bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative pathological study of Carbon‐11 labeled Pittsburgh compound‐B PET Centiloid Scale and amyloid beta deposition in postmortem brains
Authors: Matsubara Tomoyasu , Murayama Shigeo , Ihara Ryoko , Higashihara Mana , Nishina Yasushi , Kanemaru Kazutomi , Iwata Atsushi , Arai Tomio , Kameyama Masashi , Tokumaru Aya M. , Imabayashi Etsuko , Ishibashi Kenji , Toyohara Jun , Saito Yuko , Ishii Kenji
Published: June 2023

Background

Centiloid Scale (CL) was developed to standardize the quantitative results of amyloid beta (Aβ) positron emission tomography (PET). CL can allow not only categorization of the binary results of amyloid PET as positive or negative, but also parametric weighting within each category. To date, several neuropathological studies evaluated the performance of CL, but further validation studies of the Asian population, elderly cohorts, and relatively short intervals between PET scanning and autopsy may be required.

Method

Twenty‐two consecutive autopsy cases registered to the Brain Bank for Aging Research, who received Carbon‐11 labeled Pittsburgh compound‐B PET were included. Amyloid PET results of CL were compared with the final neuropathological diagnosis and the grading of Aβ deposition.

Result

The mean age of the 22 patients at death was 81.0 (SD: 8.4) years, seven of whom fulfilled pathological diagnosis of Alzheimer’s disease (AD). The mean interval from PET to autopsy was 17.5 (SD: 15.3) months. The mean CL was higher in the AD group (88.5 [SD: 30.9]) than in the non‐AD group (9.7 [SD: 25.6], p <0.001). Cutoff value of 50 could segregated seven AD and two non‐AD patients above and 13 non‐AD patients below. CL correlated with CERAD plaque score, Thal phase, and Braak amyloid stage with polyserial correlation coefficient of 0.93, 0.87, and 0.87, respectively. The lower limit of the CL value corresponding to moderate to frequent CERAD plaque score or equal to or more than Thal phase 4 was 17.31.

Conclusion

The CL value is in good agreement with the extent of Aβ accumulation. The cutoff value for predicting moderate or greater accumulation of Aβ was 15‐20, and the cutoff value for predicting AD pathology was 50‐60. Further accumulation and integration of data will allow us to establish more appropriate cutoff value.
In vitro activity of polyphenol‐rich extract of sorghum relevant to treatment of Alzheimer’s disease
Authors: Rezaee Nasim , Fernando Binosha , Hone Eugene , Sohrabi Hamid R , Johnson Stuart K , Gunzburg Stuart , Martins Ralph N
Published: June 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for most dementia cases. It has become a serious international health and economic concern as there is no effective treatment. Naturally derived products, particularly polyphenols (PP), have become very popular for developing effective therapeutic strategies for AD. PP apply their neuroprotective actions through targeting various pathological hallmarks of the disease, such as Aβ and/or aggregation, oxidative stress and mitochondrial dysfunction. Aβ aggregation is majorly implicated in the pathogenesis of AD. Therefore, finding a way to attenuate Aβ‐induced toxicity could be a potential approach for disease‐modifying treatments of AD. In the current study, the effect of polyphenolic extract from different sorghum varieties was assessed against Aβ42‐induced cytotoxicity.

Method

A cell viability assay (MTS) was utilized to assess the protective effect of the extracts on Aβ‐induced cytotoxicity in human neuroblastoma BE (2)‐M17 cells. Following that, a thioflavin T (Th‐T) assay was performed to assess the anti‐Aβ aggregation effect of the extracts.

Result

The sorghum extracts significantly increased the cell viability. Of the six different tested extracts, QL33(2000 µg/ml) and B923296(1000 µg/ml) demonstrated the strongest and weakest protective effect in decreasing Aβ‐induced cell death (p < 0.01), respectively. In addition, the sorghum extracts were effective at inhibiting the Aβ aggregation.

Conclusion

Sorghum polyphenolic extracts demonstrated a promising neuroprotective effect against Aβ‐induced cytotoxicity and therefore can be considered as a potential naturally derived agent for AD treatment. However, further studies are required to confirm the anti‐AD effects of these sorghum extracts.
Fused multi‐modal similarity network as prior in guiding brain imaging genetic association
Authors: He Bing , Xie Linhui , Varathan Pradeep , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Yan Jingwen
Published: June 2023

Background

Brain imaging genetics aims to explore the genetic architecture underlying brain structure and functions. Recent studies showed that incorporation of prior knowledge, such as subject diagnosis information and brain regional correlation, can help identify significantly stronger imaging genetic associations. However, sometimes such information may be incomplete or even unavailable. In this project, we explore a new data‐driven prior knowledge that captures the subject‐level similarity matrix derived from fusion of multi‐modal similarity networks. It was built into the sparse canonical correlation analysis model, which is expected to identify brain imaging and genetic markers that contribute to the fused similarity matrix.

Method

The Amyloid and Tau imaging data were downloaded from the ADNI database. We have 800 and 291 subjects for amyloid and tau imaging respectively (Table. 1). SNPs with p<5×10−6 (n = 1080) were extracted from the large‐scale GWAS summary statistics from the IGAP. We built similarity networks for imaging and genetic data individually using normalized mutual information and then fused these network following (Fig. 1). Fused network was then applied as a prior knowledge in the discriminative sparse canonical correlation analysis (DSCCA) model. We also tested other prior knowledge in SCCA model for comparison including diagnosis group network and transcriptomic brain network. All methods were evaluated using ADNI genotype, amyloid and tau imaging data, where nested 5‐fold cross validation with the same set of training and test data was applied for fair comparison.

Result

SCCA with fused network and diagnosis group showed better performances over others in both training and testing data set (Table. 2,3). In Fig. 2 are top 10 ROIs identified by SCCA with fused network, whose amyloid deposition are strongly associated with APOE SNP (rs429358). For tau, we identified left and right amygdala with tau accumulation strongly and consistently associated with rs429358 (fig.3).

Conclusion

As prior knowledge incorporated into SCCA algorithm, fused similarity network can help improve the performance of imaging genetic association over traditional SCCA and that guided by the brain co‐expression network. It showed comparable performance as diagnosis information and thus could be a potential prior knowledge to consider when lack of diagnosis information.
No added value of Sex and APOE*4 stratification for Alzheimer’s Disease Genetic Risk Scores
Authors: Belloy Michael E , Guen Yann Le , Greicius Michael D , Altmann Andre
Published: June 2023

Background

Genetic risk scores (GRS), be it polygenic risk scores (PRS) or polygenic hazard scores (PHS), have shown promise to support genetic risk prediction and clinical trial recruitment for Alzheimer’s disease (AD). A recent study further suggested that sex‐matched AD PHS (e.g., male‐to‐male) outperform sex‐mismatched PHS (e.g., male‐to‐female), while no benefit was observed for PRS. Similar benefits may be expected for matching by APOE*4 positivity status, but this question has remained unexplored. The prior sex‐stratified work neither evaluated whether full sample GRS (males+females) outperform sex‐matched GRS, nor compared polygenic (including many variants regardless of significance) to oligogenic (including fewer more significant variants) effects. Here, we performed the largest‐to‐date sex‐stratified, and first APOE*4‐stratified, evaluation of AD GRS.

Methods

The study design is detailed in Figure‐1: genome‐wide association studies (GWAS) were performed in a Discovery cohort (LMM‐BOLT v.2.3.5) and GRS were constructed and evaluated in an independent Replication cohort (PRSice‐2 & R v3.6). All analyses performed multiple linear regression on an AD‐age score that models resilience to age‐related risk for AD (Figure‐2). Models adjusted for sex, APOE*4/APOE*2 dosage (rendering GRS estimates/effects independent of APOE), the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. GRS were evaluated at different P‐value thresholds to elucidate oligogenic versus polygenic effects, while all GRS with other covariates were combined to evaluate predictive performance in the Replication.

Results

Stratified discovery GWAS are shown in Figure‐3. GRS tended to perform best at more stringent P‐value thresholds (i.e., oligogenic) and GRS derived from the full‐sample discovery virtually always outperformed stratified GRS (Figure‐4‐5). Predictive performance was similarly the highest for GRS derived from the full‐sample discovery (Table‐1).

Conclusions

Our results were consistent with emerging literature supporting that AD is oligogenic and showed that the performance of sex‐ or APOE*4‐stratificatied GRS was outweighed by using full‐sample derived GRS. While not shown here, we made consistent observations when using a case‐control model (thus equivalent to PRS) without age adjustment. These findings have important implications to guide further efforts at translating AD GRS into clinical practice.

aging after age 90.
PENSA study for the prevention of cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline: Description of baseline demographic and neuropsychological data of the study population
Authors: Forcano Laura , Domenech Natalia Soldevila , Cuenca Aida , Lorenzo Thais , Boronat Anna , Piera Iris , Pijoan Albert Puig , Knezevic Iva , Toma Ilario de , Fauria Karine , Molinuevo Jose Luis , Torre Rafael de la
Published: June 2023

Background

Alzheimer’s disease (AD) is a multifactorial disorder likely caused by a complex interplay of different pathological processes that are influenced by internal and external determinants. In the absence of effective treatments to reverse cognitive deterioration related to AD, there is a need to develop novel non‐pharmacological prevention interventions that may delay or prevent these pathological processes at early preclinical stages of AD. The PENSA study, framed within the WW‐FINGERS consortium, is a randomized clinical trial involving cognitively normal elderly individuals with an increased risk of developing AD (meeting subjective cognitive decline, SCD‐plus criteria and being APOE‐ɛ4 carriers). The aim of the study is to evaluate the efficacy of a multimodal personalized lifestyle intervention (dietary and physical activity counseling and cognitive training) combined with a dietary supplement, epigallocatechin gallate (EGCG) in slowing down cognitive decline.

Method

Baseline sociodemographic, mood and cognitive characteristics of the entire study sample participants is presented. Cognitive function was measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC) and adding to this original version the interference score from the Stroop Color and Word Test and the Five Digit Test (ADCS‐PACC‐Plus‐exe). Additionally, the Digit Span, the Boston Naming Test and the Animal Fluency Test were administered. Psychological distress was measured with the Hospital Anxiety and Depression Scale.

Result

On Desember 2021 the study had enrolled 128 individuals (64.8% women) with a mean (SD) age of 67.3 (4.73) years and the following APOE genotype: 87% ɛ3/ɛ4, 7% ɛ4/ɛ4 and 6% ɛ2/ɛ4. Most had higher education (44.1%) and 81.9% were retired (Table 1). 11% of participants exhibited relevant anxiety and depressive symptoms measured by the Hospital Anxiety and Depression Scale. According to an ad‐hoc SCD questionnaire, 65.8% of participants referred memory centered complaints. Considering the different domains, participants reported alterations on memory (97.6%), concentration (62.6%), language (69.9%) and visuospatial skills (10.6%). Table 2 shows the ADCS‐PACC‐Plus‐exe scores

Conclusion

The PENSA study will help shed light on the effectiveness of lifestyle interventions supplemented with EGCG to prevent cognitive decline in people at risk of developing AD.
Using deep learning models to examine the biological impact of polygenic risks for Alzheimer’s disease
Authors: Zhou Xiaopu , Ip Fanny C. F. , Lv Ge , JIANG Yuanbing , Cao Han , Zhong Huan , Chen Lei , Fu Amy K.Y. , Ip Nancy Y.
Published: June 2023

Background

Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. Genetics studies suggest that AD is polygenic in nature; thus, an individual’s risk of AD can be predicted by polygenic risk score (PRS) models. Of these models, the deep learning models more accurately capture nonlinear interactions among different genetic risks and are more suitable for modeling disease polygenic risk.

Method

We used the neural network‐based deep learning models to evaluate the polygenic risk of AD. Meanwhile, we examined the associations of resultant PRSs and plasma protein biomarkers for AD by regression analysis. We also identified the biological pathways that contribute to the polygenic risk using Gene Set Enrichment Analysis.

Result

We found that the resultant PRSs of AD are associated with the levels of specific AD plasma protein biomarkers, including amyloid beta and p‐tau181, as well as changes in the activity of specific biological events, such as TNF‐α and cytokine‐related pathways.

Conclusion

Our findings suggest that AD polygenic risk is associated with AD progression and modulates immune‐associated pathways. They also highlight the potential use of deep learning methods in investigating the underlying genetic mechanisms of AD.
Dementia and influenza vaccination ‐ Time trends and predictors of vaccine uptake among older adults
Authors: Appel Andreas Moses , Janbek Janet , Laursen Thomas Munk , Gasse Christiane , Waldemar Gunhild , Jensen‐Dahm Christina
Published: June 2023

Background

Older adults with dementia are at an increased risk of hospitalizations with respiratory infections and death. This emphasizes the need for increased focus on preventive measures, such as influenza vaccination, in this vulnerable group. The aim of our study was to investigate whether dementia, along with other factors, is associated with likelihood of influenza vaccination among older adults as well as to estimate time trends of vaccine uptake for older adults with dementia.

Method

We conducted a nationwide cross‐sectional study with data from national registries on the entire Danish population aged ≥65 years. We mapped the time trends of vaccination for each vaccination season (September to August) from 2002/2003 to 2018/2019. Using multivariable logistic regression, we estimated the likelihood of vaccination in 2018/2019 for a combined measure of dementia status and living situation (home living vs. nursing home). In the same model, we estimated the effect of other potential predictors of influenza vaccination.

Result

The study population was 801,710 individuals in 2002/2003, and 1,122,489 in 2018/2019. In the entire elderly population vaccine uptake increased steadily from 6% in 2002/2003 to 51% in 2009/2010 and then plateaued but was 10% higher among people with dementia. Compared to home living without dementia, the likelihood of vaccination in 2018/2019 was lower for home living with dementia (OR: 0·80; 95% CI: 0·78‐0·82), while it was higher for nursing home residents both with (1·36; 95% CI:1·31‐1·41) and without dementia (1·21; 95% CI: 1·17‐1·25). Higher age, more GP contacts, higher number of drugs and CCI score were associated with higher vaccination likelihood, while lower educational level, lower residential urbanization and being unmarried were associated with lower vaccination likelihood.

Conclusion

Influenza vaccination coverage has remained below 60% among older adults regardless of dementia status, not reaching the WHO target of 75% immunization in this group. Home‐living older adults with dementia were 20% less likely to receive an influenza vaccination, representing an important target group for future vaccination campaigns
miR‐181b expression as a potential biomarker in Alzheimer’s Disease
Authors: TUNALI Nagehan ERSOY , Keske Ezgi , Çınar Nilgün , Şahiner Türker AH
Published: June 2023

Background

Alzheimer’s Disease (AD) is a multifactorial neurodegenerative disorder with complex molecular pathophysiology at the cellular level. Despite intensive research to decipher genetic and molecular players, non‐invasive markers of early diagnosis and progression are yet to be discovered. MicroRNAs (miRNAs) regulate post‐transcriptional gene expression and hold the potential to act as biomarkers for disease prediction, diagnosis and prognosis. Identification of differentially expressed circulating miRNAs in late‐onset AD will serve for the establishment of non‐invasive biomarker panels for disease prediction at earlier ages. In this regard, miR‐181b may serve as a candidate molecule. Here we aimed to evaluate the expression pattern of hsa‐miR‐181b in the serum samples of late‐onset AD patients and healthy controls.

Method

Blood samples were collected from 33 late‐onset AD patients and 34 healthy individuals. Samples were processed immediately for plasma isolation and kept at ‐80°C. Following total RNA extraction and cDNA synthesis, expression levels of hsa‐miR‐181b‐5p were determined in all samples via qRT‐PCR using SyberGreen. Cel‐miR39 was used as a spike‐in control and all samples were processed in duplicates. Data were analyzed by the ∆∆CT method. p<0,05 was considered to be significant.

Result

The average ages of AD patients and healthy controls were 82 and 59 years, respectively. Females constituted 60% of the samples in both groups. Patients were being treated with Donepezil or Donepezil and Memantine. According to the qPCR results, miR181b levels were found to be significantly reduced by 3 folds in AD patients, compared to controls.

Conclusion

There are conflicting data in the literature regarding up or down regulation of miR181b in AD. This may be due to different experimental set‐ups, ethnicities of the study populations, sample characteristics or other confounding factors. To the best of our knowledge, this is the first study evaluating the expression pattern of miR181b in the plasma samples of Turkish AD patients. Our results indicate that hsa‐miR‐181b‐5p can be regarded as a potential blood biomarker for the prediction of AD. miR181 was shown to be involved in immune response regulation and neuroinflammation in the literature, therefore it is of high importance in AD.
Search strategy analysis reveals sex‐specific deficits in spatial reference memory in 5xFAD mice
Authors: Quintanilla‐Sanchez Carolina , Bänfer Irina Wanda Helene , Curdt Nadine , Schmitt Franziska , Bouter Yvonne
Published: June 2023

Background

Spatial disorientation is one of the earliest symptoms in Alzheimer’s disease. Search strategy classification systems to study navigational deficits in Alzheimer disease have been developed but aren’t widely available. Hence, we studied the navigational strategies in the 5xFAD murine model and evaluated differences between sexes.

Method

We studied spatial reference memory in 3‐month‐, 7‐month‐ and 12‐month‐old female and male 5xFAD mice and their aged‐matched controls in the Morris water maze. Furthermore, a detailed analysis of the swimming strategies using “Pathfinder” was performed. Navigational strategies were classified in spatial (“direct path”, “directed search”, “focal search”, “indirect search”) and non‐spatial categories (“chaining”, “scanning”, “random search”, thigmotaxis”).

Result

Escape latency was prolonged in 5xFAD mice compared to WT, only at 7 and 12 months, with greater magnitude in females than males. Regarding search strategies during acquisition training, the most common spatial strategy was “indirect search” whereas “random search” was the most frequent non‐spatial strategy. At 3 months, no clear difference was seen between 5xFAD and WT animals. However, at 7 months, 5xFAD mice used more frequently non‐spatial strategies. Although transgenic mice progressively shifted to more spatial strategies as they learned (mainly “indirect search”), WT animals applied more frequently spatial strategies with higher cognitive value such as “direct path”, “directed search” and “focal search”. In comparison, 12 month‐old 5xFAD mice used more non‐spatial strategies, mainly “random search”, than the WT and their transition to “indirect search” occurred more rarely than in younger mice. Overall, all animals increased the use of non‐spatial strategies as they aged but this increment was greater and earlier in 5xFAD females than in 5xFAD males. Lastly, in the probe trial, 5xFAD female mice at 3 and 12 months applied “random search” more often, while the WT chose “indirect search” with higher frequency. No difference was seen in males during probe trial.

Conclusion

Conventional behavior analysis of escape latencies revealed spatial reference memory deficits in 7m and 12m 5XFAD mice. Deficits in spatial memory were more pronounced in female 5XFAD mice than in male mice. 5XFAD mice, regardless of sex, used a qualitatively and quantitatively different search strategy pattern than WT animals.
Digital Biomarkers and Wearable Neurotechnologies: A Cost of Privacy and Security for Alzheimer’s Patients
Authors: Moonga Julie
Published: June 2023

Background

Alzheimer’s disease (AD) is one of several neurodegenerative diseases affecting millions of people worldwide. While a cure for AD is unobtainable, state‐of‐the art medical interventions such as digital biomarkers and neuro‐applications systems, namely brain computer interfaces (BCIs) are proven to be revolutionary. Currently, neurotechnologies show clinical effectiveness in assisting impairment, improving cognition and coordinating motor function in AD patients. Various wearable devices sold on the direct‐to‐customer (DTC) as non‐invasive are made compatible with Apps, mobile applications including smart phones. Increasingly neurotechnology devices are coordinated to improve memory loss and cognitive function in AD patients. As outpatient clinical tools, they can control and monitor health, promote wellbeing and provide entertainment. However, they also raised various concerns for privacy and security among users. In addition, the growing popularity of those devices bring major social and ethical implications. As innovative neurotechnology continues to expand on the brain function and mechanisms, policy framework should be in place to mitigate the potential risks for vulnerable AD patients.

Methods

Drawing from big data, a systematic review provides an in‐depth analysis with an overview in the emergence, development and usage of wearable neurotechnology and devices in patients with AD. The risks of privacy and security are assessed. Evaluation of recent EU Software regulation, in addition to the approval of the Food and Drug Administration implementations suggests the need for better policy and governance.

Result

Policies gaps are identified. A framework is introduced that models how digital biomarkers and wearable neurotechnology have potential risks for AD patients. An increasing body of evidence shows biomarkers and wearable devices are effective in assisting AD patients with cognition, memory loss, and social activity. However, potential privacy and security risks raise questions for neuroethics. Underscoring recent classification of software regulation and guidelines conceptualised the utility of recent regulatory procedures and process.

Conclusion

The cascading issues with privacy and security remain a dilemma for AD patients. Neuro‐privacy frameworks are as important as clinical effectiveness for regulation calibration and address social and ethical issues. Policy and guidelines are necessary to delineate outcomes and specific measure for privacy, threat and security.
Automated detection of lacunar infarcts from MRI images
Authors: Gong Jin , Koikkalainen Juha , Korvenoja Antti , Paavilainen Teemu , Vanninen Ritva , Lötjönen Markus , Mecocci Patrizia , Frederiksen Kristian Steen , Meester Hanneke F.M. Rhodius‐ , Barkhof Frederik , Lötjönen Jyrki
Published: June 2023

Background

When MRI images of patients with memory problems are assessed, the presence of lacunar infarcts is evaluated. Lacunar infarcts, fluid‐filled cavities of 3‐15 mm in diameter, are one possible result of cerebral small vessel disease and therefore relevant in dementia diagnostics. In this study, we propose an automated tool for detecting lacunar infarcts on MRI images.

Method

We adapted our previous approach [1] in three ways: 1) post‐processing steps were added to the convolutional neural network segmentation pipeline, e.g., to exclude enlarged perivascular spaces and segmentations located inside sulci or ventricles, 2) memory clinic data from the Amsterdam Dementia Cohort and PredictND cohort were included in addition to the LADIS cohort data, and 3) the ground truth was defined by three experienced neuroradiologists (A, B, C) instead of one rater. T1 and T2‐FLAIR images were available for all cases and T2 for a subset in visual rating. The dataset was composed of 393 subjects and each expert rated 1156 potential lacunar infarcts as “1 = no”, “2 = probably no”, “3 = probably yes” or “4 = yes”. A consensus (CO) was created by calculating the average and using a cutoff at 2.5. The agreement was measured between individual raters (A‐B, B‐C, A‐C), between automatic rating and individual raters (AU‐A, AU‐B, AU‐C), and between the automatic rating and the consensus rating (AU‐CO) using Kappa. Correlation coefficient for the number of lacunar infarcts per subject was defined. Cross‐validation was used in training the algorithm.

Result

Out of 1156 candidate regions evaluated, 540 were considered as lacunar infarcts based on consensus. The individual raters agreed with each other in 74% of cases whether the shown lesion was lacunar infarct (kappa = 0.48). Correspondingly, automatic rating agreed with the individual raters in 74% of cases (kappa = 0.47). When automatic rating was compared with consensus, agreement/accuracy was 78% (kappa = 0.55). The correlation coefficient for the number of lacunar infarcts detected automatically from the whole image and visually (consensus) was 0.85 (Figure 1).

Conclusion

This study suggests that the agreement in detecting lacunar infarcts automatically is comparable to inter‐rater variability between experienced neuroradiologists. [1] Jokinen et al. Stroke 2020 Nov 9; 50(1)
A novel approach to measure awareness of memory decline and its ability to predict clinical progression in cognitively normal older adults
Authors: Mimmack Kayden J. , Gagliardi Geoffroy Pierre , Marshall Gad A , Vannini Patrizia
Published: June 2023

Background

Heightened awareness and unawareness of memory decline are known to manifest at different stages in AD, and both have been shown to predict clinical progression. Awareness is often measured by the discrepancy between the informant’s and participant’s mean scores on a memory complaints questionnaire. A major limitation of this approach is that a participant may display heightened awareness on some items and unawareness on others, averaging out each’s effect. Here, we present a new item‐level methodological approach, allowing us to examine these two dimensions of awareness (heightened/unawareness). We aimed to compare all these measures and investigate their ability to predict clinical progression.

Method

This study included 438 ADNI participants with CDR global = 0 at the time of their baseline Everyday Cognition (ECog) measurement and at least two follow‐up CDR assessments (Tab.1). Disease progression was defined as the first instance of two consecutive CDR global≥0.5. A traditional awareness score was calculated by subtracting the mean average ECog score between the informant and participant complaints (Fig.1A). An unawareness score was generated by capping item‐level positive differences at zero and then averaging (Fig.1B). Its complementary heightened awareness score was generated by capping negative differences at zero (Fig.1C). For all three measures, baseline group differences were analyzed using Wilcoxon rank‐sum tests. Robust Cox regression models were run to test the association between each baseline measure and progression, adjusted for age, gender, and education.

Result

The progressing (N = 91) and stable (N = 347) groups demonstrated similar scores for traditional (p = .11) and heightened awareness (p = .72). A significant difference was found for unawareness, with progressors displaying more unawareness than stable participants (p<.001;Tab.1,Fig.1). Robust Cox regression models showed a significant association between greater risk of progression and unawareness (p<.001) and a marginal association with lower traditional scores (p = .06). There was not a significant association with heightened awareness (p = .75).

Conclusion

By separating its two dimensions, our novel approach allows us to refine the analysis of awareness and to determine each dimension’s respective contributions to future clinical progression. These findings provide evidence that unawareness rather than heightened awareness is associated with clinical progression and supports the utility of informant report of decline.
MINDER Smart home test bed site – embedding dementia research into primary health and social care. Wingfield, D. Daniels, S. Norman, C. Lai, H. Hassim, N. Nilforooshan, R. Barnarghi, P. Sharp, D
Authors: Wingfield David
Published: June 2023

Background

Digitally enabled healthcare is becoming mainstream NHS (1) and adoption has been accelerated in response to the COVID‐19 pandemic (2) The UK Dementia Research Institute Care Research & Technology Centre, established in 2019, explores the value of using technology in people’s homes to improve care and has developed a system (MINDER) using IOT/smart home technology and medical devices, integrating activity and health data for research purposes and generating health alerts to the mainstream provider via a clinical monitoring team. Initially launched in Surrey and Borders Partnership NHS Trust (n = 40); in April 2021, an additional research site was established within primary care in North West London.

Method

We collated data from both sites and describe an integrated delivery model for research within primary health and social care. Cohort description and case studies illustrate the challenges and benefits of conducting this research across urban and sub‐urban settings.

Results

Over 55 participants are currently enrolled on the study. 15 of these from primary care/general practice in the London Borough of Hammersmith and Fulham. Opportunities arising from this setting include leveraging the patient – provider (nurse/doctor/allied health professional/social care) relationship to introduce the study and recruit, and rapid escalation of any problems arising in a research context to the clinical/care teams responsible to delivering care (for example; potential urinary tract infections). Challenges to recruitment have included lack of specialist confirmation of dementia diagnosis in primary care records, lack of consistent engagement/availability of the required MINDER study partner as well as the impact of the COVID 19 pandemic limited face to face contact.

Conclusion

Early data suggests that a complex dementia study can be embedded successfully in General Practice and leads to strengthening of relations with care giving bodies. This offers the opportunity for development and translation of new technologies within front line primary and social care, that can be fully evaluated within the real world context of service delivery.

References 1)The NHS Long Term Plan (2019) gov.uk 2) Baird B, Maguire D. Understanding factors that enabled digital service change in general practice during the Covid‐19 pandemic. London: The King’s Fund. 2021 Feb.
Effects of long‐term oral treatment with a novel estrogen receptor beta agonist on memory, vasomotor, and anxiety outcomes in an EFAD mouse model of Alzheimer’s disease
Authors: Fleischer Aaron W , Schwabe Miranda R , Kuehn Rachel K , Chaudury Subhabrata , York Jason , Ladu Mary Jo , Sem Daniel S , Donaldson William A , Frick Karyn M
Published: June 2023

Background

The prevalence and severity of Alzheimer’s disease (AD) are increased by female sex, apolipoprotein E (APOE) genotype, and age, such that postmenopausal female carriers of the Apoe4 allele are at greater risk of developing AD than age‐matched males. Although estrogen therapy shows promise in preventing and reducing menopause‐ and AD‐related symptoms, activation of estrogen receptor alpha (ERa) is associated with increased risk for health concerns, such as breast cancer. Therefore, treatments more selective for estrogen receptor beta (ERb) may provide estrogen‐related health benefits without the risks of activating ERa. Long‐term or acute treatment of wild‐type mice with the novel ERb agonist, EGX358, improves memory and reduces drug‐induced vasomotor alterations. However, efficacy of this compound in an AD model is unknown.

Method

Female APOE‐TR+/+/5xFAD+/− (EFAD) mice expressed five familial AD and were homozygous for human APOE3 (E3FAD) or heterozygous for APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and then treated orally with vehicle (1% DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Mice were weighed weekly and tested for spatial and object memory in the object placement (OP) and object recognition (OR) tasks, respectively. Anxiety‐like behaviors were also tested in the open field and elevated plus maze, and vasomotor symptoms were assessed via tail temperature following injection of the tachykinin receptor 3 agonist, senktide.

Result

EGX358 significantly enhanced OR memory in both E3FAD and E3/4FAD mice. However, treatment did not affect OP memory or anxiety in the open field or elevated plus maze. Interestingly, there were significant genotype differences in open field, vasomotor response, and body weight such that E3/4FADs spent more time in the center of open field, had a greater increase in tail temperature following senktide injection, and gained more weight compared to E3FADs.

Conclusion

Our findings indicate a potential for ERβ‐specific estrogen treatment to improve memory for the identity of objects. Unexpected genotype differences indicate the need to further study how APOE genotype affects anxiety and metabolic outcomes in AD.
Prevalence and pathological correlates of unawareness of memory impairment in non‐demented individuals with autosomal dominant Alzheimer’s disease: an item‐level investigation of the Memory Complaints Scale
Authors: Vannini Patrizia , Gagliardi Geoffroy Pierre , Gatchel Jennifer R , Hanseeuw Bernard J , Vila‐Castelar Clara , Langella Stephanie , Munera Diana , Martinez Jairo E. , Baena Ana Y. , Johnson Keith A. , Sperling Reisa A. , Lopera Francisco , Quiroz Yakeel T.
Published: June 2023

Background

Awareness of memory was previously found to be reduced in the pre‐dementia stages, reaching unawareness/anosognosia 6‐years before dementia onset in individuals who carry the PSEN1 E280A mutation for autosomal dominant Alzheimer’s disease (Vannini et al.,2021). Whether there are potential differences in awareness for specific types of situations involving memory as well as their association with molecular markers of AD disease progression in preclinical AD is unknown. Here, we investigated memory awareness on an item‐level basis as well as its relationship to neocortical amyloid and regional tau levels in non‐demented mutation carriers and non‐carrier family members.

Method

A total of 119 Colombian kindred members, 56 carriers (7 mildly impaired) and 63 non‐carriers were included (Table.1). Awareness indexes were calculated using participant and study‐partner discrepancy scores for each of the 15 questions of the Memory Complaint Scale (Spanish version). A score of ≥0 indicates that the participant is aware and <0 unaware. A subset of 67 kindred members (N = 31 carriers, 1 impaired) underwent amyloid (PiB) and tau (FTP) scans. For each question, odds ratio and Fisher’s exact test were used to evaluate prevalence of awareness/unawareness in carriers and non‐carriers. Pearson correlations, corrected for multiple comparisons, were used to assess the associations between awareness and pathology in the mutation carriers.

Result

Mutation carriers had significantly decreased overall awareness (p = 0.03), increased mean cortical amyloid (p<0.001) and inferior temporal tau (p = 0.001), compared to non‐carriers. Two questions (items 10 and 15), showed significantly lower awareness in the carriers than non‐carriers (both p = 0.002, Table.2). These results remained significant after removing impaired carriers. In carriers, decreased awareness was related to increased tau for 5/15 (33%) questions (Table.3 and Figure.1). No significant associations were found between awareness and amyloid.

Conclusion

Our results support previous findings that awareness is decreased in pre‐dementia stages of AD and related to tau, and not to amyloid pathology (Gagliardi et al.,2021). Importantly, we found that loss of awareness of specific memory items could differentiate carriers from non‐carriers. These findings support the usefulness of study‐partner‐reported cognitive decline. Individuals who become unaware of cognitive changes may represent a specific risk group to harbor pathology and develop AD dementia.
Single walled carbon nanotube optical reporter for amyloid beta detection
Authors: Antman‐Passig Merav , Heller Daniel A , Wong Eitan , Frost Georgia , Cupo Christian , Shah Janki , Agustinus Albert , Chen Ziyu , Mancinelli Chiara , Kamel Maikel , Li Thomas , Jones Lauren A , Li Yueming
Published: June 2023

Background

Amyloid beta (Aß) extracellular deposits are one of the pathohistological hallmarks of Alzheimer’s Disease (AD). In recent years intracellular accumulation of Aß has been linked with early pathogenic mechanisms. Recent reports now associate intracellular Aβ accumulation, and lysosomal disfunction as an early event in the disease, preceding extracellular amyloid‐deposits. Today methods to visualize intracellular Aβ accumulation rely on antibody staining or pre‐labeled Aβ. There is an outstanding need for live‐imaging tools capable of monitoring Aβ dynamics at the cellular level.

Method

We have developed an optical sensor that can monitor Aß in live cells transiently. Single wall carbon nanotubes (SWCNT) present advantages as optical sensors owing to their near‐infrared emission, as well as photostability and high‐sensitivity. SWCNT emission spectra (wavelength ranges of 1100‐1150nm) is within the biological transparency window (1000‐1700nm) allowing for optimal imaging in live samples. SWCNT were non‐covalently biofunctionalized; by which we confer selectivity to Aβ.

To obtain intracellular detection we used two cell lines: monocytes (THP‐1) and differentiated SH‐SY5Y. Cells were incubated with functionalized nanotubes. We utilized near‐infrared spectroscopy and hyper‐spectral microscopy to obtain spectral response from live‐cells.

Result

We developed and characterized a new class of bio‐functionalized intrinsically photoluminescent SWCNT sensor that can detect Aß via shifting of their intrinsic near‐infrared emission wavelength. Our biofunctionalized sensors specifically recognize Aβ in the solution phase, showing a monochromatic center wavelength decrease in a dose‐dependent fashion. The reporters show high specificity compared to competing analytes and in serum samples. In cell models, nanosensors accumulate intracellularly and probe Aβ introduced to the cells specifically. Finally, initial through‐skull near‐IR imaging in‐vivo in an AD model (5XFAD), following intracranial injection, show significant decrease in central wavelength in AD mice compared to wild type.

Conclusion

The SWCNT sensor provide a framework for dynamically investigating Aβ in live samples. We believe utilizing the nanosensors can enhance the study of Aβ ‐pathogenic mechanism, structure and molecular function and consequently improve and accelerate effective amyloid‐targeted therapies.
Increased cerebral blood flow is associated with higher baseline amyloid burden in a cognitively unimpaired population
Authors: Padrela Beatriz E. , Lorenzini Luigi , Collij Lyduine E. , Tomassen Jori , Bader Ilse , Shekari Mahnaz , van Berckel Bart N.M. , Visser Pieter Jelle , Barkhof Frederik , Petr Jan , Mutsaerts Henk‐Jan
Published: June 2023

Background

As cerebrovascular and Alzheimer’s proteinopathy have previously shown to affect cerebral blood flow (CBF) as well as cognition, CBF could be a potential early hemodynamic biomarker of cognitive decline. Here, we investigated to what extent cardiovascular risk factors and amyloid burden affect CBF in an elderly cognitively unimpaired (CU) population.

Method

We included 153 CU participants (minimal MMSE = 28) from the EMIF‐AD PreclinAD Twin60++ cohort (Table 1), who underwent [18F]flutemetamol PET and arterial spin labeling (ASL) MRI. Amyloid‐PET scans were visually assessed as negative or positive, upon which participants were grouped based on their longitudinal changes in amyloid positivity (visual read groups). Cortical amyloid burden was quantified with the Centiloid method globally and for 4 early amyloid accumulation regions of interest (ROIs). ASL scans were processed and quantified with ExploreASL for total gray matter (GM), and for vascular territories overlapping with the amyloid ROIs (Figure 1). Longitudinal analysis including baseline Centiloid values and yearly CBF change rates (Delta CBF) was performed for 98 participants with longitudinal imaging data available (4.23 years ± 0.43 follow‐up time). Associations between CBF and amyloid — with and without the interaction of vascular risk factors (i.e., Framingham score) — were assessed using generalized estimating equations (GEEs), both for baseline and rates of change measurements. Models were adjusted for age, sex, and twin dependency.

Result

While no association between amyloid burden and CBF was observed across the cohort, in participants with a high Framingham vascular risk score, higher amyloid was associated with increased CBF, for most ROIs (Table 2, Figure 2). Additionally, precuneus amyloid burden was predictive of CBF change in the corresponding vascular territory (Figure 3). Visual reading shows that subjects with high amyloid burden at baseline had a higher increase of CBF at follow‐up (Stable AB+, Figure 4).

Conclusion

We found that the combination of cardiovascular risk and amyloid burden in AD signature regions was associated with increased CBF in CU individuals, which may reflect a vascular or inflammatory compensatory response to early Alzheimer pathology. Future studies may help understanding how these mechanisms affect cognition.
Mobile memory gas station: A valid phone screen for cognitive impairment
Authors: Huang Yu‐Yuan , Yu Jin‐Tai
Published: June 2023

Background

Conventional neuropsychological assessments for cognitive impairment are burdensome. We developed a novel Wechat applet for detecting cognitive impairment. The Mobile Memory Gas Station is an assessment tool for rapid screening of cognitive functions, covering 7 important cognitive domains (memory, attention, executive function, language, visuospatial skills, social cognition, and computing).

Method

102 patients were recruited (Normal control: 51; mild cognitive impairment: 32, dementia: 19) to detect the diagnostic ability of this applet.

Result

Compared to conventional neuropsychological assessments, Mobile Memory Gas Station results in faster evaluations (10 min) and generates higher accuracy at detecting abnormal cognition. Our Results showed that this applet had good correlation with MMSE (P < 0.01), MoCA (P< 0.01) and moderate agreement for detecting MCI and dementia.

Conclusion

This applet demonstrated sufficient psychometric properties to be useful for screening of MCI, especially when clinic visits are not feasible. These findings are instrumental for patient screening, monitoring and management.
Vitamin D’s influence on aging brain function: Literature review
Authors: Elsayed Sarah , Patel Krupa , Dahab Lubaba , Elshaikh Abeer , Ibrahim Mohammed B. , Obeid Tamadur , Alatta Lina , Mohamed Suzan , Joda Malaz , Ahmed Khlood , Abdelrahman Nadir G
Published: June 2023

Background

Vitamin D receptors are located in neurons and glial cells of the brain. Vitamin D protects the nervous system by stimulating the synthesis of neurotrophin and neuromodulators, maintaining intracellular calcium homeostasis, and preventing oxidative brain damage. Vitamin D deficiency/insufficiency affects around 50% of the population, with rates varying according to race and ethnic origin. Vitamin D deficiency/insufficiency is a major public health concern because of its association with cognitive impairment and dementia. We aim to do a follow‐up review of the literature on the association between vitamin D insufficiency and cognitive impairment, including dementia.

Method

We reviewed vitamin D insufficiency and cognitive function studies published between 2010 and 2021. Except for animal models and research on human subjects with dementia, stroke, or brain malignancies, we reviewed clinical trials, case‐control, cohort, cross‐sectional, systematic reviews, and meta‐analyses. Adults worldwide were the target demographic. There were no limits on vitamin D levels or intake. PubMed, Cochrane, Clinicaltrials.gov, and Google Scholar were all accessed databases using keyword combinations such as “Vitamin D AND Alzheimer’s,” “Vitamin D AND cognitive,” “Vitamin D AND Geriatric,” and “Vitamin D AND Dementia”. All team members reviewed and verified the studies.

Result

Nine studies matched our inclusion criteria, involving 69,643 people with an average age of 53.6 years old. Vitamin D deficiency/insufficiency has been linked to impaired executive function, processing speed, visuoperceptual ability, and dementia in five studies. Two investigations established a direct proportional association between the degree of vitamin D insufficiency and the severity of memory and cognitive impairment. Vitamin D supplementation, according to one study, increases cognitive and memory functions.

Conclusion

Adults with vitamin D deficiency have reduced cognitive function and an increased risk of dementia. A significant limitation is that Africans, Hispanics, and Asians are underrepresented in the studies. Additionally, larger randomized controlled trials are needed to examine the many effects of vitamin D deficiency/insufficiency, supplementation, and its relationship to cognition in the aging brain.