bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of individual dietary factors for cognitive performance in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, FINGER
Authors: Uusimäki Kerttu , Hemiö Katri , Ngandu Tiia , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta , Tuomilehto Jaakko , Soininen Hilkka , Kivipelto Miia , Lehtisalo Jenni ,   FINGER study group
Published: December 2023

Background

Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a randomized trial that showed beneficial effect on cognition with a 2‐year multidomain lifestyle intervention. One of the four multidomain intervention components was diet and we have earlier shown that overall adherence to the FINGER dietary intervention goals was associated with better cognition. Here our aim is to investigate how the individual components of the dietary adherence score are associated with cognitive performance during the 2‐year period.

Method

The FINGER cohort included 1259 individuals at risk of dementia aged 60‐77 years at baseline, randomized into the multidomain intervention (n = 631) or the control group (n = 628). They underwent extensive data collection annually (total of 3 assessments), including detailed neuropsychological test battery (NTB) and a 3‐day food record. Adherence to dietary intervention was evaluated on 9 items based on dietary recommendations: intake of saturated fat, polyunsaturated fat, sucrose, fiber, protein, alcohol, vegetables, fruits, and fish. Data analyses were completed with mixed‐effects regression.

Result

The goal for low alcohol intake was inversely associated with cognition at baseline, but no other dietary items showed cross‐sectional associations. Reaching the goal for saturated fat, fiber, vegetables, fruits, and fish predicted better cognitive change at two years (p <0.05 for goal*time each). Results were similar when continuous variables rather than dichotomized goals were investigated. Intake of polyunsaturated fats additionally predicted better cognitive change and vegetable intake showed positive cross‐sectional association with cognition. There were no significant interactions with the study group.

Conclusion

Six out of nine FINGER dietary goals predicted a favorable cognitive change over time, indicating that a dietary pattern adherence with general dietary recommendations is beneficial for brain health. However, alcohol intake goal, i.e. lower alcohol intake, was associated with worse cognition; and cut‐offs for polyunsaturated fats based on the recommendations appeared suboptimal. The FINGER dietary adherence score should be compared with food‐based dietary patterns like Mediterranean Diet to investigate if nutrient intakes should be better taken into account when analyzing diet in relation to cognitive performance.
Psycho‐social risk factors for worse cognitive performance in sexual minority older adults
Authors: Manca Riccardo , Venneri Annalena
Published: December 2023

Background

Sexual minority older adults (SMOA) may have a greater risk of developing cognitive impairment than heterosexual older adults (HOA), but currently available findings are inconsistent. Minority stress (i.e. sexual orientation‐related stigma) has been suggested to drive worse cognitive health in this population. Therefore, the present study aimed to investigate whether minority stress and other risk factors for worse cognition in SMOA, namely depression and marital status, were associated with worse cognitive performance in SMOA.

Method

A total of 336 SMOA and 5561 HOA participants aged 50+, non‐institutionalised and free from neurodegenerative diseases from Wave 6 of the English Longitudinal Study of Ageing were included. Cognitive performance (i.e. temporal orientation, episodic memory and fluid intelligence) of SMOA and HOA was compared using general linear models including age, sex and education as covariates. The impact of depressive symptoms, marital status and minority stress on cognition in the two groups was also investigated. Weighting was performed to correct for sampling probability and differential non‐response.

Result

SMOA were more likely to be single and to report stressful social experiences due to sexual orientation than HOA participants. SMOA had better episodic memory than HOA and depressive symptoms and being single were associated with worse cognitive performance across all tests. Associations between cognitive performance and all risk factors were found not to be significantly different between the two groups. However, minority stress was negatively associated (b = ‐2.116, p = 0.016) with fluid intelligence in the SMOA group only.

Conclusion

Consistently with previous evidence, the SMOA had better episodic memory performance than the HOA group and both more severe depression and not being in a relationship had a generalised detrimental impact on cognition. However, this study provided the first evidence of a potential negative impact of a proxy measure of minority stress on cognitive performance, i.e. worse fluid intelligence, in SMOA. Further investigations are needed to assess minority stress more comprehensively and to clarify the potential mechanisms driving decline in both self‐reported and objectively assessed cognitive health in SMOA.
A clinical trial of cognitive and biological effects of citrus phytochemicals in subjective cognitive decline: baseline sociodemographic, clinical, and cognitive characteristics
Authors: Gatti Elena , Sgrò Giovanni , Fiorito Serena , Genovese Salvatore , Marchetti Lorenzo , Palumbo Lucia , Frisoni Giovanni , Pievani Michela , Epifano Francesco , Galluzzi Samantha
Published: December 2023

Background

We designed a clinical trial to evaluate cognitive and biological effects of a 36‐week treatment with citrus peel extract in older adults with subjective cognitive decline (SCD) (ClinicalTrials.gov identifier: NCT04744922). Here we present baseline sociodemographic, clinical, and cognitive characteristics of the enrolled subjects.

Method

Eighty subjects were enrolled between April 2021 and August 2022, and randomly assigned to receive either active treatment (400 mg citrus peel extract standardized in content of auraptene ‐ 0.1 mg ‐ and naringenin – 3 mg) or placebo in a 1:1 ratio for 36 weeks. Data about nutritional state and comorbidity, current therapy, health‐related behaviours, cognitive performance on verbal and non‐verbal memory, attention, executive and visuospatial functions were collected. Differences between groups (termed group A and B to avoid unblinding – the treatment allocation is unknown to the investigators) were compared using independent t‐test or Fisher’s exact test.

Result

The enrolled subjects have a mean age of 69.2±4.3 years, a high level of education (mean 13.7±3.5 years) and a higher prevalence of females (75%), with no significant differences between groups A and B. Nutritional state and comorbidity were similar (Body Mass Index: 25.1±4.8 vs 24.0±3.9, p = .27 and Cumulative Illness Rating Scale: 1.46±0.22 vs 1.51±0.24, p = .38, groups A and B, respectively). The most frequent concurrent therapies included cardiovascular system and alimentary tract and metabolism drugs, with no significant differences between A and B (55% vs 63%, p = .32; 61% vs 66%, p = .41, respectively). Health‐related behaviours were also similar between A and B (Mediterranean Diet Adherence Screener: 9.0±1.9 vs 8.8±1.8; Smoking: 13% vs 8%; Alcohol consumption: wine 81% vs 83%, coffee consumption 93% vs 88%, all p = >.30). Cognitive scores were all within the normal range and similar between groups, except for the Wisconsin Card Sorting test total score, where group A performed marginally better than group B (27.9±21.6 vs 40.7±32.2, p = .049).

Conclusion

The trial is expected to complete the longitudinal assessment in April 2023. The results of this trial will enable to evaluate the efficacy of citrus phytochemicals in SCD, informing the design of future nutritional interventions in people at risk of decline cognitive.
Attitudes and Practices towards the use of technology‐screening tools, diagnosis, and management of cognitive impairment in primary care
Authors: Almirall‐Sanchez Arianna , Rodriguez‐Velasco Arianne , Llibre‐Guerra Jorge J , Rodriguez‐Salgado Ana M , Peñalver Ana Ibis , Rodriguez Juan J Llibre
Published: December 2023

Background

Previous studies in the Cuban population suggest that Alzheimer’s Disease and related dementias (ADRD) are under‐diagnosed at primary care relative to population estimates. Recent interventions aimed to introduce the use of technology based cognitive assessments have been validated for primary care (e.g., Brain Health Assessment).However, the implementation of newly develop tools depends on the Primary care providers’ (PCPs) barrier and attitudes toward the diagnosis and management of patients with ADRD at a primary care level. Here we aimed to assess PCPs’ attitudes towards ADRD diagnosis, and the use of technology based cognitive assessments.

Method

84 PCPs were randomly selected form 10 primary care clinics. Sample size include a wide range of PCPs, including: family medicine (n = 54), neurologist (n = 2), psychiatrists(n = 13), psychologists(n = 10), clinicians (n = 3) and geriatricians (n = 2)). A questionnaire on Dementia assessment and management in primary care settings was administered to the participants. Descriptive statistics were employed for summarizing the data. Kruskal Wallis association test was utilized for determining associations between provider characteristics and outcomes.

Results

Most participants were female (n = 64, 76.2%), over 50 years old (n = 36, 52.9%) and family medicine practitioners (64.3%). The average number of patients consulted per month by PCPs were 250 (CI95% 250‐367) and over 60% of them were 55 years or older. Most of the PCPs (n = 63, 75.0%) will not refer patients with suspected ADRD if they had the training and instruments and technologies for the diagnosis at a primary care level. Lack of time (n = 59, 70.2%) and lack of confidence in their abilities (n = 68, 81.0%) were the most cited barriers for the diagnosis and management of ADRD . Around 80.0% of the interviewed practitioners considered the use of technology based cognitive assessments as important or very important tool for ADRD diagnosis. The positive attitudes of the PCPs for using technologies were correlated with the municipalities where they work (p = 0.01) and the continuous professional development of the PCPs (p = 0.03).

Conclusion

There are still barriers for the diagnosis of ADRD at a primary care level. Though PCPs are willing to implement technology based cognitive assessments in their daily practice, addressing existing barriers is key for success
Synaptic vs Extrasynaptic NMDA receptors distribution in Alzheimer’s human brain
Authors: Escamilla Sergio , Badillos‐Rodriguez Raquel , Solé Montse , Comella Joan X , Pérez‐Otaño Isabel , Sánchez‐Mut José Vicente , Cuchillo‐Ibañez Inmaculada , Sáez‐Valero Javier
Published: December 2023

Background

The malfunction of NMDA receptors (NMDARs) is believed to play a key role in Alzheimer’s Disease (AD), the most prevalent type of dementia. NMDARs are activated in different ways: activation at synapses leads to synaptic plasticity, while activation outside of synapses causes excitotoxicity, harm to mitochondria, and cell death. The objective of our research is to better understand the distribution of NMDARs in the brain of individuals with AD, specifically focusing on the distinction between synaptically and extrasynaptically activated NMDARs.

Method

Our research involved separating the synaptic and extrasynaptic membranes from the frontal cortex of both Alzheimer’s Disease (AD) patients and individuals without dementia. We examined the quantity of NMDAR subunits GluN1, GluN2B, and GluN2A. Additionally, we investigated the phosphorylation of GluN2B at Y1472 and Y1336, which are linked to synaptic and extrasynaptic membranes, respectively. To achieve our goal, we employed two distinct mouse models of AD: TAUP301S and APPswe/PS1dE9.

Result

Our findings revealed that in comparison to non‐demented individuals, the levels of GluN1, GluN2B, GluN2A, and pY1472‐GluN2B at synaptic membranes were lower in Alzheimer’s Disease (AD) patients. At extrasynaptic membranes, we observed an elevation in GluN2B levels and a decline in Y1336‐GluN2B phosphorylation. We also found that the changes in GluN2B phosphorylation were consistent with the APPswe/PS1dE9 mouse models of AD.

Conclusion

Our research discovered that levels of GluN1, GluN2B, GluN2A, and pY1472‐GluN2B were decreased at the synaptic membranes of Alzheimer’s Disease patients compared to individuals without dementia. Additionally, an increase of GluN2B levels and a decrease in Y1336‐GluN2B phosphorylation were seen at extrasynaptic membranes. Furthermore, the alterations in GluN2B phosphorylation were also mirrored in the APPswe/PS1dE9 mouse models for AD.
A preliminary in vitro study on Adult Neural Stem cells from 3xTg mice
Authors: Cerqueni Giorgia , Piccirillo Silvia , Terenzi Valentina , Preziuso Alessandra , Serfilippi Tiziano , Amoroso Salvatore , Lariccia Vincenzo , Orciani Monia , Magi Simona
Published: December 2023

Background

In AD, abnormalities in brain wiring and variations of the brain energetic metabolism are considered a key pathological framework of cognitive decline (Heininger, 2000). Neural stem cells (NSCs) can contribute to brain regeneration and, their transplantation improves the behaviour of neurodegenerative mice models (De Gioia et.al., 2021) although, the molecular mechanisms involved are still unidentified. Our preliminary study aims to explore the potential differences between NSCs‐derived neurons from 6‐months‐old healthy and AD mice in terms of neuronal network morphology. Furthermore, the study wants to provide a tool to investigate whether cell energy metabolism is modified, considering that bioenergetic failure can influence the regenerative potential of adult AD brain, an issue that is still ill defined.

Method

NSCs were isolated from subventricular zone of healthy (H) and 3xTg (AD) mice. NSCs selection was based on their ability to proliferate and to form 3D floating neurospheres. Isolated cells were amplified and characterised for their expression of stem‐related markers. Subsequently, neuron and astrocyte differentiation protocols were set up. Morphological analyses were performed on H and AD NSC‐derived neurons and the expressions of glutamate transporters and sodium/calcium exchangers (NCXs) were investigated.

Result

H and AD NSCs were strongly positive for Nestin and Sox2 stem markers and a faint expression of NeuN and Gfap, markers related to neuron and astrocyte mature phenotype respectively, was detected. These data confirmed the purity of the cell cultures as well as the reliability of the protocols. Morphological investigations highlighted a different distribution of the neurite network between NSCs‐derived neurons isolated from H and AD mice. Furthermore, H and AD mature cells expressed glutamate transporters essential not only for cellular transmission but also for energy production by their interplay with NCXs.

Conclusion

Preliminary data suggest that the pathological features of adult neurons from AD brain can be traced back to “stem level” and continue during differentiation. The different morphological organization of neurite network observed in NSCs‐derive AD neurons could be involved in the alteration of the impulse transmission and plasticity. Further studies will be necessary to better clarify the consequence of dysregulated glutamate transporters as well the role of astrocytes.
Exploring Narrative Identity via Linguistic Positioning in the Context of Alzheimer’s Dementia Risk Prediction – an Ethical and Linguistic Analysis
Authors: Hübner Constanze , Baumeister Annika , Gerards Michelle , Cantero‐Fortiz Yahveth , Marquié Marta , Ribaldi Federica , Schmitz‐Luhn Björn , Wittrock Julia , Boada Mercè , Frisoni Giovanni B , Jessen Frank , Rostamzadeh Ayda , Woopen Christiane , Schwegler Carolin
Published: December 2023

Background

In the field of Alzheimer’s disease (AD), possibilities of prediction are advancing due to the ever‐widening spectrum of technical and biomedical development. Such procedures become available to healthy persons, revealing risk probabilities to develop Alzheimer’s dementia in the course of one’s lifespan. The disclosure of and confrontation with such information can influence the individual’s self‐understanding, identity and life planning which raises various (bio‐)ethical issues on an individual and societal level. In this qualitative part of the PreTAD project, we aim to reveal information on the participants’ identity, through the analysis of their narrations ( = narrative identity), by focusing on language patterns participants use to express their positioning concerning risk prediction.

Method

In this qualitative‐explorative approach, we conduct N = 40 interviews with the following groups of participants: (a) general population, (b) first‐degree relatives of persons with Alzheimer’s dementia, (c) patients diagnosed with subjective cognitive decline (SCD). The interview design is guided by three themes relating to risk prediction of Alzheimer’s dementia: (1) individual experiences, (2) points of access and needs, (3) contextualization and associations. With this approach we seek to enable a ‘conversational’ interview in which linguistic patterns, (self‐)positioning and stance towards risk, health and disease reveal attitudes, individual values and therefore narrative identity. The basis of the multifaceted qualitative and linguistic analysis are Interpretative Phenomenological Analysis (IPA) and Conversation Analysis (CA).

Result

Preliminary results show that the deliberate approach of thematically segmented but rather unstructured interaction and the focus on patients’ narrations proved fruitful in identifying findings concerning the participants’ identity and sense of self in the context of risk‐prediction of dementia. By focusing analytically on linguistic stance (attitude) and direct/indirect (self‐)positioning of the participants, we can gain in‐depth insights into individual values and attitudes towards risk, risk prediction of Alzheimer’s dementia and health.

Conclusion

According to initial findings, the focus on narrative identity leads to important insights into self‐understanding of persons confronted with a potential risk and can help to refine ethical questions concerning risk prediction. To ensure good clinical practice regarding predictive interventions those should be acknowledged in counselling and risk disclosure communication.
The Minilinguistic State Examination for Primary Progressive Aphasia: validity evidences for the Argentinean version
Authors: Vivas Leticia , Redondo Santiago , Garavaglia Monica , Andreotti Daniela , Linares Nicolás , Matar Lourdes , Paolantonio Patricia
Published: December 2023

Background

This work presents a new brief language assessment tool for Primary Progressive aphasia: the Minilinguistic State Examination (MLSE). It has been developed with the intention to have equivalent version in different countries. We translated and adapted the test to Argentinean Spanish. Here we present the psychometric properties of the Argentinean Spanish version of the MLSE.

Method

The sample comprised 29 aphasic patients from different etiologies and 94 healthy community‐dwelling adults. All of them were native Argentinean Spanish speaking. The Argentinean MLSE was administered as well as the following equivalent subtests with validated Argentinean versions in order to analyze the concurrent validity through a Spearman´s Rho correlation coefficient: the Boston Aphasia Battery, the BEA (Batería de Evaluación de la Afasia), Pyramids and Palm tree test and Repeat and Point. Score´s reliability was analyzed according to K‐R 20 coefficient for each kind of possible error: motor, phonologic, semantic and working memory. Three independent clinicians scored a sub‐group of 16 patients in order to determine interraters reliability. Krippendorff´s alpha was calculated.

Result

All correlations with the equivalent tasks were statistically significant except for semantic association task that was near statistical significance (p = .061). Score´s reliability for motor errors was .825, for phonological errors .889, for semantic .841 and for working memory .874. Krippendorff´s alpha obtained for the total MLSE score was .877, while the following values were obtained for each type of error identified in the MLSE: motor = .398; phonological = .707; semantic = .729; syntactic = .831; working memory = .539; omissions = .672.

Conclusion

All these analyses provide evidence of validity of the scores of the test and suggest that it can be used with confidence by clinicians. They also showed in general acceptable interrater reliability. However, some clarifications should be added to the motor and working memory scoring guide in order to avoid interrater´s divergencies, as the obtained values were low.
Comparative efficacy of cholinesterase inhibitors and memantine on cognition in AD patients with application of network meta‐analysis
Authors: Mostafaei Shayan , Garcia‐Ptacek Sara , Zargarzadeh Nikan , Habich Annegret , Eriksdotter Maria
Published: December 2023

Background

This study aimed to assess the comparative efficacy of monotherapy and combined therapy of cholinesterase inhibitors plus memantine on cognition in AD and determine efficacy across doses for these pharmacological drugs.

Method

The screening of 2,113 articles were initiated. Finally, forty randomized controlled trials (RCTs) from PubMed, Web of Science, and Scopus databases inception to the end of Dec. 2022 were finally included in this review. The included RCTs contain donepezil, rivastigmine, galantamine and memantine alone or in any combination of them were compared with placebo in terms of MMSE score. The mean difference (MD) in MMSE score was considered as the effect size of efficacy. The quality of the RCTs were appraised using the Cochrane risk‐of‐bias tool (RoB‐2). An additive network meta‐analysis (NMA) was applied to compare the efficacy of the drugs. Trends of efficacy across doses for each available treatment were checked using a dose‐response modeling. Finally, P‐score as a probability of being the most effective treatment, was used to rank the treatments. All statistical analyses were done using netmeta and dosresmeta R packages. The study protocol was registered in the PROSPERO (CRD42022358469).

Result

These RCTs included 16,785 AD patients with mean age 73 (SD = 3.5) yrs., and weight 64.5 (SD = 5.55) kg. Of these patients, 65.15% were women. The median follow‐up time was 6 (range = 3‐48) months. The main NMA results showed that galantamine 32mg/day (MD = 3.71; 95% CI = 2.21, 5.21; P‐score = 0.89), donepezil 10mg/day combined with memantine 20mg/day (MD = 3.27; 95% CI = 1.79, 4.76; P‐score = 0.83), and then galantamine 24mg/day (MD = 3.02; 95% CI = 2.19, 3.84; P‐score = 0.79) were significantly the most effective treatments compared with placebo, respectively. According to the sub‐group analysis of stages, donepezil 10mg/day combined with memantine 20mg/day (MD = 4.78; 95% CI = 2.86, 6.71) and galantamine 32mg/day (MD = 3.81; 95% CI = 2.20, 5.34) were recommended for moderate to severe and mild to moderate AD patients, respectively. Moreover, we found there was a significant positive linear trend of efficacy across doses of galantamine.

Conclusion

Monotherapy with a high dose of galantamine or the combination of donepezil plus memantine have the most favorable effects on cognition for 6 months follow up in AD patients.
Prevalence of mild cognitive impairment in an urban, community dwelling, elderly population and its association with Serum Vitamin B12 levels in South India.
Authors: Menon Jayakumar , Kantipudi Suvarna Jyothi
Published: December 2023

Background

Prevalence of cognitive disorders is becoming higher in low and middle income societies with increasing lifespan1. Multiple factors contribute to emergence of cognitive disorders including genes, lifestyle, diet and nutrition, co‐morbid metabolic and vascular risk factors 2. There has been only a few studies from India, looking at the prevalence of cognitive impairment in the community. Ageing and dietary preferences pose a higher risk for B12 and Folic acid deficiencies, contributing to cognitive difficulties3. Our study aims to look at the prevalence of cognitive impairment in a community dwelling elderly population and the association of mild cognitive Impairment (MCI) with serum B12 levels.

Method

A total of 308 individuals above the age of 60 were screened for medical issues and psychiatric illnesses. Those who fulfilled the intake criteria were evaluated using Subjective Memory Complaint Questionnaire (SMCQ), MOCA, ACE‐R or RUDAS and FAB. Serum B12 levels were evaluated for all the individuals.

Result

51.8 percent of individuals had normal cognitive function. The prevalence of cognitive impairment was 48.8%. Among these 42.3% of individuals had mild cognitive impairment. There was no significant correlation between MCI and Serum B12 levels in the screened population.

Conclusion

There is a high prevalence of cognitive difficulties in the studied population.Dietary deficiency of Vitamin B12 does not appear to be a major factor contributing to the MCI. Alzheimer’s disease, vascular cognitive impairment and lifestyle and metabolic risk factors may need to be considered as contributory factors

References:

1) Ravindranath V, Sundarakumar JS. Changing demography and the challenge of dementia in India. Nat Rev Neurol. 2021 Dec;17(12):747‐58.

2)Scheltens P et al. Alzheimer’s disease. The Lancet. 2021 Apr 24;397(10284):1577‐90.

3) Zhang C et al; Vitamin B12, B6, or Folate and Cognitive Function in Community‐Dwelling Older Adults: A Systematic Review and Meta‐Analysis. Journal of Alzheimer’s Disease. 2020 Jan 1;77(2):781‐94.
‘These are my friends’: Persons living with advanced dementia Zooming from Home during COVID‐19
Authors: Brown Nancy L
Published: December 2023

Older people can Zoom, even in the later stages of dementia! My research, conducted during the COVID‐19 lockdown, demonstrates that persons living with advanced stages of dementia can engage with one another in a virtual community, recognize one another on a Zoom screen, and participate in activities online. These sessions, designed according to the Validation Group methodology, enhanced the participants' remaining emotive capacities and reduced the effects of social isolation.

Online sessions were conducted for 8 weeks, 2 hours each week during the COVID‐19 lockdown. Carers were instructed on using their tablet or computer along with preparations needed for the Zoom session. An agenda based upon the Validation group method developed by Naomi Feil provided the structure for each session. Sessions were video recorded following the ethics guidelines of the day center MELABEV and manually transcribed. NVivo software was used in the qualitative analysis.

Clients enjoyed the familiar activities and demonstrated great pride when sharing items from their homes. This group format evoked memories of earlier social roles. They recognized and interacted with one another in the little squares. Even their non‐verbal communication through their eyes, their smiles, and their gestures increased during each session. During one activity, 100‐year‐old Annie pointed to the screen and said, “These are my friends.” The successful application of group theory adapted by Naomi Feil for disoriented older adults that includes: Welcome, Opening song, Discussion, Activity, Refreshments, Closing Song. The format provides opportunities for familiar social roles and individual and group empowerment. Themes that emerged from the data collection include Self‐identity, Social Connectivity, and Cultural Identity.

Results support the notion that technology like Zoom offers an option for preventing social isolation and mitigating the negative impact of supporting someone with dementia during a pandemic and other crises. From a societal perspective, the importance of making available technology to persons with dementia and seeing them socially connect and engage through a medium not part of their generation has far‐reaching implications not only for future research but also for policy considerations, mitigating social isolation and caregiver burden among a vulnerable population.
Hippocampal subfield volume in relation to cerebrospinal fluid Amyloidβ1‐42 in early Alzheimer’s disease: A 7T MRI study
Authors: Adeyemi Oluwatobi F , Mougin Olivier , Penny Gowland , Bowtell Richard , Hosseini Akram A.
Published: December 2023

Background

7T MRI can provide high contrast and spatial resolution images for studying the volume of hippocampal subfields which can be used in conjunction with Amyloidβ1‐42 and tau measures in the cerebrospinal fluid (CSF) to provide a non‐invasive alternative marker for Alzheimer’s disease (AD).

Method

41 participants (20 AD and 21 healthy age‐ and gender‐matched controls) were recruited [aged 40 ‐ 76 years; 64% female). The protocol for the analysis of the CSF for the Amyloidβ1‐42 (reference range: 627‐1322 pg/ml), total tau (reference range: 146‐595 pg/ml), Thr181‐phosphorylated tau (reference range <68 pg/ml) have been previously published (Hosseini et al, 2022) and the measures were used for the ATN classification of Alzheimer’s disease. Imaging was carried out on a Philips Achieva 7T scanner using a Nova Medical (Wilmington MA, USA) single‐channel transmit, 32‐channel receive (1Tx32Rx) head coil. Images acquired are PSIR (TE/TR = 3.1/6.9ms; FA = 6o, isotropic 0.55 mm resolution) and T2‐weighted FSE (TE/TR = 119/59001ms, FA = 90o, 0.38×0.39×1.50 mm3 resolution).

Result

Fig 1 show the T2‐weighted image and the segmentation of the hippocampus obtained using ASHS (Yushkevich et al., 2015b)

There was a significant decrease in the volume of each hippocampal subfield (Fig2) in AD patients compared to controls. The change in volume was not significant for the whole brain showing that the hippocampal volume loss was not simply part of general brain atrophy.

There was an approximately linear relationship between the CSF Amyloidβ1‐42 and volume of the hippocampus for the AD participants (Fig 3). A positive linear relationship was observed in all the subfields of the hippocampus but a statistically significant relation was only achieved in the Entorhinal Cortex (ERC) [p<0.022, r = 0.508].

The ERC is known to represent perception of time, memory and navigation (Tsao et al., 2018)(Du et al., 2001), and AD pathology may start from the ERC before migrating along the hippocampus (Braak & Braak, 1997). Further, the ERC volume loss on 1.5 T MRI has been reported greater in AD as compared with Mild Cognitive Impairment(Du et al., 2001).

Conclusion

The association of the volume of ERC and CSF Amyloidβ1‐42 suggests the potential for using 7T MRI as a biomarker for an early identification of AD.
Urban‐rural differences in the prevalence of Subjective Cognitive Decline in India: A comparative study
Authors: Narayanasamy Rajitha , Malo Palash Kumar , Hameed Shafeeq K Shahul , Stezin Albert , R Meghana , Menon Meenakshi , L Abhishek M , Mallikarjun Divya N , Partha Ajith , M Amitha C , Velavarajan Goutham , Singh Sadhana , HS Sunitha , Arvind Prathima , Kommaddi Reddy Peera , Diwakar Latha , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: December 2023

Background

Subjective Cognitive Decline (SCD), defined as a self‐experienced persistent cognitive decline with a normal performance in objective neuropsychological assessments is one of the first clinical manifestations of dementia. SCD has a strong association with depression, and more research is needed to understand the relationship between the two. When they co‐occur the risk of developing dementia increases. Despite the increased focus on the preclinical stages of dementia such as SCD there is limited research on its prevalence specifically in India. The present study aims to bridge this research gap by estimating the prevalence of SCD in India and assessing urban‐rural differences in its prevalence as well as sociodemographic factors.

Method

The study used data from two ongoing community‐based prospective cohort studies, namely the Tata Longitudinal Study of Ageing (TLSA) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) in urban Bangalore and Srinivaspura respectively (Sundarakumar et al., 2020). Baseline data collected from 4429 participants aged 45 years and older were included in the analysis. The study used Clinical Dementia Rating Scale (CDR) scores and participants' responses to the questions pertaining to subjective cognitive impairment in Cognitive Function Instrument (CFI) and Geriatric Depression Scale (GDS) to estimate the prevalence of SCD.

Result

Of 4429 participants recruited between 2015 and 2022, a total of 1010 (22.8%) participants [median (IQR) age, 60 (15)] were classified as having SCD. As shown in Tabe1, the prevalence was higher in the rural cohort than in the urban cohort (25.1% vs 14.0%, p<0.001). The rural cohort was also found to be comparatively younger (57 (15) vs 63 (14)), and have fewer years of education (4 (9) vs 15(2)). Depression was found to have significant association with SCD in both the cohorts, with more depressive symptoms observed in the rural cohort. As shown in Table 2, the prevalence of SCD was higher in women than men in the urban cohort.

Conclusion

The study’s findings indicate that despite being comparatively younger, the rural cohort had a higher prevalence of SCD, potentially due to the protective effect of higher years of education in the urban cohort.
The PACt‐MD randomized clinical trial: Prevention of Alzheimer’s dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression
Authors: Rajji Tarek K. , Bowie Christopher R , Herrmann Nathan , Pollock Bruce G. , Lanctôt Krista L. , Kumar Sanjeev , Flint Alastair , Mah Linda , Fischer Corinne E. , Butters Meryl A. , Bikson Marom , Blumberger Daniel M. , Daskalakis Zafiris J. , Rapoport Mark J. , Verhoeff Nicolaas Paul L.G. , Golas Angela C , Graff‐Guerrero Ariel , Vieira Erica , Voineskos Aristotle N. , Brooks Heather , Melichercik Ashley , Thorpe Kevin E , Mulsant Benoit H. ,   PACt‐MD Study Group
Published: December 2023

Background

Interventions to prevent cognitive decline and dementia in high‐risk populations such as those with remitted Major Depressive Disorder (rMDD) or Mild Cognitive Impairment (MCI) are urgently needed.

Method

PACt‐MD was a double‐blind randomized trial conducted between 2015 and 2022 comparing cognitive remediation (CR) plus transcranial Direct Current Stimulation (tDCS) vs. sham‐CR+sham‐tDCS delivered 5 days/week for 8 weeks followed by 5‐day semi‐annual boosters and at‐home daily CR, in participants with rMDD or MCI. Participants were assessed at baseline, week‐8, and yearly.

The hypotheses were that compared to sham+sham, CR+tDCS would: slow cognitive decline (H1); reduce progression to MCI or dementia (H2); and acutely improve cognition (H3).

The primary outcome composite score was calculated when at least half of the tests for at least four of six cognitive domains were completed. Due to COVID‐19, some participants did not complete enough tests and a second composite score using all available data was generated.

Result

375 participants were randomized (Active: N = 188, Mean Age = 72.1 ± 6.3; Sham: N = 187, Mean Age = 72.3 ± 6.4) and received at least one intervention session. Over up to six years, there was no time‐by‐treatment interaction using the primary composite score but there was using the all‐data score. Change in composite score differed between the two intervention groups for the primary and all‐data scores for all years except for year‐6 primary score. The year‐5 adjusted z‐score difference was ‐0.15 (95%CI [‐0.29, ‐0.005]) for the primary and ‐0.21 (95%CI [‐0.34, ‐0.067]) for all‐data score (Fig.1). Comparing active vs. sham at 8‐week (H3), the adjusted z‐score difference was ‐0.06 (95%CI: [‐0.12, 0.005]; p = 0.072); and for progression (H2), HR was 0.66 (95%CI [0.40, 1.08] p = 0.101) in a stratified Cox model. In a preplanned secondary analysis of domain scores, there was a time‐by‐treatment interaction for verbal memory with a year‐5 adjusted z‐score difference of ‐0.30 (95%CI [‐0.53, ‐0.074]) (Fig.2) but not the other domains. In another preplanned secondary analysis, the model with a randomization diagnosis‐by‐time‐by‐treatment was different from the model without this three‐way interaction (p = 0.012; Fig.3).

Conclusion

CR+tDCS may be effective in slowing cognitive decline (particularly verbal memory) in older patients with rMDD or MCI.
The effect of psychosocial state in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer’s disease: A cross‐sectional study
Authors: Xu Weijia , Zhao Junyu , Li Hong , Li Yulian , Luo Tingyu , Lin Rong , Yan Yuanjiao , Chen Lili , Pan Xiaodong , Xin Jiawei
Published: December 2023

Background

Social support and mental health are important issues in the context of elderly care. Social support is beneficial to both mental health and cognition. The purpose of this study was to investigate the effect of social support and mental health in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and Alzheimer´s disease (AD).

Method

In this cross‐sectional, observational study, participants were 219 people between 45 and 93 (mean age = 61.82; SD = 10.13), and divided into three cognitive groups (SCD, MCI, AD). Neuropsychological assessment and psychological questionnaires were used for data collection and analysis.

Result

The SCD group and MCI group scored higher than patients with AD on the Adult Mental Health Scale (AMHS) and the Social Support Rating Scale (SSRS). The results of this study suggest that the degree of cognitive impairment of middle‐aged and old people is affected by age and education level, and is related to the level of social support and mental health status (P<0.05).

Conclusion

The level of social support, mental health and cognitive decline are closely related in patients with cognitive impairments. Therefore, it is very important to give early intervention to middle‐aged and old people with poor mental health status and social support status, so as to delay the progression of cognitive impairment.
The role of synbiotics in Alzheimer`s management
Authors: Corrie Leander , Singh Sachin Kumar , Gulati Monica
Published: December 2023

Background

Quercetin and Lactobacillus Brevis were used in the development of S‐SNEDDS for their antiinflammaging effect in Alzheimer`s disease

Method

The isotropic mixture was prepared by incorporating Capmul MCM, Tween 80 and Transcutol P as oil, surfactant and co surfactant phases respectively. Quercetin was then added. The probiotic mixture was selected as a solid carrier and drug loading was calculated. The droplet size and zeta potential was also determined. The formulation was also assessed for differential scanning colorimetry (DSC), powder x ray diffraction studies (PXRD), and field emission scanning electron microscopy studies (FESEM). Stability studies of the developed formulation was also carried out. Alzheimer’s disease was induced in rats by the use of aluminum chloride (100mg/kg) after taking necessary permission from the institution animal ethical committee. The Morris water maze (MWM) test was used to assess the animals 48 hours following the last treatment. Utilizing marketed ELISA kits, the concentrations of TNF, IL‐1, and IL‐6 were determined.

Result

Quercetin was solubilized in the isotropic mixture. The drug loading was found to be 93.4±0.75% for the liquid SNEDDS (QUE‐L‐SNEDDS) formulation. The droplet size of QUE‐L‐SNEDDS was found to be 73.24±1.45nm and had a zeta potential of ‐23.21±1.34 mV. Whereas, the solid SNEDDS (QUE‐LB‐S‐SNEDDS) was found to be 74.56±1.23 nm and had a zeta potential of ‐21.43 mV, respectively. This indicated that there was no change in the L‐SNEDDS and S‐SNEDDS formulation. Further, the amorphous nature of quercetin was confirmed by the DSC, PXRD and FESEM studies. Aluminum chloride was successful in inducing Alzheimer`s disease in the rats. Impaired learning and memory impairments, increased short‐term memory loss, and decreased locomotor activity were all observed in the negative controls. The developed formulation was successful in reversing the inflammatory effects of Alzheimer’s disease.

Conclusion

The present study reveals that Quercetin and Lactobacillus Brevis can be used as a symbiotic combination as well as an adjuvant therapy in the treatment of inflammation related to Alzheimer’s disease. The results reveal an interesting outcome at the preclinical level and warrants future studies aimed at other plant based polyphenolic compounds especially in neurodegenerative diseases such as Alzheimer’s disease.
Anti‐mouse CD98hc nanobodies for brain delivery of a therapeutic moiety
Authors: Rué Laura , Jaspers Tom , Degors Isabelle , De Strooper Bart , Dewilde Maarten
Published: December 2023

Background

The blood‐brain barrier (BBB) limits the therapeutic perspective for central nervous system (CNS) disorders such as Alzheimer’s disease. Interestingly, monoclonal antibodies generated against receptor‐mediated transcytosis receptors are able to transport therapeutic proteins across the BBB. Nanobodies, which are the variable domain isolated from camelid heavy‐chain only antibodies have also shown their potential to deliver therapeutics into the CNS. Here we aimed to expand the panel of nanobodies targeting other brain endothelial cell receptors.

Method

Camelids were immunized with a pool of DNA encoding for several brain endothelial cell receptors. One target was chosen to validate the immunization and discovery approach, CD98hc, previously suggested to allow drug shuttling across the BBB. Nanobody libraries were selected on Chinese Hamster Ovarian (CHO) cells overexpressing the target of interest. Selected nanobodies were screened in vivo based on their potential to deliver into the CNS either a biologically active neuropeptide neurotensin to reduce body temperature, or a BACE1 inhibiting antibody that reduces the accumulation of Aβ1‐40 species.

Result

DNA immunization followed by selections on CHO cells overexpressing the target of interest resulted in specific anti‐mouse CD98hc binders with affinities in the low nanomolar range. In vivo screening of mouse CD98hc nanobody binders revealed some discrepancy between the two methods used. Whereas none of the tested nanobodies fused to neurotensin was able to reduce body temperature, nanobodies fused to the anti‐BACE1 antibody 1A11 effectively reduced Aβ1‐40 levels in the brain. We suggest that the neurotensin approach, although having shown robustness with anti‐TfR nanobodies, might lack sensitivity when screening non‐TfR binders. We suggest BACE1 inhibition as a more robust model to validate CD98hc‐mediated transport across the BBB.

Conclusion

This is a proof of concept study in which we have optimized our nanobody discovery approach to find nanobodies against BBB targets, and validated CD98hc as a receptor to target in order to shuttle drugs into the brain. In the future we will explore whether nanobodies raised against novel brain endothelial cell receptors could also improve brain penetration of biologics.
A risk variant in TTC3 modifies the actin cytoskeleton organization and PI3K‐Akt signaling in iPSC‐derived forebrain neurons
Authors: Cukier Holly N. , Duarte Carolina L. , Laverde‐Paz Juliana , Simon Shaina A. , Van Booven Derek , Miyares Amanda T. , Vance Jeffery M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Dykxhoorn Derek M.
Published: December 2023

Background

We identified a rare, nonsynonymous variant in the tetratricopeptide repeat domain 3 (TTC3) gene that segregated in a non‐Hispanic white late onset Alzheimer disease (LOAD) family (Kohli, et al, 2016). This missense alteration, rs377155188 (p.S1038C), is predicted to be deleterious and is extremely rare. Studies have reported that cortical TTC3 expression is reduced in LOAD patients and negatively correlated with AD neuropathology.

Method

To understand the mechanism by which the TTC3 p.S1038C may contribute to LOAD risk, CRISPR/Cas9 genome edited induced pluripotent stem cells (iPSCs) were developed that were homozygous for the variant to examine cellular and transcriptional consequences in iPSC‐derived neuronal cells (Laverde‐Paz, et al, 2021).

Result

Quantitative PCR and western blot analysis demonstrated that TTC3 levels were decreased in edited compared to unedited iPSCs, as well as differentiated neurons. In growing neuronal precursor cells (NPCs), cells with the TTC3 variant recovered more quickly from a scratch wound. Since there is evidence that modulation of TTC3 affects neurite growth, morphological measures of axon formation were assessed using the Incucyte Zoom. Studies demonstrate an increase in neurite outgrowth, which phenotypically corresponds with previous studies of a decrease in TTC3 function. This phenotype was tempered by treatment with Cytochalasin D, an inhibitor of actin polymerization. Additionally, TTC3 ubiquitinates phosphorylated AKT and regulates AKT signaling. The edited cells were found to have an increase in phosphorylated AKT (pAKT) relative to total AKT. RNA‐seq of day 70 neurons identified 979 genes that were differentially expressed (FDR<0.05). This included known AD genes (BACE1) and genes in AD GWAS loci (ADAMTS1, MAF, NCK2). KEGG pathway analysis identified differential expression in PI3K‐Akt signaling pathway components, in which TTC3 has been previously implicated, as well as the axon guidance pathway, the GABAergic synapse pathway, and the Wnt signaling pathway.

Conclusion

Combined, these results suggest that the TTC3 p.S1038C variant causes a loss of function. Utilizing a CRISPR genome edited iPSC carrying a homozygous alteration in TTC3, we were able to identify potential mechanisms by which TTC3 may contribute to LOAD risk.