bluuebunny/crossref_metadata_2025 huggingface dataset:
Homocysteine, vitamin B12, folic acid levels and its association with Mild Cognitive Impairment in urban and rural dwelling Indians
Authors: Mallikarjun Divya N , Malo Palash Kumar , Partha Ajith , L Abhishek M , Stezin Albert , Velavarajan Goutham , Narayanasamy Rajitha , R Meghana , M Amitha C , Menon Meenakshi , Arvind Prathima , Hameed Shafeeq K Shahul , S Sunitha H , Singh Sadhana , Kommaddi Reddy Peera , Sundarakumar Jonas S. , Issac Thomas Gregor , Diwakar Latha
Published: December 2023

Background

Homocysteine (Hcy) is a sulfur containing amino acid generated in the metabolism of methionine involving co‐factors such as B vitamins and folic acid. Deficiency of these co‐factors have been associated with increased Hcy levels (Hutto, 1997). Relationship between differing levels of plasma Hcy, vitamin B12, folic acid and cognitive impairment is inconclusive.

Method

Cross sectional analysis was done using the baseline data from two ongoing longitudinal studies such as Tata Longitudinal Study of Ageing (TLSA, N = 984) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG, N = 4404), an urban and rural cohorts (Sundarakumar et al, 2020) respectively. Hcy, vitamin B12, folic acid levels were compared between the subjects of both cohorts. Comparison of these levels between healthy and MCI (Mild Cognitive Impairment) subjects within and across the cohorts were done. CDR (Clinical Dementia Rating) scale was used to classify subjects having normal cognition and MCI, considering score of 0.5 as MCI. Mann‐Whitney U test was used to compare these levels between the groups.

Result

Hcy, vitamin B12, folic acid levels between the two cohorts showed significant difference, with higher levels of Hcy (median (IQR)) = (17.08 (11) vs 14.63 (10); p <0.001), vitamin B12 (247 (252) vs 220 (143); p <0.001) and folic acid (8.55 (9) vs 5.55(4); p <0.05) in TLSA than SANSCOG. Significant difference seen in Hcy (17.73(11) vs 14.73 (10); p <0.001), vitamin B12 (246 (249) vs 220 (136); p <0.001) and folic acid (8.42 (9) vs 5.53 (4): p <0.001) levels for healthy subjects between cohorts, higher levels were seen in TLSA subjects. Hcy (16.08 (8) vs 14.43 (12); p <0.001) vitamin B12 (305 (341) vs 216 (174); p = 0.03) and folic acid (8.52 (9) vs 5.34 (4): p <0.001) levels were significantly high in TLSA than SANSCOG for MCI subjects. However, these levels were not significantly different between healthy and MCI subjects within cohorts.

Conclusion

Consistently elevated levels of Hcy was observed in urban cohort. Though elevated level of Hcy was observed with normal vitamin B12 and folic acid, it was not associated with MCI.
Knowledge and Perception of caregivers on therapeutic gardens in Elderly care homes in Lagos Nigeria
Authors: Akindejoye Funmi , Achor Micheal
Published: December 2023

Gardening can be an activity that promotes overall health and quality of life, physical strength, fitness, flexibility, cognitive ability, and socialization [1]. Horticulture therapy employs plants and gardening activities in therapeutic and rehabilitation activities and could be utilized to improve the quality of life of the worldwide aging population [2].

In Nigeria families mainly provide support for their elderly ones [3], however, some families are gradually accepting the concept of care‐homes. Such care‐homes are in scarce supply and the available ones are operated by the private sector amidst limited resources. An appraisal of the availability of gardens in care‐homes showed that garden and gardening activities are mostly utilized in high‐income countries (HIC). However, the potential benefits of gardening activity are less well understood by related stakeholders in low‐ and middle‐income countries (LMICs) [4]. There is a dearth in the literature on the health impact of gardening in LMICs, thus the unavailability and lack of awareness of STH gardens in LMICs [4].

This study is an aspect of a social therapeutic horticulture project in two identified care homes in Lagos Nigeria. The study accesses the knowledge of caregivers and the management of STH gardens and the perceived need for such gardens in their respective homes. Utilizing online surveys and interviews for data collection.

Currently, the study is ongoing, and ethical approval is being sourced. We aim to conclude the study before the scheduled 2023 AAIC conference.

References

1. Wang, D., & MacMillan, T. (2013). The benefits of gardening for older adults: a systematic review of the literature.

2. Detweiler, M. B., Sharma, T., Detweiler, J. G., Murphy, P. F., Lane, S., Carman, J., & Kim, K. Y. (2012). What is the evidence to support the use of therapeutic gardens for the elderly?

3. Dokpesi, A. O. (2015). The future of elderly care in Nigeria: borrowing a leaf from a foreign land.

4. Ainamani, H. E., Bamwerinde, W. M., Rukundo, G. Z., Tumwesigire, S., Kalibwani, R. M., Bikaitwaho, E. M., & Tsai, A. C. (2021). Participation in gardening activity and its association with improved mental health among family caregivers of people with dementia in rural Uganda.
Novel High‐Donepezil Loaded One‐Month Release Microspheres for Alzheimer’s Disease Treatment
Authors: Lee Jinwoo , Kim Hyemin , Lee Wonyoung , Jeong Yeojin , Lee Juhan , Seol Eunyoung , Lee Heeyong
Published: December 2023

Background

Donepezil is the most commonly prescribed medication for treating Alzheimer’s disease. However, the most commonly used once daily oral formulation or recently developed once or twice weekly patch formulations have side effects such as nausea, vomiting and weight loss or skin irritation, and the patient’s compliance with these medications is very low. One month release injectable of donepezil microspheres can be a good alternative to increase patient compliance and reduce these side effects. The biggest obstacle in the development of one month donepezil microspheres is that patients tend to feel pain at the injection site due to the large volume of dosage. We have developed novel donepezil microspheres with high drug contents which can improve patient compliance and medication convenience by lowering dosage volume at the injection site.

Method

Mono‐dispersed and spherical shaped donepezil microspheres with different drug contents were manufactured by membrane emulsification method. The morphology of the microspheres was observed by electron microscope, and the particle size distribution was measured by laser diffraction analysis. The donepezil contents in the microspheres were analyzed using HPLC. Pharmacokinetic studies were performed after a single injection in male SD rats. The concentration of donepezil in the plasma samples was determined by LC‐MS/MS.

Result

Donepezil microspheres with three different drug contents (27%, 45% and 60%) were prepared successfully with high drug encapsulation efficiency. All the donepezil microspheres regardless of high drug content have a spherical shape and smooth surface with a narrow side distribution. Despite the high content of donepezil, the initial release was well controlled to less than 5% during the first 24 hours after injection. In rat PK studies of donepezil microspheres after a single injection, plasma donepezil concentration of all three formulations was kept within the therapeutic range for more than one month.

Conclusion

We have developed novel donepezil microspheres with high drug contents and without initial burst release. These high donepezil‐loaded microspheres can improve patient compliance and medication convenience by lowering dosage volume at the injection site. Currently, this novel donepezil formulation is planned for commercialization after clinical trials.
Organizational, intra‐ and interpersonal factors contributing to person‐centred care in long‐term care facilities for people with dementia
Authors: van der Kuil Milan N.A. , Hartstra Egbert , Overbeek Anouk , van der Roest Henriëtte G. , Van der Velden Claudia
Published: December 2023

Background

Person‐centred care (PCC) is seen as the golden standard for dementia care. PCC is characterized by care and support that are in line with the needs, preferences and capacities of people with dementia. Previous research showed that PCC has beneficial effects on the quality of life of people with dementia and improve healthcare professional’s working conditions. Within long‐term care PCC seems to hinge on different factors on integrated levels of care provisioning. The current study aims to provide healthcare organizations and policy makers with more insight into the modifiable factors that contribute to PCC for people with dementia living in long‐term care facilities. To this end, we aim to identify whether and which intrapersonal factors (care professional’s attitude towards dementia, attitude towards technology use, and working experience), interpersonal factors (learning potential of the workplace, vision of care, transformational leadership, emotional job demands and resources), and organizational factors (learning climate of the organization, small‐scale setting and amount of residents per care professional) contribute to higher levels of PCC.

Method

Data were derived from the fifth assessment of the Living Arrangements for people with Dementia (LAD)‐study, which had a cross‐sectional design. The study was performed amongst 58 long‐term care facilities providing clustered care for people with dementia under the Chronic Care Act (WLZ) in the Netherlands. Care professionals completed an adapted version of the ‘Person‐centred care questionnaire’ (PCCq) to assess the level of PCC in the participating facilities. We performed multilevel analyses, controlling for clustering effects.

Result

In total 606 care professionals participated. On the intrapersonal level, care professional’s attitude towards dementia and working experience contributed significantly to PCC. Interpersonal factors that contributed significantly to PCC were possibilities of learning during day‐to‐day work, transformational leadership, and job resources. Organizational factors were not found to significantly contribute to PCC in the model.

Conclusion

Several intra‐ and interpersonal factors, rather than organizational factors, contribute to person‐centred care.
Exploration of novel biomarkers for neurodegenerative diseases using ligand‐binding assays
Authors: Kenzelmann Annalena , Boch Christina , Schulz Michael , Challagundla Malleswari , Just David , Klein Marco , Griesbeck Anne , Schroeder Christoph , Richter Mario
Published: December 2023

Background

Neurodegeneration is a complex area involving multiple pathways and often has a long prodromal phase. Reliable biomarkers are needed to allow earlier diagnosis, monitoring of the disease progression, and studying the impact of therapeutic approaches.

Method

Therefore, a screening was performed by Sciomics GmbH to identify potential protein biomarkers. The most promising analytes were selected, including cluster of differentiation 14 (CD14), osteopontin (OPN), vascular endothelial growth factor A (VEGF‐A), cancer antigen 15‐3 (CA15‐3) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1). Using quantitative ligand‐binding assays based on fluorescence or electrochemiluminescence these analytes were investigated regarding up‐ or downregulation in the presence of Alzheimer´s disease (AD), Parkinson´s disease (PD), Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS) compared to healthy patients.

Result

The quantitative assays confirmed the screening in that CD14 levels were elevated in cerebrospinal fluid (CSF) of AD patients and that OPN levels were increased in CSF of PD patients. In addition, the following significant changes were observed: OPN was elevated in plasma of PD and MS patients, while it was decreased in CSF of MS patients. VEGF‐A levels were increased in the plasma of ALS patients and decreased in CSF of MS patients.

Conclusion

Increased CD14 levels in AD CSF are in agreement with studies suggesting that CD14, a co‐receptor of toll like receptor 4 (TLR4) expressed on the surface of e.g. microglia, might mediate the interaction of fibrillar Aβ to TLR4 and thus induce inflammation. OPN has already been shown to be increased in CSF and blood of PD patients previously and it is suggested to be involved in PD pathogenesis due to its role in oxidative stress, apoptosis, mitochondrial dysfunction, and cytokine regulation. Other studies have shown increased levels of OPN in plasma of MS patients potentially due to its expression in activated T‐cells. However, some studies also show increased MS CSF levels in contrast to our findings, where OPN levels are lower in MS CSF. Literature data for VEGF‐A is more conflicting possibly due to different assays detecting different isoforms. To further solidify these findings, large‐scale analyses using well characterized samples should be done in the future.
Roles of HDAC6 in the pathogenesis of Alzheimer’s disease
Authors: Lee Yujeong , Lee Jeongmi , Jo Dong‐Gyu
Published: December 2023

Background

It has recently been demonstrated that HDAC6 depletion ameliorates the impairment of memory function and mitochondrial axonal transport induced by the accumulation of Aβ. However, very little is known about molecular mechanisms through which HDAC6 regulates APP processing. Also, it remains controversial whether HDAC6 induces inflammation or reduces it.

Method

We analyzed the expression of HDAC6 in AD patients and 5xFAD mice. We confirmed that HDAC6 regulates BACE1 in primary neurons and NLRP3 inflammasome in primary microglia. And we crossed HDAC6 knock‐out mice with 5xFAD mice and got 5xFAD/HDAC6 KO. We compared 5xFAD (n = 11) and 5xFAD/HDAC6 KO (n = 13). We did a nest building test, open field test, Morris water maze, Y‐maze, passive avoidance, and elevated plus maze. After finishing all these behaviour tests, we sacrificed the mouse and checked protein and mRNA. We did Immunohistochemistry using Aβ plaque, NLRP3 inflammasome and synapse‐related markers. We also did RNA‐seq analysis in these mice’s brains.

Result

We confirmed that the expression of HDAC6 was increased in the AD cortex compared to neuropathologically normal brains. The stability of BACE1 is regulated by its C‐terminal lysine, and HDAC6 deacetylates the C‐terminal lysine of BACE1 by direct binding. Also, HDAC6 deficiency reduced NLRP3 inflammasome activation‐, and subsequent inflammatory responses in microglia. By crossing HDAC6 knock‐out mice with 5xFAD mice, the role of HDAC6 was confirmed in an animal model of AD. HDAC6 deletion improved cognitive function and reduced the protein expression of BACE1 and inflammatory factors in 5xFAD mice. Also, HDAC6‐deficient 5xFAD mice developed fewer dense‐core plaques, IL‐1β, and ASC specks than 5xFAD mice. Furthermore, RNA‐sequencing was analyzed from the hippocampus of 5xFAD and 5xFAD/HDAC6 KO mice. Synapse and neuron development‐related genes were significantly up‐regulated, and type I interferon, immune response, and prion disease‐related genes were down‐regulated in HDAC6‐depleted mice. Finally, we confirmed that the ratio of PSD95 colocalized with C1q was significantly decreased in 5xFAD/HDAC6 KO compared to 5xFAD mice, which suggested that synapse loss was inhibited in AD mice.

Conclusion

This study reveals distinct functions of HDAC6 and suggests HDAC6 as a significant regulator in the pathogenesis of AD that could be exploited therapeutically.
A proposed scheme for comprehensive and systematic evaluation of normal pressure hydrocephalus
Authors: Pitaksuteepong Pichaya , Supharatpariyakorn Thirawat , Wangsawatwong Piyanat , Thanprasertsuk Sekh , Chunamchai Sedthapong , Chunharas Chaipat , Pobpan Pea , Sringean Jirada , Paprad Tunchanok , Hemachudha Thiravat , Thanapornsangsuth Poosanu
Published: December 2023

Background

As ageing population continues to rise across the globe, age‐related conditions such as normal pressure hydrocephalus (NPH) are expected to become a prevalent health problem effecting gait and cognition in the elderly. Alas, the vague definition of NPH, coupled with the absence of standardized assessment protocols, can potentially result in unnecessary surgical interventions and complications. We aim to demonstrate the feasibility of our proposed objective scheme for a comprehensive and systematic evaluation of NPH, which we anticipate will be beneficial in guiding future management of this enigmatic disorder.

Method

Participants suspected of idiopathic NPH (iNPH) selected to undergo a trial of fluid diversion (i.e. large volume spinal tap) were enrolled to receive structured assessment with various biomarkers. This assessment includes pre‐fluid diversion evaluation of the following: iNPH grading scale (Kubo et al., 2008), voxel based morphometry analysis of the MRI, tablet‐based digitalized Montreal Cognitive Assessment, International Consultation on Incontinence Questionnaires, urodynamic studies. Tests that were conducted both pre‐ and post‐fluid diversion test included actigraphy, video gait analysis using Kinovea®, in‐house tablet‐based go/no‐go test and conjunction search test. During the fluid diversion trial, participants underwent an infusion test for objective quantification of cerebrospinal fluid dynamics. Cerebrospinal fluid was collected and analyzed for levels of Alzheimer’s disease biomarkers, specifically Aβ and tau species, using ELISA, as well as an α‐synuclein seeding assay. The decision to operate was made according to subjective improvement, which is the current standard of care, and subsequent assessments were repeated at 4‐month intervals for 1, 2, and 3 years postoperatively

Result

Between May 2022 and November 2022, six participants were recruited. Each test was completed by at least three out of the six participants. The participant who completed the most tests completed all but one of the tests. It is important to note that none of the participants recruited underwent shunt surgery.

Conclusion

The proposed scheme for the assessment of NPH demonstrates feasibility, however, certain optimizations are necessary. Further research should be conducted to determine the correlation between these parameters and their performance in predicting long‐term responsiveness to shunt surgery.
Natural trimethoxyflavone improves memory in mice via cholinergic, oxidative, inflammatory and apoptotic pathways
Authors: Singh Varinder , Singh Manjinder , Singh Thakur Gurjeet , Shri Richa
Published: December 2023

Background

Dementia is a deliberating neurodegenerative disorder which causes impairment of intellectual functions. The USFDA approved drugs has limited efficacy and numerous side effects. Thus, finding newer drugs to manage dementia and cognitive disorders is certainly required. The present study explores the potential of a natural flavone, 5,7‐dihydroxy‐3',4',5'‐trimethoxyflavone (DHF), as memory enhancer drug against scopolamine‐induced cognitive deficit in mice.

Methods

Animals were treated with DHF (5‐10 mg/kg, p.o.) for 7 days after inducing cognitive impairment by scopolamine (1mg/kg,i.p.). Memory functions (passive shock avoidance task and Morris Water Maze), brain acetylcholinesterase (AChE) activity, inflammatory markers, oxidative stress, apoptotic biomarkers and histopathological studies (H&E and congo red staining for beta amyloid) were determined to measure memory improvement effects of DHF. In‐silico (molecular docking) studies were performed to understand the interactions of DHF with key pathological enzymes related to dementia.

Results

Treatment of scopolamine administered mice with DHF improved scopolamine‐induced cognitive impairment and restore brain biochemical parameters (inhibited acetylcholinesterase activity, enhanced glutathione levels, and reduced TBARS, TNF‐α, IL‐6, IL‐1β and caspase‐3 levels). Moreover, histopathological studies showed that DHF treatment reduced the neuronal cell death and amyloid depositions in mice brain. Further, molecular docking studies revealed string interactions of DHF with crucial amino acids of AChE and caspase‐3.

Conclusion

These results suggest that DHF was effective in treating scopolamine induced cognitive deficit by improving cerebral cholinergic dysfunction and reducing brain oxidative stress, inflammation, apoptosis and beta‐amyloid depositions in mice. Thus, DHF could be developed as a potential alternative drug to treat memory disorders.
Multimodal retinal imaging in individuals with frontotemporal dementia compared to controls
Authors: Allen Ariana , Joseph Suzanna , Hemesath Angela , Kundu Anita , Robbins Cason B , Ma Justin , Haystead Alice , Winslow Lauren , Bozoki Andrea , Johnson Kim G , Stinnett Sandra , Grewal Dilraj S , Fekrat Sharon , Group MIND Study , School Duke University
Published: December 2023

Background

A growing body of literature has shown a relationship between neurodegenerative diseases and ocular changes. Frontotemporal dementia (FTD) affects individuals under age 65. We use optical coherence tomography (OCT) and OCT angiography (OCTA) to characterize the retinal microvasculature and retinal and choroidal structure in patients with FTD vs normal cognition.

Method

Cross‐sectional comparison of patients with FTD to age‐ and sex‐matched controls with normal cognition. Exclusion criteria included diabetes, glaucoma, uncontrolled hypertension, and retinal or optic nerve pathology. Participants underwent OCT and OCTA imaging using the Zeiss Cirrus HD‐5000 Spectral‐Domain OCT with AngioPlex. Primary outcome measures included OCT parameters: subfoveal choroidal thickness, central subfield thickness, ganglion cell layer‐inner plexiform layer (GC‐IPL) thickness, and retinal nerve fiber layer (RNFL) thickness; and OCTA parameters: superficial capillary plexus foveal avascular zone area, 3×3mm and 6×6mm macular vessel density (VD) and perfusion density (PD), and 4.5×4.5mm peripapillary capillary perfusion density (CPD) and capillary flux index (CFI). Generalized estimating equations accounting for correlation between 2 eyes of the same subject were utilized for statistical analysis.

Result

Twenty‐eight eyes of 17 participants with FTD and 85 eyes of 48 patients with normal cognition were analyzed. Individuals with FTD were matched to their normal cognition counterparts with regard to sex (64.7% vs 62.5% men, p = 0.871) and age (67.82 vs 68.98 years, p = 0.958). Compared to normal cognition participants, MMSE scores of FTD participants were significantly lower (p < 0.001). In FTD, average 4.5×4.5‐mm CFI was decreased compared to controls (p = 0.032). There was no difference in average 4.5×4.5mm CPD between FTD and controls (p = 0.172).

Conclusion

Individuals with FTD exhibited significantly reduced average CFI compared to controls. Retinal microvasculature changes may be useful as a biomarker for FTD diagnosis.
Differences in metabolomic profiles of APOE4 carrier vs non‐carrier patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease
Authors: Minguet Carla , Ortiz Ana Maria , Gonzalo Ricardo , Núñez Laura , Ruiz Agustin , Lopez Oscar L. , Boada Mercè , Páez Antonio , Bravo Isabel , Costa Montserrat
Published: December 2023

Background

Apolipoprotein E is the major apolipoprotein found in plasma, involved in lipid transport and metabolism. Carrying the ε4 allele of the APOE gene (ApoE4) is a risk factor for developing Alzheimer’s disease (AD) and is associated with altered plasma lipid levels and lipoprotein particle distribution. The AMBAR phase 2b/3 trial is a therapeutic approach for AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma‐exchange procedures with albumin replacement (PE‐Alb) to remove pathological substances from plasma, slowing AD progression. The aim of this study was to assess PE‐Alb differential effects on metabolites across the AMBAR trial between ApoE4 carriers and non‐carriers.

Method

442 metabolites were quantified in serum samples of 296 ApoE‐genotyped patients included in the AMBAR trial (225 PE‐Alb‐treated and 71 placebo), at 3 time‐points, using high‐throughput UHPLC‐MS (OWL‐Metabolomics, Spain). Data was stratified by ApoE4 carriers (n = 145) and non‐carriers (n = 151) and analyzed through a mixed model for repeated measures. Differences from placebo were assessed through month*treatment group interaction estimates. Reported p‐values were adjusted by Benjamini‐Hochberg procedure.

Result

Baseline differences between ApoE4 carriers and non‐carriers were found according to what has been reported in the literature. In ApoE4 carriers, 29 metabolites significantly changed (Adjusted p‐value<0.05) in PE‐Alb‐treated patients compared to placebo at end of study (month 14). Eleven of them, which were in the free Fatty Acids (FA) class (6 monounsaturated‐FA, 3 polyunsaturated‐FA, 2 saturated‐FA), were down regulated. This would agree with the previously reported finding that free‐FA levels increase in blood from AD patients and participate in the pathogenesis of AD by multiple mechanisms. In Non‐carriers, 19 metabolites showed statistically significant change at month 14, 2 of them being downregulated. In both stratifications, most upregulated metabolites were in the Glycerophospholipid class (21/35) which has been reported to be decreased in AD. All other metabolites were in the Glycerolipids (4), Sphingolipids (4), Sterols (3), Bile acids (2) and Amino Acids (1) classes.

Conclusion

These results demonstrate modulation of fatty acid metabolism in PE‐Alb‐treated patients from the AMBAR trial in relation to its ApoE genotype. Furthermore, treatment induced positive metabolite changes compared to placebo. These results deserve further investigation.
Sex impacts the association of plasma Glial Fibrillary Acidic Protein with neurodegeneration in Alzheimer’s disease
Authors: Abbas Sarah , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Lemaire Peter Charles , Soares Carolina , Rohden Francieli , Aguzzoli Cristiano Schaffer , Cabrera Arlec , Leffa Douglas Teixeira , Therriault Joseph , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Chamoun Mira , Bezgin Gleb , Stevenson Jenna , Stevenson Alyssa , Rahmouni Nesrine , Pallen Vanessa , Karikari Thomas K , Ashton Nicholas J. , Benedet Andrea Lessa , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Pascoal Tharick Ali
Published: December 2023

Background

Growing evidence suggests an increased prevalence of Alzheimer’s disease (AD) in females compared to males. Elucidating how disease biomarkers correlate in females and males is critical to understanding the basis of sex differences in AD. Our aim was to evaluate sex‐related differences in the association of plasma Glial fibrillary acidic protein (GFAP) levels, a biomarker of astrocyte reactivity, with downstream neurodegeneration in Alzheimer’s disease (AD) pathophysiology.

Method

We cross‐sectionally assessed participants from TRIAD cohorts. Unpaired t‐test compare the difference in plasma GFAP levels between females and males. We performed linear regression with an interaction term for sex to compare the association of plasma GFAP with neurodegeneration measured with hippocampal volume (HCV) between cognitively impaired females and males.

Result

We assessed 308 participants (MCI = 63, AD = 45 CN = 200, mean age = 69.8 (8)). Females showed significantly higher GFAP levels than males (Fig 1). We found a significant interaction term and strong correlation between plasma GFAP and neurodegeneration (HCV atrophy) (R‐squared = 0.13; P = 0.003) only in females. No association was found between GFAP and AD biomarkers in females or males without cognitive impairment (Fig 2).

Conclusion

Our results suggest astrocyte reactivity is highly associated with neurodegeneration, a process known to play a key role in AD pathophysiology, in females than males. This may have important implications for elucidating the basis of the higher prevalence of AD in females. Yet, these results were generated with a limited number of subjects and using a cross‐sectional design. Therefore, replication in larger, independent longitudinal datasets is needed to better understand the association of GFAP levels, sex, and AD pathophysiology.
Clinical validation of TAS Test automated hand motor analysis to discriminate subjective cognitive decline, mild cognitive impairment and dementia in a multidisciplinary cognitive clinic
Authors: Alty Jane E , Wang Xinyi , Li Renjie , Rudd Kaylee , Lawler Katherine , Salmon Katharine , McDonald Scott , Stuart Kimberley E , Bindoff Aidan D , Bai Quan , Vickers James C
Published: December 2023

Background

Gait analysis studies have shown that motor function declines across the Alzheimer’s disease (AD) continuum and may aid early detection of dementia risk. Hand movement analysis has been poorly investigated in comparison to gait but may be easier to assess using computer keyboards. TAS Test is a new automated online test of hand movements. The aim of this study was to evaluate TAS Test keyboard tapping tests compared to gold standard consensus diagnosis in a multidisciplinary team (MDT) cognitive clinic.

Method

Participants attending the ISLAND Cognitive Clinic in Tasmania, Australia underwent extensive neuropsychological, medical and MRI assessments before an MDT consensus diagnosis was formulated. They also completed 5 minutes of TAS Test keyboard tapping tests including single‐, alternate‐ and 3 step‐ key tapping tests. Motor features of frequency, rhythm, accuracy, and dwell time were extracted. Healthy controls (HC) with normal cognition also completed TAS Test. Accuracy to discriminate diagnostic groups using TAS Test motor features, adjusted for age, in ridge regression models was assessed using area under ROC curves (AUC) and compared to a null model which comprised only confounding variables.

Result

205 participants were recruited (mean [SD] age 69.0 [8.9] years): 91 from the Cognitive Clinic with Subjective Cognitive Decline (SCD, N = 16), Mild Cognitive Impairment (MCI, N = 40) or Dementia (N = 35) and 114 HCs. TAS Test discriminated better than null models with the following AUCs [95% CI]: SCD from HC: 0.82 [0.73‐0.91], MCI from HC: 0.78 [0.69‐0.86], Dementia from HC: 0.91 [0.86‐0.97], MCI from SCD: 0.7 [0.63‐ 0.92], Dementia from MCI: 0.82 [0.82‐0.97], all p <0.01. Hand tests were characterized by progressively slower, less rhythmic movements, with more pauses and less accuracy across the dementia continuum. Dominant hand features were more discriminatory than non‐dominant hand features.

Conclusion

A simple brief battery of keyboard tapping tests via the TAS Test website aids stratification of diagnostic groups. This novel hand motor approach is more accessible than gait analysis and opens new opportunities for objective motor measure in clinical and research applications. Longitudinal research is underway to assess if TAS Test can aid prediction of cognitive decline in cognitively healthy controls.
Neuroprotective potential of safinamide mesylate in streptozotocin induced sporadic Alzheimer’s disease in rats
Authors: Kajal Ms , Kumari Shamly , Deshmukh Rahul Renukadas
Published: December 2023

Background

Alzheimer’s disease (AD) is an age related progressive neurodegenerative disorder mainly characterized by cognitive decline, synaptic loss, and other mental functions. Extracellular amyloid beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein are the two major hallmarks of AD. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost is the dysregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit. The present study was designed to investigate the neuroprotective potential of Safinamide mesylate in Streptozotocin induced sporadic Alzheimer’s disease in rats. STZ (3mg/kg) was administered bilaterally through the intracerebroventricular (i.c.v.) route on the 1st and 3rd days in rats.

Method

In the present study, we have explored the neuroprotective potential of Safinamide a potent MAO‐B inhibitor and a neuroprotective drug against STZ infused rats at dose levels of 15 and 30 mg/kg/i.p. for treating AD from day 15th to 28th. Spatial and non‐spatial memory was evaluated by using Morris Water Maze (MWM) and Object Recognition Test (ORT) while spontaneous locomotion is examined by Open field test . We further performed biochemical tests to check the levels of different oxidative stress markers & histopathological evaluation to analyze the neurodegeneration.

Result

The cognitive and memory deficits by the significant increase in oxidative stress markers produced by i.c.v. STZ was determined by biochemical analysis. The neurodegeneration in the hippocampus and cortex region was observed through histopathological analysis. Safinamide treatment significantly attenuated the STZ induced memory decline, neuroinflammation and prevented the neuronal loss. The observed cognitive improvement followed by safinamide administration may be due to its neuroprotective, anti‐inflammatory, and anti‐apoptotic activity.

Conclusion

Based on the outcomes of the current investigations it would be safe to conclude that safinamide mesylate has neuroprotective potential and the observed cognitive enhancement in STZ rats following safinamide mesylate treatment may be due to its antioxidant potential and its ability to protect or preserve neuronal cells.
Factors associated with caregiver burden in early onset dementia: the LEAF study
Authors: Lee Sun Min , Kim Hee Jin , Jung Na‐Yeon , Park Kee Hyung , Cho Hanna , Kim Yeshin , Jang Jae‐Won , Kang Heeyoung , Lee Jin San , Kang Sung Hoon , Yoon Soo Jin , Kim Hang‐Rai , Park Kyung Won , Chung Eunjoo , Park Young Ho , Jang Hyemin , Lim Jae Sung , Kim Geon Ha , Jeong Jee Hyang , Choi Seong Hye , Cho Su Hyun , Kim Seung Joo , Kwon Jay Cheol , Lee Juyoun , Kang Kyunghun , Kim Jaeho , Kim Hee‐Jin , Kim Si Eun , Yi Hyon‐Ah , Park Ji Yoon , Kim Eun‐Joo , Moon So Young
Published: December 2023

Background

Early‐onset dementia is often predicted to have a greater care burden than late‐onset dementia. Indeed, previous studies have reported that caregivers of early‐onset dementia suffer more than those of late‐onset dementia. We explored the factors that determine care burden in early‐onset dementia.

Method

Caregivers whose patients participated in a longitudinal study of early onset dementia and family members (LEAF) were asked to respond to questionnaires regarding caregiver features and care burden such as CAS‐K (Korean Version of Caregiver Activity Survey), ZBI (Zarit Burden Interview), and SF‐36v2® (Short‐Form Health Survey 36 version 2). Correlation and linear regression analyses were conducted to clarify the factors affecting care burden, using commercial software (SPSS 23.0;SPSS Inc. Chicago,IL,USA).

Result

A total of 255 caregivers (54.5±25.3 years old, 54.9% female) were divided into three groups depending on the clinical diagnosis of the patients they cared for (EOAD 181; FTD 53; other EOD 21). There were no statistical differences of demographic characteristics and care burden related variables among three groups of caregivers. The general burden for caregivers and time spent in caregiving were higher in patients with shorter education years, lower mini‐mental state examination(MMSE) scores (‐0.381, p<0.001), higher clinical dementia rating(CDR) (0.359, p<0.001), higher CDR sum of boxes (0.418, p<0.001), decreased level of activities of daily living (ADL, basic ‐0.334, p<0.001; instrumental 0.527, p<0.001), higher geriatric depression scale (GDS, 0.245, p<0.001) and higher body mass index(BMI, 0.149, p<0.05). Caregivers with a high Beck depression inventory(BDI) (0.218, p<0.001) spent more time for caring patients. The general care burden was greater in younger caregivers (‐0.142, p<0.05) and in caregivers with lower average monthly income(‐0.166, p<0.001), decreased physical function (‐0.142, p<0.05), poorer mental health (‐0.150, p<0.05), and more physical/emotional role limitation (‐0.464, p<0.001).

Conclusion

This study is expected to have implications in that it also reviews the economic status of caregivers and ongoing personal and social changes according to the care burden. Demographic and clinical factors of patients and caregivers predict care burden in early‐onset dementia. This suggests that it is possible and necessary to attempt to reduce care burden through adjustment and support for related factors.
Identification of CSF biomarkers for cerebral amyloid angiopathy using a targeted proteomics approach
Authors: Kuiperij H. Bea , de Kort Anna M. , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Verbeek Marcel M.
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) is characterized by progressive vascular deposition of amyloid‐β (Aβ), and can cause cognitive decline in the elderly. Currently, the diagnosis of CAA is based on neuroimaging and includes the identification of lobar (micro‐)bleeds and cortical superficial siderosis. There is, however, a need for alternative methods as these neuroimaging methods are not optimal for detection of CAA during life. Moreover, CAA is strongly associated with the risk to develop edematous or hemorrhagic amyloid‐related imaging abnormalities (ARIA) as a consequence of anti‐Aβ immunotherapy (e.g. aducanumab and lecanemab) for Alzheimer’s disease (AD). There is a need for biomarkers that can provide an accurate and early diagnosis of CAA, and additionally help in the identification of AD patients with a high burden of CAA, who are at risk of developing ARIA due to immunotherapy. We aimed to identify novel biomarker candidates for CAA in cerebrospinal fluid (CSF) using a targeted proteomics approach.

Method

We analyzed a panel of 367 proteins in CSF samples of 34 CAA patients and 51 age‐ and sex‐matched controls using the Olink Explore multiplex immunoassay platform (Neurology panel; Olink, Uppsala, Sweden). Proteins were considered measurable when their levels were above the limit of detection of the assay in at least 70% of the samples.

Result

For 15 of the 263 proteins that could be measured in CSF, we identified significantly different (p<0.05) levels in CSF of CAA patients as compared to controls. The strongest difference was observed for neurofilament light chain (NFL). Among these 15 proteins, there were two proteins (milk fat globule‐epidermal growth factor 8 (MFG‐E8/lactadherin) and urokinase‐type plasminogen activator (uPA)) for which we previously observed a significant changed level in CSF of CAA patients compared to controls 1,2.

Conclusion

Confirmation of previously identified CAA biomarker candidates shows the validity and strength of our biomarker identification study using a targeted proteomics approach. The 15 candidates identified in our study, therefore, hold promise for development into biomarkers that may improve the detection of CAA.

References: 1 Marazuela et al, Acta Neuropathol Commun. 2021;9(1):154.

2 Vervuurt et al, Neuropathol Appl Neurobiol. 2022;48(5):e12804.
The development of therapeutic nanovaccine that elicits anti‐Aβ antibodies and Aβ‐specific regulatory T cells for the treatment of Alzheimer’s disease.
Authors: Lee Songmin , Jung Mungyo , Kim Byung‐Soo , Kim YoungSoo
Published: December 2023

Background

Alzheimer’s disease (AD) is a multi‐factorial cognitive disorder with complex pathogenesis including the accumulation of beta‐amyloid (Aβ) plaque and neuroinflammation. In previous studies, active immunotherapy injecting Aβ peptide as an antigen achieved the prophylaxis of Aβ accumulation by generating anti‐Aβ antibodies. Otherwise, the adoptive transfer of regulatory T (Treg) cells attenuated neuroinflammation by secreting anti‐inflammatory cytokines in the AD brain. To combine both approaches and improve the therapeutic efficacy against AD, we developed a nanovaccine that presents Aβ peptides as antigen and simultaneously induce the differentiation of naive T cells into Aβ‐specific Treg cells.

Method

A lipid nanoparticle loaded with Aβ peptides and rapamycin (LNP‐R/Aβ) was intradermally injected once a week for five weeks into a transgenic AD mouse model, 5XFAD. The generation of Aβ‐specific antibodies in the plasma and brain was measured by indirect enzyme‐linked immunosorbent assay. Induction of Treg cells in the spleen was measured by flow cytometric analysis and RT‐qPCR analysis. The accumulation of Aβ aggregates in the brain and the level of neuroinflammation were evaluated by immunohistochemical and immunoblotting assay. The cognitive function of 5XFAD was assessed through the Morris water maze test.

Result

Administration of LNP‐R/Aβ generated anti‐Aβ polyclonal antibodies detecting the N‐terminus (Aβ1‐8) of the Aβ peptide. Also, the increased level of CD4+Foxp3+Treg cells was observed in the spleen and brain. The Treg cells induced by the LNP‐R/Aβ more efficiently reduced the Aβ plaque accumulation than general Treg cells, indicating that LNP‐R/Aβ promoted the generation of Aβ‐specific Treg cells. Also, the Aβ‐specific Treg cells led to the differentiation of microglia into anti‐inflammatory form of microglia secreting anti‐inflammatory cytokines such as TGF‐β1 and IL‐10. These changes resulted in a significantly decreased amount of Aβ plaques and the attenuated proliferation of reactive microglia and astrocyte in the 5XFAD mice brains. Furthermore, LNP‐R/Aβ injected 5XFAD mice showed improved learning and memory function in the Morris water maze test.

Conclusion

LNP‐R/Aβ proposes a novel approach to AD treatment that achieves synergistic therapeutic efficacy by combining the mode of action of anti‐Aβ antibodies and Aβ‐specific Treg cells.
Association of waist‐to‐hip ratio with Alzheimer’s disease and neuroinflammation biomarkers in cognitively unimpaired adults
Authors: Tort‐Colet Núria , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Kollmorgen Gwendlyn , Carboni Margherita , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Suarez‐Calvet Marc , Grau‐Rivera Oriol
Published: December 2023

Background

Obesity is associated with higher risk of Alzheimer’s disease (AD) and other dementias. This association could be mediated by a pro‐inflammatory effect of abdominal adiposity. Here, we used the waist‐to‐hip ratio (WHR) as a proxy for central adiposity to explore its association with AD and neuroinflammation biomarkers, as well as its interaction with sex in cognitively unimpaired adults from the ALFA+ cohort.

Method

We analyzed data from 353 participants (61.2% females; 64.3% β‐amyloid [Aβ]+; 61.04 ± 4.77 years on average). We measured CSF p‐tau and t‐tau with the Elecsys® immunoassays and CSF Aβ42, Aβ40 and neuroinflammation biomarkers (sTREM2, GFAP, YKL40, S100 and IL‐6) with the exploratory Roche NeuroToolKit robust prototype assays. We used separated linear regression models to analyze associations of WHR with CSF AD and neuroinflammation biomarkers while adjusting by age, sex, APOE status, education years, mean blood pressure and triglycerides. We ran interaction analyses between WHR and sex.

Result

We did not find significant main effects of WHR on CSF AD or neuroinflammation biomarkers. We found a significant interaction between WHR and sex on IL‐6 (p = 0.008; correcting by multiple hypotheses, p_adjusted = 0.067). After stratifying by sex, WHR was associated with IL‐6 in the male group (p = 0.032; p_adjusted = 0.242), but not in the female group (p = 0.596).

Conclusion

WHR is positively associated with IL‐6 levels in males. The effect of sex, and the role of neuroinflammation as a potential mediator in the association between obesity and dementia risk warrant further research.
Concordant and antagonistic associations of genetic variants with Alzheimer’s disease and diabetes mellitus through blood glucose and body‐mass index
Authors: Kulminski Alexander M. , Feng Fan , Loika Yury , Loiko Elena , Kulminskaya Irina
Published: December 2023

Background

Mounting evidence suggests common etiologies of Alzheimer’s disease (AD) and diabetes mellitus (DM). Genetic mechanisms underlying the risks of AD and DM remain elusive.

Method

We used individual‐level data from four longitudinal studies,—the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study, and UK Biobank,—to examine causal mediation effects in the associations of single nucleotide polymorphisms (SNPs) with AD and DM. We selected 178 lead SNPs representing 74 previously identified AD‐ and/or DM‐associated loci on 20 chromosomes (excluding chromosomes 6 and 21). First, we used marginal structural models to perform a univariate mediation meta‐analysis considering AD or DM as an outcome and blood glucose (BG) or body mass index (BMI) measured before the onset of AD and DM as a mediator. Then, we utilized summary statistics from these univariate analyses to examine pleiotropic mediation effects on AD and DM using an omnibus test.

Result

We identified 56 SNPs in 26 loci on 12 chromosomes attaining p<0.05 in the univariate mediation meta‐analyses and genome‐wide significance (p<5×10−8) in the pleiotropic meta‐analysis of indirect effects on AD and DM through BG and BMI. BG and BMI mediated associations of 27 SNPs—14 loci on nine chromosomes; none in the APOE locus— and 33 SNPs—14 loci on eight chromosomes, including the APOE locus—, respectively. SNPs only from two of 26 loci on chromosomes 7p15.1 (JAZF1 gene) and 10q25.2 (TCF7L2 gene) showed pleiotropic effects through both BG and BMI. Directions of the mediation effects on AD and DM were the same for the same alleles through BG and the opposite through BMI. The exclusion of DM‐affected subjects explained mediation effects on AD through BG in all 14 loci. In contrast, this exclusion improved the significance of the mediation effects on AD through BMI also in all loci by decreasing p‐values 0.5 to 2 orders of magnitude.

Conclusion

Most of the identified genetic variants increase susceptibility to AD and DM through different mechanisms. The BG‐associated genetic mechanism is common for AD and DM, whereas the BMI‐related genetic mechanism mediates the AD and DM risks in an antagonistic manner.