bluuebunny/crossref_metadata_2025 huggingface dataset:
Perspectives of older adults and general practitioners on ageing and cognitive decline in primary care within the context of a decentralised antihypertensive dementia prevention trial
Authors: Hurden Alexandra , Anderson Craig S. , Cotter Isabella , Naismith Sharon L , Mowszowski Loren , Peters Ruth
Published: December 2023

Background

Blood pressure (BP) lowering is the most promising strategy for dementia risk reduction.1 However, few clinical trials have been designed to evaluate the impact of BP lowering on dementia as a primary endpoint, and concerns persist over harms associated with this treatment, particularly in older, frailer people.2 Community engagement will guide the design and conduct of such a trial. To gain a better understanding of concerns and potential barriers in this topic, we undertook focus group discussions with memory‐clinic patients without dementia and interviews with general practitioners to gain insights on the topics of cognitive decline, antihypertensive medications, and motivation to participate in a dementia prevention trial.

Method

Two focus groups (N = 7) with memory‐clinic participants (patients [age ≥60yr] with a history of mild cognitive and/or memory complaints without dementia and family carers of a patient with dementia) and 5 individual interviews with practitioners (metropolitan Sydney) were conducted in July 2022. Thematic analysis was used to identify recurring themes .

Result

The most common themes identified by patients included: valuing clear and timely communication from practitioners; valuing accessible options and considerations for computer‐based testing and treatment; and having fears and experience of dismissal from practitioners and peers about their ageing and declining health. Practitioners identified similar priorities of: clear and timely communication and accessibility in the context of a clinical trial; and insights into how cognitive decline is noticed and how individuals are supported, across different community contexts (i.e., social groups with higher levels of social connection and neighbourly bonds corresponded with lower perceived impact of cognitive decline). Importantly, although practitioners expressed concern for their patients, they reported that time restrictions limited the comprehensiveness of their ability to provide diagnostics and care.

Conclusion

Although limited by sample size, this study identified large issues for the conduct of clinical trials and in community dementia care. These concerns need due consideration for future trial designs and primary healthcare guidelines in the areas of dementia prevention, diagnoses, and care.

References

1. Peters et al., 2022 https://doi.org/10.1093/eurheartj/ehac584

2. Veenhuizen et al., 2021 https://doi.org/10.1093/ageing/afaa198
A Europe‐wide randomised controlled trial of hearing and vision rehabilitation in dementia: Additional findings from the SENSE‐Cog trial
Authors: Leroi Iracema , Camacho Elizabeth , Chaghil‐Boissier Nathalie , Charalambous Anna Pavlina , Connelly JP , Constantinidou Fofi , David Renaud , Elliott Rachel , Frison Eric , Hann Mark , Holden Alison , Kennelly Sean P , Lawlor Brian , Longobardi Julie , Politis Antonios , Kontogianni Evangelia , Rao Vinay Sudhindra , Reeves David , Termote Monique , Thodi Chryssoula , Worthington Mark , Yeung Wai ,   SENSE‐Cog RCT Study Group
Published: December 2023

Background

Hearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimise sensory impairment and support sensory function may be a means of improving dementia‐related outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part ‘sensory support’ intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their partners.

Method

This was a pan‐European, multi‐centre, observer blind, randomised controlled trial (RCT), of PwD with hearing and/or vision impairment and their partners. We evaluated a multi‐part complex intervention of hearing and vision rehabilitation tailored to each participant dyad, compared to care as usual (CAU). The intervention included at a minimum: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment (i.e., lighting), communication training, and signposting to other support agencies.

Result

Across 7 centres in the UK, Ireland, Greece, France and Cyprus, 291 participants with dementia were randomised from May 2018 to May 2021 to receive either ‘care as usual’, or a multi‐component sensory intervention (10 visits over 18 weeks). Mitigating strategies to adapt study procedure to the COVID‐19 pandemic were implemented. Significant difference in Quality of Life at 36 weeks was not seen; however, significant differences at 18 weeks were seen, with average DEMQoL scores being lower (poorer QoL) in the CAU group by between 2.6 and 2.7 units/ points at this time point, adjusted for covariates. The focus of this presentation will be on secondary outcomes including activities of daily living and functional ability (dementia‐ or sensory‐related) across the two groups. No serious adverse effects were related to the intervention; low grade adverse effects related to the intervention were reported by five participants only.

Conclusion

Hearing and vision support and rehabilitation in PwD living at home is a potentially important means of improving the lived experience of dementia and may represent a critical step in the diagnostic and post‐diagnostic care pathway. However, effects may not be sustained over the longer term.
Multi‐Omics Insights Into The Heterogeneity Of Depression In Alzheimer’s Disease
Authors: Chiba‐Falek Ornit , Upadhya Suraj , Lutz Michael W
Published: December 2023

Background

Depression is a common, though heterogenous, comorbidity in late‐onset Alzheimer’s Disease (LOAD) patients. Moreover, individuals with depression are at greater risk to develop LOAD. In prior work, we performed pleiotropy analysis and found shared genetic etiology between LOAD and Major Depressive Disorder (MDD), suggesting inter‐relationship between LOAD and depression symptoms. However, the underpinning genetic, epigenetic, and transcriptomic etiologies predisposing the comorbidity of depression in LOAD, are largely unknown.

Method

This work applied various bioinformatics methods including analyses of polygenic risk scores (PRS), differential gene expression and DNA‐methylation. The discovery analyses were performed using ROSMAP datasets including, genotypes, transcriptomic, DNA‐methylomic and depression diagnosis. When available the NACC dataset was used for validation. In addition, MDD‐GWAS summary statistics from the Psychiatric Genomics Consortium were used to create the PRS.

Result

We constructed PRS based on MDD‐GWAS data and assessed its performance in predicting depression onset in LOAD patients. The PRS showed marginal results in standalone models for predicting depression onset in both ROSMAP (AUC = 0.540) and NACC (AUC = 0.527). Full models, with baseline age, sex, education, and APOEε4 allele count, showed improved prediction of depression onset (ROSMAP AUC: 0.606, NACC AUC: 0.581). In time‐to‐event analysis, standalone PRS models showed significant effects in ROSMAP (P = 0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in LOAD for both datasets (P<0.001). Next, we investigated differential gene expression in LOAD patients with and without comorbid depression and didn’t reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex‐stratification, we identified 25 differential expressed genes (DEGs) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Finally, we tested differences in DNA‐methylation and found significant hypomethylation with only one CpG probe.

Conclusion

Our study is the first multi‐omics genome‐wide exploration of the genomic landscapes underlying the heterogeneity of depression in LOAD. Our developed PRS accurately predicted LOAD patients with depressive symptoms. Furthermore, we discovered sex‐dependent differences in gene expression associated with the risk of depression symptoms in LOAD. Collectively, our results have clinical implications for the diagnosis and treatment of depression in LOAD patients.
Ameliorative potential of thymoquinone in four vessel occlusion induced vascular dementia in rats
Authors: Rishitha Narahari , Muthuraman Arunachalam
Published: December 2023

Background

Vascular dementia (VaD) is a common type of dementia caused by reduction of blood flow to the brain via deprivation of brain cellular oxygen and nutrients supply. At present VaD is the second most occurring type of dementia in older adults and stoke patients. Around 55 million people have dementia globally. As per WHO survey is expected to rise to 78 million in 2030 and triple by 2050. Generally Hypo perfusion and thromboembolic events reduces the cerebral blood flow to the brain which leads to oxidative stress, hypoxia and inflammation further it causes mitochondrial dysfunction results in VaD. The current treatment for VaD relieves various unwanted side effects. However, the specific medicines with more potent and high efficacy are not explored yet. Neuro‐inflammation and oxidative stress has been widely correlated to be involved in the pathogenesis of VaD. Therefore, finding new therapeutic targets or drugs for VaD treatment is vital. Some of the herbal moieties and synthetic derivatives are reported to prevent cognitive disorders via amelioration of neurovascular disorders.

Method

Male Wistar Albino Rats (weight, 150 to 180 g), Cerebral hypo perfusion (CPH) was done in rats to create hypoxia in order to induce VaD, after the CPH all animals were treated with Thymoquinone (TQ (5 and 10mg/kg)). Invitro study of mast cell degranulation, Behavioral assessments; Biochemical markers and Histopathological evaluation.

Result

4VO cause the potential neurovascular damage leads to significant changes in learning and memory functions along with the alteration of psychosocial and neuromotor functions. Besides, Four vessel occlusion (4VO) induces the bio‐molecular changes in hippocampus. Treatment of TQ shown significant (p < 0.05) ameliorative effect against 4VO induced cerebrovascular injury, cognitive impairments, neuroinflammation in rats. It is also comparable with the reference compound donepezil treatment. In the present study, it also showed the cognitive dysfunction with alteration of learning and memory functions. And, it also psychosocial behavior.

Conclusion

Our findings suggested that TQ may be use as a future medicine for metabolic and neurotoxic associated neurovascular disorders due to its potential anti‐oxidative, anti‐lipid peroxidative, anti‐inflammatory, and acetylcholinesterase inhibitory actions.
Are serial position effect patterns in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) invariant across genders?
Authors: Suhr Julie A , Do Cardinal A. , Jankowski Adrienne A.
Published: December 2023

Background

Although more men are diagnosed with Mild Cognitive Impairment, more women are diagnosed with Alzheimer’s disease. Disparities in diagnosis may reflect a female advantage in verbal memory across the lifespan such that, when norms are collapsed across gender, women with subtle cognitive decline are not detected until further in the course of illness. Patterns of verbal memory performance, such as the serial position effect (SPE) may be invariant to gender and thus may minimize these diagnostic discrepancies. However, few studies have examined whether SPE patterns and their relationships to outcome are invariant to gender.

Method

338 adults 50 years of age or older participated in community dementia screening, which included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Average age was 66.9 years, 94% were white, and 67% identified as women. None had major neuromedical or neurodegernative diagnosis. RBANS List Learning was used to identify primacy, middle, and recency recall on Trial 1 and at delayed recall. We also calculated recency ratio (percent of recency words recalled at delay/percent recency words at Trial 1).

Result

We identified expected SPE patterns for Trial 1 and at delayed recall; the patterns were invariant to gender. Primacy at Trial 1, middle of the list at Trial 1, and recency ratio all predicted RBANS Delayed Memory Index; there was no interaction with gender. Using cluster analysis, we divided the sample into those with better primacy than recency and those with better recency than primacy at Trial 1. Those with better primacy than recency on Trial 1 did better on the Delayed Memory Index; this was not moderated by gender. SPE findings were specific to delayed memory.

Conclusion

Results show that the SPE patterns identified on longer word list learning tasks can also be identified on a cognitive screening battery. Further, although traditional memory scores showed gender disparities, SPE patterns and relationships were invariant to gender.
Genetic predisposition to Alzheimer’s disease is differentially associated with joint volumetric variations in the disease continuum
Authors: Genius Patricia , Calle Maria Luz , Cacciaglia Raffaele , Evans Tavia E , Falcon Carles , Minguillón Carolina , Adams Hieab H.H. , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia ,   for the ALFA study
Published: December 2023

Background

Imaging genetics studies commonly assess the individual association between genetic information and brain features without considering joint brain modulations. The aim of this study was to explore the structural variation of the brain at different stages of Alzheimer’s disease (AD), depending on the genetic predisposition to AD.

Method

A total of 351 cognitively unimpaired (CU) middle‐age participants from the ALFA (Alzheimer’s and FAmilies) study and 330 cognitively impaired participants from ADNI (Alzheimer’s Disease Neuroimaging Initiative) with magnetic resonance imaging scans, genetic information and CSF‐amyloid status were included. They were classified as CU Aβ‐, CU Aβ+, (mild cognitive impairment) MCI Aβ+ and AD Aβ+[Table 1]. Freesurfer was used to obtain cortical and subcortical parcellations using the Desikan‐Killiany atlas. A polygenic risk score estimating each participant’s genetic predisposition to AD (PRS‐AD) was calculated including genetic variants at the genome‐wide suggestive level (5×10‐6). Individuals were classified into high/low genetic predisposition groups. Statistical analysis was based on compositional data analysis. First, we computed the optimal multivariate brain structural variation signature (elastic net selection). Then, a logistic regression was performed to determine the association between the optimal signature and the PRS‐AD. Models were stratified by disease stage and adjusted for age and sex.

Result

Individuals at different stages on the AD continuum displayed different brain volumetric modulations associated with higher genetic predisposition to AD [Figure 1]. For instance, the optimal signature associated with an increased risk of AD was mainly characterized by increased hippocampal volumes in Aβ‐ individuals, but decreased volumes in MCI individuals along with the modulation of other temporal regions. Moreover, in AD patients at higher genetic predisposition of AD, the optimal signature was characterized by increased and decreased volumes in frontal regions (e.g. pars triangularis, lateral orbitofrontal vs. medial orbitofrontal, respectively) [Figure 2].

Conclusion

Results showed AD stage‐specific multivariate volumetric variation associated with an increased genetic risk of AD. Main results suggested that regions that modulated together, although differing according to AD stage, were implicated in the structural brain topology of specific memory networks. The analysis of the joint volumetric variation of brain subregions brings an innovative modeling perspective for neurogenetic studies of AD.
Association Between Internet Accessibility and Health Literacy among Community‐Dwelling Older Adults with Cognitive Frailty (CF) from Lower Socioeconomic Status (LES) group: A Cross‐sectional Study
Authors: Fadzil Nurul Hidayah MD
Published: December 2023

Background

The objective of this study was to determine the association between internet accessibility, health literacy and sociodemographic factors among older adults with cognitive frailty (CF) from lower socioeconomic status (LES) group.

Method

This study was a part of the AGELESS trial’s screening phase, which was conducted from October 2021 till March 2022 for developing telehealth multi‐domain intervention. The data included were sociodemographic variables, internet access and health literacy index. About 282 community‐dwelling older people aged 60 years (mean age 68.65 ± 6.52) from lower socioeconomic status (LES) participated in this study. Purposive sampling was utilized to identify cognitive frailty using Fried’s Criteria and Clinical Dementia Rating (CDR) while health literacy was measured using Health Literacy Questionnaire HLS‐M‐18 (Health Literacy Index). Linear regression was performed to analyse the sociodemographic factors influencing health literacy.

Result

In this study, we found that more participants who accessed to Internet compared to Internet non‐users, 68.1% and 31.9%, respectively. They significantly consisted of females (54.1%), married (56.8%), obtained secondary education level (61.1%) and still working (69.7%) (p<0.05). The majority of them (75.1%) utilised digital technology devices in their daily life for example smartphones (70%), computers or laptops (4.4%), followed by tablets (3.7%) which their primary functions were for family interaction and update online news, 67.8% and 31.3% respectively. In addition, Internet users among older adults with cognitive frailty from the LES group had a 3‐fold better health literacy than internet non‐users (OR 3.248, 95% CI: 1.059 – 5.436, p<0.05). Those who were married and higher education level were also the main factors influencing their health literacy in this target population (OR 2.314, 95% CI: 0.241 – 4.386, p<0.05; OR 0.494, 95% CI: 0.219 – 0.768, p<0.05).

Conclusion

Our findings imply that Internet users among older people with CF from the LES group adopted the Internet mainly for family connection and update online news. Future research should emphasize the understanding of Internet adoption as a non‐pharmalogical intervention for cognitive frailty such as telehealth or mobile health (mHealth) using specific mechanisms for instance qualitative or mixed method design.
Pilot Study of Reticular Activating System (RAS) in Mild Dementia
Authors: Ho‐yin Lai Frank , Hai Eddie , Chan Catherine
Published: December 2023

Background

Clinically, the common early symptoms of dementia include memory problems, reduced concentration, behaviour changes, apathy and withdrawal, loss of ability to do everyday tasks. These cognitive functions are mediated by the reticular activating system (RAS) that is a collection of interconnected brain nuclei that regulates wakefulness, alertness and modulate behaviors. The RAS degenerates early during Alzheimer’s disease progression in association with abnormal tau build‐up.

Method

This study aimed to explore the relationship between the RAS functioning and older people with mild grade dementia. The Kendrick Object Learning Test (KOLT) is a test of recall of everyday objects after viewing for a brief period, an immediate recall of briefly perceived visual data. The Kendrick Digit Copying Test (KDCT) is a test of speed in processing and recording information. These tests suggested cortical excitation mediated by both the RAS and the hypothalamic limbic network which deteriorate in older people with mild grade dementia.

Result

In this pilot study, 25 demented patients with mild grade dementia and 20 participants with known depression were recruited. They are matched in age (mean age 72 with sd 4.89) and shared similar demographic background. The participants were tested with the Kendrick Object Learning Test (KOLT) and the Kendrick Digit Copying Test (KDCT). To observe the short term longitudinal change of their RAS functioning, these tests were administered again 4 weeks following baseline. With regular day activity treatment, the depressive group showed improvement in KOLT (p < 0.1), but not on KDCT (p = .82). However, in the dementia group, there were no significant difference noted in both KOLT and KDCT (p < 0.5).

Conclusion

The present findings echo some findings of RAS does not function properly as in the older people with dementia. The reticular system is not compromised in group of depressive participants, there would be improvement in object learning, but no significant difference on speed in processing and recording information as measured by speed‐performance tests (KDCT). Proper and targeted rehabilitation trainings and care giving techniques could be arranged in meeting the specific patients’ needs.
The Effects of Computerized Cognitive Training on Memory Performance in Adults with Mild Cognitive Impairment or Dementia. A Systematic Review and Meta‐analysis
Authors: Chan Aaron TC , Tran Yeuk Shun Joshua , Ip Tsz Fung , Yiu Karen KL , Chan Joyce YC , Goh Wilson Wen Bin , Tsoi Kelvin KF
Published: December 2023

Background

Memory impairment is a predominant symptom in people with mild cognitive impairment (MCI) and dementia. Computerized cognitive training (CCT) has been proposed as a promising non‐pharmaceutical intervention to slow down the deterioration of cognitive functions. While previous studies have reported the benefits of CCT on global cognition, few have focused specifically on memory outcomes. Therefore, the aim of this study is to investigate the benefits of CCT on memory outcomes in adults with MCI or dementia.

Method

A literature search was conducted via the PubMed, Medline, Embase and PsycINFO databases from inception to Sept 2022. Inclusion criteria included: (1) participants with MCI or dementia, (2) CCT as one of the interventions, (3) randomized trials with a non‐CCT comparison group, and (4) studies that reported changes in memory‐related neuropsychological scores before and after the intervention. The outcomes were measures of verbal memory, visual memory and working memory. With the heterogeneous definitions of CCT, the standardized mean differences (SMD) were pooled using a random‐effects model.

Result

Thirty‐nine clinical trials with 2,010 participants with MCI or dementia were included. The mean age ranged from 44 to 83, and the percentage of males ranged from 21% to 73%. Participants with MCI that received CCT demonstrated significantly better performance in verbal memory (SMD = 0.69, 95% CI = 0.41 to 0.90), visual memory (SMD = 0.49, 95% CI = 0.14 to 0.84) and working memory (SMD = 0.42, 95% CI = 0.12 to 0.72) than the control groups. In the sub‐group analyses of different control groups, those MCI patients who received CCT demonstrated better verbal memory performance than the usual care and the active control groups, but comparable results as the paper‐and‐pencil cognitive training group. For the studies that include dementia participants, CCT effects were not significantly better than the control groups.

Conclusion

Computerized cognitive training conferred significant benefits in preserving memory function in people with MCI, while the benefits were not statistically significant in patients with dementia. This study also supports that computerized cognitive training can be enhanced by using mobile devices, gamification and immersive technologies.
Can construct specification equations help us progress the biomarker‐cognition debate in dementia?
Authors: Melin Jeanette , Göschel Laura , Teunissen Charlotte E. , Hoede Patty , Lehmann Sylvain , Fillmer Ariane , Flöel Agnes , Cano Stefan , Marquis Sarah , Pendrill Leslie
Published: December 2023

Background

Currently, there are no widely accepted causal models of how common biomarkers linked to dementia present as cognitive symptoms. In the current study, we present a methodology and preliminary findings to ascertain relations between sets of biomarkers and cognitive symptoms where memory ability was quantified by the newly developed NeuroMET Memory Metric (NMM).

Method

The sample was from the EMPIR NeuroMET cohort (n = 213 individual assessments; healthy controls [33%], subjective cognitive decline [31%], mild cognitive impairment [15%], Alzheimer’s disease [20%]). Person memory ability was measured with the NMM and the legacy test Corsi block tests (CBT), MRI and MRS biomarkers were acquired with a 7T whole‐body Magnetom MRI system and plasma biomarker levels of GFAP and pTau were measured with Simoa. To study how person memory ability can be explained, a so‐called construct specification equation (CSE) was developed using principal component regression, where person memory ability was found to depend on a linear combination of a set of explanatory co‐variables.

Result

Memory ability, ϴi, was found to depend on several biomarkers expressed by the CSE and the most promising CSE yielded was: ϴi = 7(3) + 2(1) x Cortical thickness + 1.7(5) x Hippocampus left – 0.0045(8) GFAP – 0.03(10) x pTau181 – 0.127(2) x Myoinositol – 0.8(4) x Amygdala right + 0.035 x Age. A Pearson correlation coefficient of 0.77 of memory ability based on the CSE prediction against the NMM measured memory ability was achieved. In contrast, all univariate correlations between individual biomarkers and memory ability were lower (highest for Cortical Thickness, R = 0.59) and correlations to memory ability measured with CBT was also lower (R = 0.46).

Conclusion

This study is the first to combine a metrologically validated metric derived from set of legacy memory tests with biomarker data in an attempt to better understand predictive links through CSEs. Reflecting the CSE methodology and superior accuracy of the NMM we can get more accurate and clearer understanding of how changes in biomarkers relate to changes in cognitive symptoms can contribute to the advancement in targeting novel drugs and interventions.
Systematic assessment of microRNA‐132 therapeutic targeting in Alzheimer’s disease using iPSC‐derived neurons and microglia
Authors: Penning Amber , Tosoni Giorgia , Walgrave Hannah , Snoeck Sarah , Balusu Sriram , Salta Evgenia
Published: December 2023

Background

Mapping the mechanistic heterogeneity and multifactorial nature of Alzheimer’s Disease (AD) is a key challenge for therapeutic development and the main reason why network biology and multi‐modal therapies begin to attract attention also in AD research. MiRNA‐targeted therapeutics are particularly suited for such purposes, as they regulate multiple components of several molecular cascades converging on disease‐relevant patho‐phenotypes. MicroRNA‐132 (miR‐132), a potent neuroimmune regulator, has been identified as the most robustly and significantly downregulated microRNA in the brain of AD patients and its deficiency has been functionally linked to amyloid deposition, TAU hyperphosphorylation, neuronal cell death and memory decline, in both human and rodents. Additionally, miR‐132 was recently identified as a potent regulator of adult hippocampal neurogenesis (AHN), exerting multilayered proneurogenic effects in adult neural stem cells and their progeny. Together, these observations suggest that miR‐132‐dependent network‐based gene regulation in human AD brain converges onto biological pathways that can drive disease endophenotypes. Direct miR‐132 infusion in the AD mouse brain can counteract several aspects of pathology, providing a proof‐of‐concept of its therapeutic relevance. Despite the great benefit of the multi‐targeting nature of microRNAs for treating multifactorial diseases such as AD, such approaches also entail the risk of on‐ and off‐ target toxicity, highlighting the importance of systematic genome‐wide targetome profiling. The complex multicellular miR‐132 targetome involved in AHN and the inflammatory response in AD remains elusive, and its mapping is a crucial requirement for therapeutic targeting.

Method

In order to systematically profile the mechanisms underpinning the regulatory effects of miR‐132 in AD, we employed an RNA‐sequencing approach to assess transcriptomic responses to changes in the levels of miR‐132 in AD‐relevant study systems, such as human iPSC‐derived neurons and microglia‐like cells.

Results

We identify novel miR‐132 targets with putative neuroimmune functions possibly involved in AD pathophysiology.

Conclusion

Our results shed light on the involvement of miR‐132 in AD and further add to the systematic profiling of miR‐132 targetome, a prerequisite for successful translation of miR‐132 supplementation in AD.
Perturbed glycogen metabolism is an Alzheimer’s disease therapeutic target
Authors: Gentry Matthew S.
Published: December 2023

Background

Three clinical hallmarks of AD are amyloid beta (Aβ) plaques, neurofibrillary tangles, and glucose hypometabolism. Multiple agents can decrease Aβ and tau levels, such as the recently FDA‐approved Aducanumab. However, improvements in patient cognition are disappointing and this disappointment is potentially due to a failure to normalize cerebral glucose hypometabolism.

Clinical AD symptom severity strongly correlates with the degree of glucose hypometabolism. In the brain, one route of glucose metabolism is the biosynthesis of glycogen, a branched molecule that functions as an energy cache in times of energetic stress. Importantly, glycogen is critical for neuronal function and memory formation, and defective glycogen metabolism is an underlying driver of several neurological glycogen storage disorders (GSDs). An excess glycogen phenotype was reported in AD brains in the early 1980s, but to date, little is known about its involvement in AD symptoms.

Method

In this study, we first report that AD brains have an excess glycogen phenotype and that AD glycogen correlates with disease severity in human patient samples. Furthermore, the human excess AD glycogen is phenocopied in multiple AD mouse models and the accumulation of glycogen in these mice precedes cognitive deficits. Based on rigorous and striking data, we propose glycogen as a novel target for AD therapy that warrants additional preclinical development.

Result

We developed the enzyme therapy VAL‐0417 that combines a glycogen‐degrading amylase fused to an antibody fragment that facilitates intracellular delivery of recombinant enzymes. VAL‐0417 ablates excess glycogen and rescues disease phenotypes in a fatal GSD that causes childhood dementia called Lafora disease (LD). LD mice share several phenotypes with AD mouse models, including neurotoxic glycogen accumulation. Excitingly, VAL‐0417 also degrades AD glycogen both in vitro from human patient samples and in vivo in the 5xFAD AD mouse model. Furthermore, VAL‐0417 significantly reduces Ab plaque burden in 5xFAD mice and improves hippocampal long‐term potentiation.

Conclusion

These studies suggest that targeting AD glycogen with VAL‐0417, either alone or in combination with other therapies targeting Aβ and/or tau, is an exciting and novel preclinical therapeutic target.
Machine Learning‐Based Brief Screening Instrument for Dementia: “Six‐Questions Based Dementia Screen Test”
Authors: Li Kuan‐Ying , Huang Tang‐Wei , Yen Chen‐Wen , Fang Chien Ching‐ , Huang Ling‐Chun , Yang Yuan‐Han
Published: December 2023

Background

Machine learning (ML) applied to healthcare is increasingly and it provides innovative solutions to solve complex real‐world problems. In dementia, ML has been applied to dementia detection, discriminating different types of dementia, and prediction progression of diseases. The aim of the study was to develop a new, brief clinical tool based on machine learning for dementia screening.

Method

The training data was from 533 participants (311 dementia and 202 non‐demented participants) screened with “Six‐Question Dementia Screening Test” (6Q‐DS). The 6Q‐DS contained six simple questions to evaluate mood, memory, orientation, and concentration. We used e‐Xtreme Gradient Boosting (XGBoost) algorithm, an ensemble ML based on decision trees, to establish the prediction model for dementia.

Result

A total 533 participants, 186 men and 347 women with mean age 77.6 ± 8.2 (mean± SD) years, were recruited. The dementia group was significantly older and had lower education years compared to non‐dementia group (p < 0.01 for both). The receiver‐operator characteristic (ROC) analysis showed that the area under the curve (AUC) was 0.91 for discriminating non‐dementia vs. dementia, with the sensitivity as 0.86, specificity 0.81 and accuracy 0.84. We found that the top 3 features are the second calculations for serial 3’s test, feeling of depression and the third calculations for serial 3’s test. We hypothesized that the second and third calculations required more cognitive demands because of holding information longer and depression is frequent in dementia. In our sixth question “Please count down 100 by 3 for 5 times (Serial 3’s)”, we found that the second and third calculations for serial 3’s test were important features to discriminating dementia from non‐dementia. We also found that the feeling of depression is the second important feature to distinguish dementia in our data set.

Conclusion

We proposed the new, ease‐to‐use instrument with good classification of screening dementia based on ML. The 6Q‐DS showed an acceptable accuracy with a relatively high sensitivity and specificity. Further works are warranted to validate the model in different clinical settings and disease severity.
Trajectory of cognitive performance among virologically suppressed aging people living with HIV
Authors: Hiransuthikul Akarin , Apornpong Tanakorn , Gatechompol Sivaporn , Lwin Hay Mar Su , Han Win Min , Kerr Stephen , Ubolyam Sasiwimol , Ruxrungtham Kiat , Avihingsanon Anchale ,   HIV‐NAT 006 and 207 study team
Published: December 2023

Background

Despite the success of combination antiretroviral therapy (cART), cognitive impairment remains a problem for people living with HIV (PLWH), including those who are virologically suppressed. The presentation and course of cognitive impairment have changed significantly since the introduction of cART. We aimed to determine the trajectory of cognitive performance in a cohort of virologically suppressed aging PLWH.

Method

Thai PLWH aged ≥50 years followed in the HIV‐NAT 006 cohort were enrolled during 2015‐2017 to assess cognitive performance using the Thai‐validated Montreal Cognitive Assessment (MoCA), a cutoff of ≥25 as normal. The follow‐up MoCA was consecutively performed since 2021. Participants who had plasma HIV RNA of ≤50 copies/mL and completed the follow‐up MoCA were included in the analysis. Changes in the MoCA scores were calculated between the two visits.

Result

Among 181 eligible participants (69 [38.1%] female; mean [SD] age, 57.0 [5.7] years; 46 [25.4%] had education ≤6 years; mean duration of HIV infection, 18.0 [4.2] years), 104 (57.5%) had cognitive impairment at enrollment. There were statistically significantly higher proportion of female sex (45.2% vs 28.6%, p = 0.023) and participants who had education >6 years (85.6% vs 59.4%, p<0.001) among cognitively impaired (CI) than cognitively unimpaired (CU) participants. After mean 5.6 (0.4) years of follow‐up period, the mean difference of the MoCA score was ‐0.72 (95%CI ‐1.29 to ‐0.15, p = 0.01, d = 0.19) and there were statistically significant differences in the MoCA score changes between groups categorized by baseline cognitive performance (mean difference 3.25, 95%CI 2.09 to 4.41, p<0.001, after adjusting for sex assigned at birth, age, education levels, smoking status, depression, hypertension, and diabetes mellitus).The CU group showed a statistically significant decrease in the MoCA score (mean difference ‐2.58, 95%CI ‐3.26 to ‐1.90, p<0.001, d = 0.86), and 43/77 (55.8%) of CU participants developed cognitive impairment at follow‐up, while the CI group had comparable MoCA scores between the two visits (mean difference 0.65, p = 0.09) (figure).

Conclusion

CU virologically suppressed PLWH demonstrated a statistically significant reduction in cognitive performance compared to their CI counterparts over time. Further studies on the underlying pathological mechanisms and implementation of cognitive care services among virologically suppressed PLWH are warranted.
Deciphering the Roles of the Key Oligomerization Domains in Amyloid‐β to Design Amyloid Aggregation Inhibitors
Authors: Im Dongjoon , Kim Hugh Inkon
Published: December 2023

Background

Protein folding issues are significant difficulties since they are linked to various diseases, including dementia. Fibrillar amyloid aggregates composed of misfolded proteins are pathological features of several neurodegenerative diseases. Numerous attempts have been made to treat neurodegenerative diseases by focusing on amyloid aggregates of pathologically disordered proteins. The first Alzheimer’s disease (AD) curative drug was introduced as a consequence of attempts to combat the most frequent kind of dementia. Even though antibody strategies reduce clinical deterioration in mild cognitive disease, alternate techniques must be developed over a single approach (i.e., antibody treatment). Recent studies have attempted to rationally design candidate drugs to improve existing therapeutic approaches or suppress the fibrillar amyloid aggregation process altogether. Prompted by previous findings, we rationally designed amyloid‐β (1‐42) point mutants to inhibit amyloid aggregation.

Method

We investigated the structural ensembles of the monomers using small‐angle X‐ray scattering. In addition, we performed hydrogen‐deuterium exchange mass spectrometry (MS) and ion mobility MS to elucidate the molecular principles governing Aβ42‐inhibitor interactions. We also used microsecond‐scale molecular dynamics simulations to investigate the structures and interactions, and combined them with electron transfer dissociation MS analysis to tackle challenges in identifying the multiple binding sites of intrinsically disordered protein complexes.

Result

Specifically designed mutations disrupt not only amyloid aggregation but reduce its cytotoxicity. Furthermore, we proposed minimal mutation sites to control amyloid‐β (1‐42) self‐assembly behavior. We are now determining the key domains of amyloid‐β (1‐42) that facilitate its self‐assembly to design aggregation inhibitors as potential therapeutic agents. We identified three critical hydrophobic domains (17LVF19, 32IGL34, and 41IA42) on amyloid‐β (1‐42) and investigated their role in the protein’s self‐assembly process. Our results suggest that interchain interactions in the central hydrophobic region (17LVF19) of amyloid‐β (1‐42) are essential for fibrillar aggregation and that their interaction with other domains is related to the accessibility of the central hydrophobic region for initiating the pathological cascade. Our findings shed light on the mechanisms underlying amyloid‐β (1‐42) self‐assembly and reveal key structural domains that aid in this process.

Conclusion

Our findings can be used to improve the rational design of amyloid‐β (1‐42) aggregation inhibitors in the future.
Ubiquitin‐Proteasome System in Different Staging of Dominantly Inherited Alzheimer’s Disease
Authors: Liu Haiyan , Li Yan , Hassenstab Jason J. , Gordon Brian A. , Benzinger Tammie L.S. , Timsina Jigyasha , Wang Lihua , Sung Yun Ju , Bui Quoc , Karch Celeste M. , Renton Alan E. , Cruchaga Carlos , Daniels Alisha , Morris John C , Xiong Chengjie , Perrin Richard J. , Bateman Randall J. , Llibre‐Guerra Jorge J , McDade Eric
Published: December 2023

Background

Both sporadic and dominantly inherited Alzheimer’s disease (DIAD) present with similar pathobiology and symptoms. A loss of proteostasis in AD has been identified with recent studies highlighting the role of ubiquitin‐dependent mechanisms in brain homeostasis and neurodegenerative diseases. The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via an ATP‐dependent proteolytic mechanism. This process involves a cascade of ubiquitin transfer steps from E1 to E2 to E3 ligase. However, the role of the UPS in AD progression and symptom onset remains unknown.

Method

In this cross‐sectional study we aimed to examine changes in cerebral spinal fluid (CSF) levels of UPS proteins in individuals with DIAD enrolled in the Dominantly Inherited Alzheimer Network. Sample size included 176 asymptomatic mutation carriers (MC) (Clinical Dementia Rating® [CDR®] = 0), 103 symptomatic mutation carriers [CDR®>0] and 172 non‐carriers (NC). CSF levels of UPS proteins were measured using the SOMAscan high‐throughput proteomics assay. AD biomarkers (Aβ42, Aβ40, Tau, phospho‐Tau181, phospho‐Tau205, phospho‐Tu217, and Aβ‐ PET), imaging measures of neurodegeneration (MRI, FDG PET) and clinical data (estimated years from symptom onset (EYO), CDR® score, age, sex, ApoE status) were assessed.

Result

The ubiquitin‐fold modifier‐conjugating enzyme1, ubiquitin‐conjugating enzyme E2 K, E2 N, E3 ubiquitin‐protein ligase SMURF1, and small ubiquitin‐related protein modifier 2 and 3 levels were increased in MCs up to 10‐5 years before EYO, Figure 1, with highest levels found in symptomatic MCs. E3 ubiquitin‐protein ligase SMURF1 levels began increasing up to 10‐15 years before symptoms onset. Proteasome subunit beta type‐3 (PSMB3), 4 (PSMB4) and 9 (PSMB9) showed a similar pattern as ubiquitin ligase which significantly increased in symptomatic mutation carrier group. All the above ubiquitin enzymes positively correlated with Aβ‐ PET, CSF phospho‐Tau181, phospho‐Tau205, phospho‐Tau217 and negatively correlated with FDG PET, Figure 2.

Conclusion

Our study revealed E1, E2, E3 ligase, ubiquitin‐related modifiers (SUMOs), and proteasome components were involved in DIAD pathophysiology and correlated with AD biomarkers with some increasing over 10 years before symptom onset. Further investigation of the role of UPS will be needed to explore the molecular mechanism in the progression of DIAD.
Accelerated Ovarian Failure (AOF) is an Effective Transitional Menopausal Model for the Study of Alzheimer’s Disease
Authors: Mohammad Ahmad , Finch Michael , Pyle W Glen , Rouhana Sarah , Barry Ciara , MacPherson Rebecca EK
Published: December 2023

Background

Biological females account for 70% of Alzheimer’s disease (AD) cases. It’s hypothesized that the estrogen depletion females experience during menopause is a factor in the pathogenesis of AD1. The gold standard rodent model of ovariectomy doesn’t allow for the examination of the gradual loss of estrogen that occurs in humans through perimenopause to menopause2. Administration of 4‐vinylcyclohexene diepoxide (VCD) has emerged as a rodent model of transitional menopause. The goal of this study was to determine how AD and neuronal markers were impacted by the gradual depletion of estrogen in a VCD model of transitional menopause.

Method

Mature CD1 female mice were injected with VCD (160 mg/kg/d IP for 15 days) to cause gradual ovarian failure over 120 days. A control group was also injected with a vehicle. Sample was collected at four timepoints, two representative of early and late perimenopause (60 and 120 days post injection) while the other two represented early and late menopause (137 and 176 days post injection). At each timepoint, novel object recognition testing (NORT) was performed to assess changes in behavior and memory2. At euthanasia, the prefrontal cortex and hippocampus were collected for protein analysis.

Result

The NORT demonstrated that the VCD groups at all timepoints had lowered activate memory recall. The prefrontal cortex western blotting results demonstrated that the VCD mice had lower NeuN content across all timepoints. NeuN is a marker of mature neurons which when lowered can have detrimental consequences on memory. SNAP25, a pre‐synaptic protein involved in neuronal synaptic communication, was also lower in the prefrontal cortex of VCD mice across all timepoints.

Conclusion

The VCD model had impacts on active memory recall which was accompanied by reductions in neuronal and synaptic markers. This indicates that the loss of estrogen through transitional menopause results in early changes in neuronal markers and memory.

1. Iqbal, J. & Zaidi, M. Understanding Estrogen Action during Menopause. Endocrinology 150, 3443‐3445 (2009).

2. Mohammad, A., Finch, M. S., Sweezey‐Munroe, J. & MacPherson, R. E. K. Voluntary wheel running alters markers of amyloid‐beta precursor protein processing in an ovarian hormone depleted model. Front. Endocrinol. 13, 1069404 (2022).
Relationship between default mode network and posterior resting‐state electroencephalographic delta rhythms in cognitively unimpaired seniors and patients with dementia due to Alzheimer’s
Authors: Babiloni Claudio
Published: December 2023

Background

Alzheimer’s disease dementia (ADD) is the most common neurodegenerative dementing disorder explaining about 60‐70% of 50 million patients worldwide (www.who.int). Some previous studies in ADD patients showed significant neurodegenerative processes as revealed by reduced gray matter volume in the cerebral cortex, including the default mode network (DMN), dorsal attention (DAN), and sensorimotor (SMN) cortical networks from structural magnetic resonance imaging (sMRI). Other studies in these patients reported the “slowing” of the resting‐state eyes‐closed electroencephalographic (rsEEG) rhythms reflecting vigilance dysfunctions. Here we tested the hypothesis of a significant relationship between these neurodegenerative and neurophysiological readouts, thus suggesting the sensitivity of rsEEG activity to intrinsic AD processes.

Method

Clinical, sMRI, and rsEEG rhythms in demographic‐ and age‐matched ADD (N = 45) and healthy cognitively unimpaired (Nold, N = 40) persons were available from an international archive (www.pdwaves.eu). Individual alpha frequency peak was used to determine the alpha frequency band on a personal basis. Fixed beta bands were considered. The eLORETA freeware estimated rsEEG sources in posterior (i.e., central, parietal, and occipital) cortical regions of interest. Freeware platforms served to estimate the normalized gray matter volume in the DMN, DAN, and SMN cortical networks from sMRI.

Result

The results (Fig. 1) showed: (1) lower DMN, DAN, and SMN volumes (maximum effects in the DMN), higher posterior rsEEG delta‐theta source activities, and lower rsEEG alpha source activities in the ADD than in the Nold group; (2) substantial inverse correlation between the DMN volume and the posterior rsEEG delta‐theta source activities in the ADD and Nold participants; and (3) a mediating effect of the posterior rsEEG delta‐theta source activities in the correlation between the DMN volume and the global cognitive status across all participants.

Conclusion

These results suggest a prominent relationship between DMN atrophy and the posterior rsEEG delta‐theta rhythms across physiological and AD‐related aging. As such, they support the enrichment of the ATN model for an extension to “Physiology” (P) = A‐T‐P‐N, as the physiology of the oscillatory activity within large inter‐connected neuronal populations due to disruptive effects of AD‐related neuropathology can be additionally informative.