshold of p<0.005 with a cluster‐extent correction of 100 voxels.

Result

According to the above‐defined criteria 19 (6.33%) participants exhibited episodic memory obj‐SCD, with significant differences considering AT profiles (Table‐1). Episodic memory obj‐SCD was associated with longitudinal reductions of GMv bilaterally in the hippocampus and the left cerebellum, as well as widespread increments of GMv involving AD‐vulnerable cortical regions (Table‐2, Figure‐1).

Conclusion

Episodic memory obj‐SCD captured longitudinal changes in GMv indicative of AD‐progression (i.e., hippocampus). These results suggested that episodic memory obj‐SCD is a consistent marker of AD‐related impairment. Characterizing obj‐SCD enhances preclinical stage identification, with implications for advancing early detection and intervention strategies in Alzheimer’s disease, informing about an elevated risk of AD‐dementia in an otherwise CU population.
Neuroimaging Insights into Subjective Cognitive Decline: Unveiling Differential Sensitivity of Cognitive Change Index and Everyday Cognition Scale
Authors: Anderson John , Dadar Mahsa , Morrison Cassandra
Published: January 2025

Background

Subjective cognitive decline (SCD), or self‐perceived declines in memory/cognition in cognitively healthy older adults is linked to increased cognitive decline, neurodegeneration, and white matter hyperintensity (WMH) burden. However, there is no consistent definition of how to classify people with SCD. This study investigated if individual questions in the Cognitive Change Index (CCI) and Everyday Cognition Scale (ECog), commonly used to classify SCD, are associated with brain volume and WMHs to the same degree.

Methods

A total of 332 cognitively healthy older adults from the Alzheimer’s Disease Neuroimaging Initiative were included in this study. Partial‐least‐squares was used to analyze the data and generate a set of orthogonal latent variables (LVs) that maximize the relationship between two sets of data. The significance of each LV was assessed by comparing the obtained result to a null distribution built with 1000 permutations. The reliability of the contributions of each of the variables to the LV was assessed with 1000 bootstrap repetitions, which were used to estimate standard errors.

Results

Two significant LVs (p’s<0.001) explained 85.89% and 8.30% of the cross‐block covariance (Figure 1). The first LV shows higher SCD scores correlate with older age and fontal, parietal, and temporal WMH burden. This pattern also correlated with lower gray matter in the entorhinal cortex, and hippocampus and larger ventricles. These changes were associated with questions from only the CCI suggesting this questionnaire is more sensitive than the ECog. The second LV shows younger individuals with higher SCD scores on three CCI questions correlate with lower WMH burden in the temporal and parietal lobes and lower entorhinal cortex volumes. A PCA memory component positively correlated with the second brain LV, suggesting that lower WMH burden may predict better memory performance.

Conclusions

Our findings identified two key LVs that demonstrate that the CCI not only more sensitively detects overall neural decline but may be more sensitive to different etiologies than the ECog.
Web Application for Deciphering Alzheimer’s Disease Prediction and Progression with Explanations
Authors: Ephrem Ben George , Varghese Abraham , Sherimon Vinu , Gouda Prasanth
Published: January 2025

Background

Early detection and personalized care for Alzheimer’s Disease (AD) mitigate the devastating consequences for millions of people around the globe. In the current scenario, there is a lack of user‐friendly AI applications for predicting and understanding the progression of AD. The application should address the critical need for a predictive analytics tool that offers timely and transparent insights by utilizing the patient data. The research aims to develop an AI‐driven application for predicting and interpreting the disease progression.

Method

The application utilizes ADNI dataset, where the available patient data has been oversampled to 13752 to balance the target class. The Random Forest Classifier, a powerful machine learning technique was used to train the set of selected features including age, cognitive scores from standardized tests, and brain imaging data. Based on these inputs, the model accurately predicts an individual’s current cognitive state, categorizing them as Normal, Mild Cognitive Impairment (MCI), or Dementia. The application also utilizes the patient’s historical and current data to predict the progression from MCI to Dementia, or Normal to MCI, or remaining in the current cognitive state. The application uses LIME (Local Interpretable Model‐agnostic Explanations) and SHAP (SHapley Additive exPlanations) for transparent explanations and providing clear insights into the rationale behind interpretability in predicting each class using different visualizations.

Result

The application (https://alzheimer‐disease‐prediction‐progression‐explanations.streamlit.app/) demonstrates accuracy in both initial diagnosis and progression prediction (Figure 1). Explainable AI techniques provide user‐friendly insights into model reasoning, promoting trust and understanding (Figure 2 and 3). The user‐friendly interface facilitates data input and interpretation for both healthcare professionals and individuals.

Conclusion

The AI‐driven application emerges as a valuable tool in AD prediction and analysis. The transparent and interpretable nature of the model, facilitated by LIME and SHAP, enhances trust and understanding. Early detection and progression prediction capabilities allow healthcare professionals with timely interventions to care the patients.
Associations between performance on a non‐immersive virtual reality task and structural correlates of Alzheimer’s disease vulnerable brain regions
Authors: Holmqvist Sophia L. , Jobson Katie , Simone Stephanie M. , Tassoni Molly B. , Mckniff Moira , DeSalme Dennis , Yamaguchi Takehiko , Olson Ingrid , Martin Nadine , Giovannetti Tania
Published: January 2025

Background

Objective and sensitive measures of everyday function are needed for accurate clinical diagnosis and evaluation of outcomes in clinical trials for dementia. However, most objective everyday function measures are difficult to administer and have not been validated against biomarkers of Alzheimer’s disease (AD) neuropathology. This study evaluated the neuroimaging correlates of a highly sensitive, ecologically valid, and easily implementable performance‐based test of function called the Virtual Kitchen Challenge (VKC). VKC measures have been validated against brain‐derived markers of cerebrovascular burden in past studies, but this study investigated associations between the VKC and AD biomarkers, including cortical thickness/volume of the hippocampus and medial temporal lobe associated areas.

Methods

Twenty (n = 14 healthy control, n = 6 mild cognitive impairment) community‐dwelling and racially diverse older adults aged 60+ completed conventional neuropsychological tests, Functional Activities Questionnaire (FAQ), and VKC, which required completion of simulated breakfast and lunch tasks on a touch‐screen computer. VKC outcomes included completion time and validated measures of performance efficiency (i.e., screen interactions, proportion of time off screen). A global cognitive composite score was calculated as the average t score across neuropsychological tests. The hippocampus, entorhinal cortex, parahippocampal gyrus, inferior temporal cortex, and inferior parietal cortex were examined as Freesurfer‐derived a priori regions of interest. Partial correlations were conducted controlling for age and estimated intracranial volume.

Results

VKC outcomes were associated with entorhinal cortical thickness (VKC completion time, r = ‐.530, p = .024; time spent off screen, r = ‐.515, p = .029) and inferior temporal lobe thickness (proportion of time spent off screen, r = ‐.747, p<.001. Conventional measures were associated with bilateral hippocampal volume (global cognitive composite, r = .446, p = .064; memory composite, r = .408, p = .092; FAQ, r = ‐.538, p = .021) and parahippocampal gyrus thickness (global cognitive composite, r = .508, p = .031; FAQ, r = ‐.643, p = .004).

Conclusion

In contrast to conventional measures, VKC outcomes were significantly associated with entorhinal and inferior temporal cortex thickness, brain regions that are typically affected early in AD‐disease progression. Overall, the VKC, particularly measures of completion time and proportion of time off screen, holds promise as a highly sensitive and valid, objective measure of everyday function in a range of contexts with racially diverse older adults, including clinical assessment and clinical trials.