bluuebunny/crossref_metadata_2025 huggingface dataset:
MR‐template‐based volumes‐of‐interest generation in individual brain PET of mouse Alzheimer model not only without MR but also without spatial normalization
Authors: Seo Seung Yeon , Oh Jungsu S , Kim Jae Seung
Published: June 2023

Background

The spatial normalization (SN) of individual mouse brain PET or MRI onto template brain space is one of prerequisites for precise quantitative analysis of positron emission tomography (PET) of mouse brains. This has recently been exploited by deep learning‐based approaches, but is still challenging. Moreover, most of them are based on SN using MR templates, which is not always available in both clinical and preclinical studies.

Method

In this study, we propose a new only PET‐based deep learning‐based image generation approach to resolve MR‐less PET SN problem. We generated individual‐brain‐specific cortical volumes‐of‐interest (VOI) based on inverse‐spatial‐normalization (iSN) and deep convolutional neural network (deep CNN) models with input of PET images instead of MR images. We applied the proposed methods to the mutated amyloid precursor protein and presenilin‐1 mouse model of Alzheimer’s disease. Eighteen mice underwent T2‐weighted MRI and F‐18 FDG PET scans twice, before and after the administration of human immunoglobulin or antibody‐based treatments. Specifically, skull‐stripped PET images were used as the model inputs and iSN‐based cortical (target) and cerebellar (reference) VOIs were used as the labels. We compared our CNN‐based VOI with conventional (template‐based) VOI by both qualitative (visual) assessment and quantitative correlation analysis of mean cortical SUVR (i.e., cortical uptake normalized by cerebellar uptake) estimated by both methods.

Result

In qualitative visual assessment, there was no visible difference between CNN‐based VOI and template‐based VOI. The mean count obtained by CNN‐based VOI and template‐based VOI were highly significantly (P<0.001) correlated in target VOI (i.e., cortex).

Conclusion

Since our deep CNN‐based method successfully generated target VOI, showing concordant results with that of conventional VOI methods in mean count correlation analysis, we believe we have established methods of template‐based VOI not only without spatial normalization but also without MR.
8‐year safety and compliance to a multinutrient intervention in mild cognitive impairment/prodromal Alzheimer’s disease: Data from the placebo‐controlled LipiDiDiet trial
Authors: Hartmann Tobias , Solomon Alina , Visser Pieter Jelle , Blennow Kaj , Kivipelto Miia , Soininen Hilkka
Published: June 2023

Background

Lifestyle factors such as nutrition and diet are increasingly recognized as modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Previous studies with the multinutrient combination Fortasyn Connect (Souvenaid) have shown benefits in mild AD dementia. The LipiDiDiet1‐3 study was designed to investigate the effects of Fortasyn Connect in individuals with prodromal AD. With up to 6 years of randomised, double‐blind, placebo‐controlled (RCT) intervention and an additional 2 years of open‐label intervention, LipiDiDiet is a unique long‐running RCT with a nutritional intervention in prodromal AD/MCIAD.

Method

Individuals with prodromal AD (IWG‐1) were recruited from 11 sites across Finland, Sweden, Germany, and the Netherlands between 2009 and 2013 and randomized to the active product (125ml once‐a‐day drink; Fortasyn Connect) or a calorie‐matched placebo control. Following the first 2 years of intervention, participants could opt in for annual extensions up to a maximum of 6‐year double‐blind and 2‐year open‐label intervention. Main efficacy outcomes included measures of cognition, function, brain atrophy, and disease progression. Inherent to long‐term follow‐up studies like LipiDiDiet, interpretability of the safety data is limited by several factors like decreasing sample size, treatment switching, and potential non‐compliance, differential attrition, and gradual underreporting of events. We will report preliminary results on long‐term safety to the intervention over the full 8‐year intervention period.

Result

From the 311 participants randomized at baseline, n = 245, 162, 84, 49, 29, 17, 8 participants completed respectively the 24‐, 36‐, 48‐, 60‐, 72‐, 84‐, and 96‐month intervention periods. The frequency, severity and types of recorded adverse events (AEs) were consistent with the studied population and none of the serious AEs was assessed by the investigators as related to the study product. The overall incidences of (serious)AEs were comparable between groups, both while on double‐blind treatment over the first 6 years and while on open‐label treatment from dementia diagnosis or start open‐label intervention onwards.

Conclusion

Preliminary results on safety suggest that there are no health concerns related to the use of Fortasyn Connect for up to 8 years in a prodromal AD/MCIAD population.

1Lancet Neurol. 2017;16:965‐975.

2Alz Dementia. 2021;17:29‐40.

3
Funding includes EU‐JPND.
Sex Differences in Regional Gray Matter Volume in Middle‐aged Adults
Authors: Kimura Kana , Blujus Jenna K , Driscoll Ira
Published: June 2023

Background

MRI–based measures of structural brain integrity are used to aid in the diagnosis of Alzheimer’s disease (AD) and as surrogate markers of disease progression. Alterations in structural brain integrity become evident years to decades prior to the onset of clinical symptoms. Differentiating structural alterations related to normal vs. pathological aging remains a significant challenge however, especially in the absence of overt disease processes. While age‐related differences in structural brain integrity have been studied extensively, middle age is often omitted despite representing potentially a key period for intervention prior to substantial disease‐related damage. Moreover, sex differences in regional structural integrity are still largely understudied, and the literature remains equivocal, partly due to differences in sampling (size, age range, exclusion criteria) and analytical methods. The purpose of the current study is to aid in establishing normative sex‐related structural differences by characterizing regional gray matter (GM) volume in middle‐aged adults.

Method

T1‐weighted images were acquired on a GE Signa 3T scanner (Waukesha, WI). Voxel‐based morphometry (VBM) (FSL v5.0.10) was applied to examine region‐specific GM sex‐differences while controlling for age, education, APOE, depressive symptoms and cognitive performance (N = 131; age range 40‐60; M/F = 52/79).

Result

In females, we observed higher GM volumes in the right frontal pole, right precentral gyrus, right superior occipital and left frontal orbital cortices, as well as the middle temporal and anterior cingulate gyrus bilaterally (P’s < 0.01). There were no regional GM differences favoring males.

Conclusion

We report sex‐related dimorphism in regional GM in cognitively healthy, middle‐aged adults. We employed a well‐established technique that provides an unbiased regional GM assessment throughout the brain, while controlling for potential confounding factors in a well‐screened sample of community‐dwelling, middle‐aged individuals. Our results are largely in accordance with the existing literature, regardless of the age‐range sampled, with the exception of the frontal pole finding which has not been previously reported to the best of our knowledge. Establishing sex‐related differences in regional volumes, especially in middle age when the prevention and treatment efforts might be more fruitful, may aid in distinguishing pathological alterations early and inform more efficacious interventions.
Investigation of SLC6A9 and SLC5A1 as a promising therapeutic target for obesity and diabetes using in silico characterization, 3D structure prediction and molecular docking analysis
Authors: Sinha Jitendra Kumar , Durgvanshi Shantanu , Verma Manish , GHOSH SHAMPA
Published: June 2023

Background

Obesity is a multi‐factorial clinical condition resulting from energy dyshomeostasis. Obesity is known to be linked with the development of Type‐1 and Type‐2 diabetes due to abnormal glucose regulation. Additionally, it is associated with the onset of insulin resistance as well as atypical nutrient and hormonal sensing in the CNS. The role of GLYT1 has been implicated in the Dorsal Vagal Complex (DVC) which forms the brain‐liver axis for glucose release into the bloodstream. On the other hand, SGLT1 is majorly responsible for glucose absorption in the intestinal lumen.

Method

The current work focuses on in silico approaches to characterize the transporter proteins: Glycine Transporter‐1 (GLYT1) and Sodium‐Glucose Linked Transporter‐1 (SGLT1) as a potential target for the treatment of obesity and diabetes in an insulin independent manner. The sequence of the two proteins were obtained from the UniProt database which was used to calculate various physicochemical parameters giving detailed insight into its molecular weight, amino acid composition, theoretical PI, extinction coefficients and GRAVY index.

Result

Primary sequence analysis using ProtParam revealed the stability of SLC6A9 and SLC5A1 in test‐tube classifying it as stable and unstable respectively while secondary structure analysis using SOPMA shed light on its alpha helix and beta sheet composition as well as random coils. Three‐dimensional (3D) protein structures were generated using SWISS‐MODEL, an integrated web‐based homology modeling server, which were then verified using the SAVES server. Docking studies were performed using AutoDock4 which yielded potential drug candidates. The validated models of SLC6A9 and SLC5A1 were successfully submitted to PMDB ‐Protein Model Database with PMDB ID: PM0082326 and PM0082333 respectively which could be utilized for further Docking analysis and spectroscopy experiments.

Conclusion

A thorough explication of these results can aid the future research in development of a novel therapeutic strategy to battle this enigmatic rising epidemic of obesity and diabetes.
Sex‐specific accumulation and therapeutic effect of the histone variant H2A.Z in Alzheimer’s disease
Authors: Creighton Samantha D , Stefanelli Gilda , Brimble Mark A , Hategan Luca , Collins Emily , Zakaria Jacqueline , Vislavski Stefan , Reda Anas , McLean Timothy AB , Walters Brandon J , Fahnestock Margaret , Orouji Elias , Zovkic Iva
Published: June 2023

Background

There is growing evidence that dysregulation of gene expression plays a role in cognitive deficits and neuropathology in Alzheimer’s disease (AD), thus prompting interest in epigenetic factors as mechanisms of neurodegeneration and memory loss. Here, we assess the therapeutic potential of the histone variant H2A.Z. H2A.Z is a memory suppressor that is actively removed from DNA during learning to promote gene expression and memory formation. The memory‐suppressive effects of H2A.Z are further supported by our finding that H2A.Z levels increase in the aged brain and may act as a prelude to age‐related memory decline. We hypothesize that H2A.Z also accumulates in AD and that targeted depletion of H2A.Z is an effective therapy for memory impairment.

Methods

To characterize H2A.Z levels in the AD brain, we assessed genome wide (ChIP‐seq) and site‐specific (ChIP‐qPCR) binding of H2A.Z to DNA as well as mRNA expression of genes encoding H2A.Z in both the human post‐mortem and 5xFAD mouse hippocampus. To directly test the therapeutic potential of H2A.Z depletion, adeno‐associated virus (AAV) vector containing short hairpin RNA against H2A.Z was delivered in the hippocampus of 5xFAD mice and memory was assessed using object location and contextual fear conditioning tasks.

Results

Consistent with the hypothesis that H2A.Z accumulates in the AD brain, binding of H2A.Z increased at several memory and AD‐related genes in the human and 5xFAD female hippocampus. Interestingly, this effect was sex specific, as H2A.Z binding decreased in the male hippocampus across species. Similarly, mRNA expression of genes encoding H2A.Z increased in the human and 5xFAD female hippocampus. This female‐specific increase in H2A.Z was paralleled by the remediation of memory impairment following H2A.Z depletion in 5xFAD females but not males.

Conclusion

Our data are the first demonstration of histone variants as regulators of AD‐related memory impairment. The sex‐specific changes in H2A.Z generalize across species and provide promising support for H2A.Z depletion as a therapeutic strategy for AD in females.
Impact of APOE ε4 allele on familial aggregation and cerebrovascular disease in Alzheimer’s Dementia: A cross‐sectional pilot study from India
Authors: Thatikonda Navya Spurthi , Balachander Srinivas , Kumar Pramod , Kannampuzha Anand Jose , Dayal Pavithra , Viswanath Biju , Jain Sanjeev , Sivakumar Palanimuthu Thangaraju , Varghese Mathew , Sen Somdatta , Purushottam Meera
Published: June 2023

Background

The ε4 variant of the apolipoprotein E gene (APOE4) is associated with the risk of Alzheimer’s dementia (AD). Previous studies have reported APOE4 status association with familial loading and vascular changes in AD. With a diverse ethnic population, and high rates of metabolic syndromes, the consequences of being a carrier of the APOE4 polymorphism needs further exploration in Indian context.

Method

Patients (N = 452) diagnosed to have AD, including 75 with a family history of AD in first‐degree relatives [‘familial’ AD (FAD)] and others without a significant family history [‘sporadic’ AD (SAD)], under evaluation at a tertiary hospital in India are described. All patients were assessed using Clinical Dementia Rating scale (CDR), Hindi Mental Status Examination (HMSE), Everyday Abilities Scale for India (EASI), Neuropsychiatric Inventory (NPI), and the Hachinski Ischemic Scale (HIS), along with detailed clinical evaluation. Blood samples were collected from AD patients, and 456 matched healthy controls for APOE genotyping using Polymerase Chain Reaction restriction fragment length polymorphism.

Results

The ε4 allele frequency was 22.57% and 9.65% among AD patients and healthy controls. APOE4 carrier status was noted in 52% of FAD, 38.46% of SAD patients, and was a significant risk factor for FAD with an odd’s ratio (OR) of 1.73 (95% confidence interval (CI):1.04‐2.9, p = 0.03). The presence of APOE4 did not have a significant association with metabolic comorbidities (p = 0.54). Furthermore, APOE4 status was a negative predictor for cerebrovascular disease among all AD patients (OR: 0.32, 95% CI: 0.12‐0.71, p = 0.008).

Conclusion

APOE4 allele has a positive association with familial aggregation and a negative association with cerebrovascular adversities in AD. The effect of APOE4 polymorphism on the clinical manifestation of AD in Indian population is unclear and needs further evaluation.
Cognitive phenotypes in probable mild Alzheimer’s disease
Authors: Dias Bruna Fugêncio , Dias Filipe Fulgencio , Costa Mônica Vieira , Ávila Rafaela , Miranda Millena Figueiredo , Miranda Mariana Figueiredo , Engelmann Gabriela Tomé Oliveira , Braga Nayara Rodrigues , Viana Bernardo de Mattos , Romano‐Silva Marco Aurelo , de Paula Jonas Jardim , Bicalho Maria Aparecida Camargo
Published: June 2023

Background

New technologies have helped the biological diagnosis of Alzheimer’s disease to make it more accurate over the years. However, establishing prognosis for each case is still a significant challenge, as there are different cognitive profiles in the same diagnosis. Also, there is no well‐defined standard for a cognitive profile that predicts future functionality impairment. In this sense, a better understanding of cognitive phenotypes can help establishing prognosis of Alzheimer’s dementia. Our aim with this study was to identify the main cognitive profiles of patients with amnestic variant of probable Alzheimer’s dementia at a mild presentation (CDR 1) with the amnestic variant. We verified the performance of these cognitive profiles applying the neuropsychological assessment.

Method

The study comprised 141 participants with probable Alzheimer dementia, recruited from a Reference Center for the Elderly in Brazil. We conducted a complete neuropsychological assessment evaluating the following domains: memory, executive functions, language, simple attention/processing speed, and visuospatial abilities. Initially, the data were transformed in z‐scores, considering age and education, according to references for the cultural adaptations and validations for the Brazilian population. We use the K‐Nearest Neighbors (K = 3) to solve the missing data problem. After preparing the base for cluster analysis, we performed the ward’s hierarchical method and the Euclidean distance to measure similarity. Finally, we performed comparisons of the groups using the Kruskal‐Wallis tests.

Result

Data analysis suggested existence of five cognitive subgroups (Figure 1). Bye general comparison, performed by the Kruskal‐Wallis test, we found the groups were different in the neuropsychological assessment instruments (p<0.001). Cognitive phenotypes varied about impaired and/or preserved ability, as well as impairment severity (Figure 2). The cognitive phenotypes were different considering educational level (Figure 3). We observed accentuated global impairment cognitive phenotype in a lower level of formal education group, and less accentuated impairment profiles in a higher formal education.

Conclusion

In conclusion, we identified five Cognitive phenotypes which had differences in severity of cognitive symptoms, and impaired abilities. These Cognitive phenotypes were based on different degrees of severity in visuospatial ability, simple attention/processing speed, and planning and had different education level.
ADSP Whole Genome Sequencing (WGS) Release 3 data update from Genome Center for Alzheimer’s Disease
Authors: Leung Yuk Yee , Lee Wan‐Ping , Kuzma Amanda B , Gangadharan Prabhakaran , Issen Heather , Qu Liming , Sreedhara Mounica , Cantwell Laura B , Valladares Otto , Zhao Yi , Vardarajan Badri N , Kunkle Brian W. , Martin Eden R. , Naj Adam C. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerard D. ,   Alzheimer’s disease Sequencing Project
Published: June 2023

Background

The Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration and meta‐analysis of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data with the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated via the collaboration of scientists from the Alzheimer’s Disease Sequencing Project (ADSP) and GCAD. With the vision to minimize data heterogeneity, introduced by different sequencing protocols and machines, GCAD processes all samples using identical pipelines and performs quality assurance (QA) checks.

Methods

Raw sequencing data (FASTQs or BAMs) were aligned to GRCh38/hg38 by BWA, and variant calling and joint genotyping were done by GATK. Furthermore, Smoove, Manta and Streka were applied to generate structural variant (SV) calls per sample. QA checks including sex, contamination and genotype concordance as well as the ADSP QC protocol were performed to evaluate the quality of samples and variants. To facilitate the access and usage of the big joint‐genotyped VCF files, we introduced a compact version for storing variant info and sample genotypes only.

Results

We dropped 235 (1.3%) samples of poor coverage (<20x) or that failed QA checks, and we flagged 173 (1.0%) samples that were of borderline quality. As a result, the dataset (ADSP Release 3, 2021) includes 16,905 genomes from 17 diverse cohorts with 3 major ethnicities: 10,651 Non‐Hispanic Whites, 3,212 Hispanics and 2,874 African Americans. Data are deeply sequenced (average genome coverage: >30x). All samples’ CRAMs, gVCFs from GATK, and VCFs from the three SV callers were deposited into NIAGADS Data Sharing Service (DSS) (https://dss.niagads.org/) for public distribution. In addition, joint‐genotype VCFs are available in both compact and QC versions. This joint‐genotype VCF contains >206M bi‐allelic single‐nucleotide variants, 16M bi‐allelic indels and 28M multi‐allelic variants, with 96% of variants remaining after stringent QC.

Conclusion

The ADSP and GCAD generate high quality genotype calls and SV calls. Currently the project is processing ∼37,000 WGS samples sequenced primarily through the ADSP Follow‐Up Study, which will contain a more ancestrally diverse set of populations. We anticipate this 2022 release will continue to benefit the research community studying AD genetics.
Human‐Derived Induced Pluripotent Stem Cells‐Based Disease Models of the Alzheimer’s Disease (AD) Patients Expressed AD Phenotypes and Responded to 17β‐Estradiol Treatment
Authors: Supakul Sopak , Maeda Sumihiro , Okano Hideyuki
Published: June 2023

Background

Neuronal models of both familial and sporadic cases of Alzheimer’s Disease (fAD/sAD) were generated from the human‐derived induced pluripotent stem cells (iPSCs) of AD patients. Using this in vitro cellular models, AD‐like phenotypes was analyzed with or without 17β‐estradiol, the sex hormone that are supposed to be involved in the AD pathogenesis.

Method

5 lines of iPSCs comprised of 1 healthy control, 2 fAD, 2 sAD were differentiated to neurons with a newly established neuronal differentiation method. The AD‐like phenotypes such as secreted Aβ peptides and neuronal excitability were measured by ELISA and Ca‐imaging (Fluo‐8 indicator). In addition, the neuronal complexity and excitability were examined after long (4 days) and short (15 minutes) 17β‐estradiol treatment, respectively.

Result

The neurons were successfully induced from the iPSCs with the newly established differentiation method. The neurons induced from AD lines secreted more Aβ(1‐40) and Aβ(1‐42) peptides and increased Ca oscillations compared to the control line. The treatment with 17β‐estradiol to neurons promoted the neuronal complexity and cellular excitability.

Conclusion

Neurons derived from the iPSCs of the AD patients expressed AD phenotypes and responded to the treatment of 17β‐estradiol. Thus, this suggested the therapeutic effects of sex steroid hormones to AD can be evaluated in human cells. This enables us to examine the variability of estradiol response among patients and plan clinical trials based on the responsiveness.
Associations between Age and Cortical Thickness in Brain Regions Supporting Speech Motor Control
Authors: Eshghi Marziye , Li Binyin , Green Jordan R. , Salat David H
Published: June 2023

Background

Prior research has demonstrated consistent associations between age and cortical thickness, as well as longitudinal reductions in cortical thickness in older adults (e.g., Salat et al., 2004; Storsve et al., 2014). To date, the aging of regions supporting speech production has not been directly investigated. Such information is, however, needed to differentiate age‐related cortical atrophy in speech regions from that occurring due to underlying neurodegenerative diseases. We examined cross‐sectional associations between age and cortical thickness of brain regions supporting speech motor control. These areas include subregions of the premotor cortex, primary motor area, supplementary motor area, pars opercularis, posterior inferior frontal sulcus, and insula as defined by the Directions Into Velocities of Articulators (DIVA) model ‐ a model for neural representation and mechanisms of speech motor control (Tourville & Guenther, 2011).

Method

The data were obtained from the Alzheimer’s Disease Neuroimaging Initiative GO/2 (ADNI). Participants included 163 (77 M, 86 F) cognitively intact adults aged 56‐89 years (Mean = 73.45, SD = 6.23). All participants were right‐handed and had at least 12 years of education (Mean = 16.53, SD = 2.55). Whole‐brain T1‐weighted MRI images were acquired by a 3‐Tesla Siemens scanner. FreeSurfer software was used for cortical surface reconstruction and to extract the cortical thickness of speech regions as identified by the SpeechLabel Parcellation System (Cai et al., 2014) developed based on the DIVA model.

Result

Significant associations between age and cortical thickness was observed in subregions of left premotor cortex, primary motor area, supplementary motor area, and presupplementary motor area with more limited effects in the right hemisphere. Cortical thickness of pars opercularis, posterior inferior frontal sulcus, and insula did not show significant changes over the aging process. Cross‐sectional interactions were found with regions in the left hemisphere being thicker at younger ages and having a larger negative age slope compared to their corresponding regions in the right hemisphere.

Conclusion

The findings of the study suggest that certain speech‐related regions show atrophy with aging, however, these changes are not uniform. In addition, laterality in cortical thickness of speech regions at younger ages was observed to diminish over the normal aging process.
Feasibility of using wearable technology to monitor agitation and sleep in patients with Alzheimer’s dementia: Lessons learned
Authors: Okhravi Hamid , Gupta Ajay K , Jain Shubham , Maly Kurt J , Nesbitt Christianne , Shivajirao Shreyas Gujjar , Murthy Thrupthi Narayana , Wainwright Lavinia , King Diamond
Published: June 2023

Background

Individuals with Alzheimer’s dementia (AD) often go through a period of significant behavioral and psychological symptoms including agitation. This can lead to impaired daily functioning, prolongation of hospitalization, early institutionalization, and higher mortality. The integration of biomedical data acquisition systems and information technology enables continuous real‐time monitoring of physiological data in daily life.

Method

This feasibility study is part of a clinical trial that examines the effects of THC‐free CBD oil on agitation in patients with AD (NCT04436081), involves caregiver/care‐recipient dyads and the use of technology to capture agitation during a 14‐week period. Participants are given 2 Fitbit versa 2 (each includes a 3‐axis accelerometer and an optical heart rate monitor), a smartphone, a tablet, and a digital timer. Participants’ Fitbit are paired with their smartphone, while the caregivers’ FitBit is paired with their tablet. Participants include males/females over 50 years old, with the diagnosis of AD, a MMSE score ≤28 & ≥4, and agitation measured with an NPI agitation/aggression subscore >3. Each dyad completes 24 forms/questionnaires throughout the study electronically via provided apps. Caregivers are instructed to send a real time electronic alert when agitation episodes happen.

Result

So far, we have enrolled 26 dyads. For this report we have collected data on 22 participants with 140 million data points for limb movement and heart rate, and 969 nights of sleep data records. Overall compliance with wearable use was 77% of the time, with 82% in 11 participants, 65% in 8 participants and 32% in 3 participants. Compliance with electronic form/questionnaire completion was 87%. Electronic alert for agitation episodes were recorded by the caregivers only 50% of time.

Conclusion

This study explores the feasibility and acceptability of using technology (wearables, electronic form data completion and submission, sleep, and real time agitation episode collection) for a 16‐week period in AD patients with agitation and their caregivers. We found high acceptability of wearing the Fitbit by AD patients with agitation. The primary issues interfering with data collection and device compliance were device battery life and memory, remembering to wear the device after charging, and technical fault in capturing the data.
Model on Impingement and consequences of Alzheimer’s disease in community‐ introductory study.
Authors: Chandran Niviya Seenivasa
Published: June 2023

Background

Alzheimer disease demands salutation and envisioning the cause for the disease. Despite the evolving scientific discoveries, the inhabitation among the global population reminds hiking alarmingly. The track of ways the spread of disease should leave a hint for the further research on the origin of the disease.

Method

This is a speculation much closure to current environment, to analyze effect and the pace of spread over a community. Penna model of biological aging [1] and model of colonization (lattice model) [2] are primitive base. For the model both inherited and non‐ inherited Alzheimer disease is taken into account and is obtruded into the lattice simulated on external factors such as age, genome, genetic mutation, mating partner, offspring and visualizing the change in population, symptoms and progress of the disease.

Result

Outcome helps in providing an introductory knowledge on the impact Alzheimer creates in the society. It shows the growth on the level of symptoms in the population, the influence of the inheritance on the population and their progress during the course of time. The symptom to analyze the level of disease at respective age of the individual is monitored. The executions for variations in the input arguments are studied to determine the effect of disease from different perspectives.

Conclusion

The Preliminary results show reasonable changes on the level of symptoms for the inherited Alzheimer’s disease. The results shell out some introductory ideas about growth of the level of symptoms of AD in the population during the course of the disease increasing number of offspring and number of mating will give a greater view of the consequences in the model and is predictable for the current scenario.

1. Stauffer, D. (2007). The Penna model of biological aging. Bioinformatics and Biology Insights, 1, 117793220700100005.

2. Mroz, I., &Pękalski, A. (1999). Model of populations colonizing a new habitat. The European Physical Journal B‐Condensed Matter and Complex Systems, 10(1), 181‐186.
Towards data‐driven video analysis for quantification of nocturnal sleep disturbance in dementia
Authors: Mohammadi Sara Mahvash , Monica Ciro Della , Revell Victoria Louise , Atzori Giuseppe , Dijk Derk‐Jan , Wells Kevin
Published: June 2023

Background

Sleep disturbance is common among people living with dementia as well as their caregivers. Non‐contact video technology can be used to characterise such disturbances as well as quantifying sleep quality by measuring the number of sleep body positions (poses). Such an approach may be beneficial for home‐based longitudinal clinical monitoring of sleep pattern changes and disturbances at all stages of dementia. Here we present our pilot results of a personalised data‐driven method applied to video data for quantification of sleep disturbance comparing older and younger participants.

Method

Data were collected in two separate studies which included an overnight 10‐12 hour laboratory sleep recording from thirteen older (65‐80 years, 9 male:4 female) and eleven younger (18‐34 years, 7 male:4 female) participants in a dedicated sleep facility. A data‐driven analysis using Principal Component Analysis and k‐means clustering was applied to infrared video data extracted from a clinical polysomnography (PSG) system. The data‐driven analysis automatically determined statistically significant groupings or clusters of unique body poses for each individual. Pose number, number of pose transitions, pose duration, and pose transition duration were computed for each participant.

Result

The number of data‐driven poses in older and younger participants was remarkably similar with 15.2±3.9 and 15.8±1.8 (mean±SD) poses per participant, respectively. However, the older group had a higher number of pose transitions (33.0±8.82) compared to the younger group (23.9±6.83) (p = 0.03). A significant 20% difference (p = 0.03) in the average duration of each body position was observed, with 62.3±7.1 minutes and 78.9±15.9 minutes for the older and younger groups, respectively (see Figure 1 and Figure 2). Pose transition duration was 19.2±7.25 seconds and 14.6±4.32 seconds for the older and younger groups, respectively where they were not significantly different.

Conclusion

Although the number of body positions did not vary significantly between the two cohorts, the older group changed body position more frequently and it took them longer to do so. Data‐driven automated analysis of video‐based sleep monitoring holds significant promise for quantifying age‐related and inter‐individual differences in sleep behavior.
Sex differences in stroke‐induced cognitive impairment and the impact of Mir20a‐3p treatment in middle‐aged Sprague Dawley rats
Authors: Sampath Dayalan , Markowsky Kylee Grace , Branyan Taylor E , Sohrabji Farida
Published: June 2023

Background

Stroke is a leading risk factor for dementia. Our previous studies show that the small non‐coding RNA, mir20a‐3p, is neuroprotective for stroke and reduces sensory‐motor impairment in the acute phase (Branyan et al., 2021). In this study, we used a battery of tests to assess the integrated functioning of affective and cognitive circuits after stroke in males and females, as well as the impact of mir20a‐3p

Method

Middle‐aged (acyclic) females and males were subject to ischemic stroke using endothelin‐1 in the left middle cerebral artery (MCA) region. Mir20a‐3p mimics or scrambled oligo was administered i.v. 4h and 24h after stroke with a supplementary dose at 60d. Long‐term cognitive changes were assessed by contextual fear conditioning (CFC) and the novel object recognition test (NORT).

Result

Both males and females showed significant sensory‐motor impairment due to stroke in the acute phase, which was attenuated by Mir20a‐3p treatment. In the chronic phase, cognitive function was assessed by cued and contextual fear conditioning, evaluated by percent freezing during acquisition, retrieval, and extinction of fear memory. When measured 30, 60 and 100d after stroke, retrieval of fear memory was significantly reduced over time in sham and stroke males and females. However, linear regression analysis revealed that among females, the rate of decline of fear memory was significantly accelerated in the stroke group that received scrambled oligo treatment, while the rate of decline in the Mir20a‐3p group was similar to the sham group, indicating a protective effect of this drug. Surprisingly, stroke+ scrambled treated male rats did not show an accelerated decline. We further examined declarative memory (as assessed by the Novel Object Recognition Task) and noted that there was a decline over time in both males and females.

Conclusion

This study shows that cognitive impairment is selectively affected by stroke and that despite the fact that acute sensory‐motor impairment is seen to a similar extent in males and females, stroke significantly affected the retrieval of fear memory in females but not males. Moreover, treatment with Mir20a‐3p abrogated this effect of stroke.
Early synaptic gene expression downregulation in the frontal cortex distinguishes Alzheimer’s disease from normal aging in a genetically diverse mouse population
Authors: Dunn Amy R , Ouellette Andrew R , Hadad Niran , Zhang Jigang , Philip Vivek M. , O'Connell Kristen , Kaczorowski Catherine C.
Published: June 2023

Background

The frontal cortex is critical to many cognitive processes and is vulnerable to pathology and neurodegeneration in Alzheimer’s disease. Cortical dysfunction and impaired connectivity in the frontal cortex have also been observed in “normal” age‐related cognitive decline, suggesting common mechanisms contributing to both age‐related and AD‐related cognitive decline. The divergence that may lead to AD versus normal aging, however, is unclear.

Method

Here, we have used genetically diverse mouse populations modeling either AD or normal aging, the AD‐BXDs and their nontransgenic littermates (Neuner et al, Neuron, 2019). We measured cognitive function from early (6mo) to middle (14mo) adulthood to capture presymptomatic and advanced AD stages and early aging processes. We performed bulk RNAseq from the frontal cortex, followed by age‐ and AD‐related differential gene expression analysis and Weighted Gene Coexpression Network Analysis (WGCNA) to identify genes and gene networks whose expression is associated with normal and pathological aging.

Result

In both differential gene expression analysis and WGCNA, we found common mechanisms underlying normal aging and AD (e.g., upregulation of inflammation‐related gene pathways). We also found that downregulation of genes and gene networks associated with synaptic function specifically occurred in AD and not in normal aging, suggesting that early synaptic dysfunction and/or synaptic loss is a unique feature of AD that distinguishes it from normal aging processes. Based on differential gene expression, network analyses, presence of high‐impact variants across the BXD panel, and association with cognitive function, we identified one gene candidate, B230209E15Rik, a lncRNA, as a potential regulator of synaptic gene networks in the frontal cortex that promotes resilience to cognitive decline in AD.

Conclusion

Overall, our data indicate that cognitive aging and AD may share common neuroimmune activation and dysregulation of neuronal maintenance, but that AD, and particularly late AD, is uniquely characterized by synaptic dysfunction. We nominate an intriguing candidate, B230209E15Rik, as a potentially key driver of synaptic gene regulation in the frontal cortex. In order to elucidate the mechanism by which this gene may promote cognitive resilience in AD, we are currently validating this finding in vivo.
Measuring attitudes, motivations and barriers to presymptomatic dementia testing
Authors: Makri Marina , Gkioka Mara , Moraitou Despoina
Published: June 2023

Background

The increasing biomarkers testing and new methods of presymptomatic screening for dementia have risen questions like: Should people get tested? Would they want to know whether they will get this fatal, untreatable disease? This has picked the demand for a well‐structured counseling program for dementia screening. In this direction, it is important to meet the needs of the target group; however, not much is known about people with a family history of dementia attitudes about testing, the motivations and barriers, and the expectations relevant to future counseling programs about testing for dementia

Method

This study was comprised of a validation study of a new psychometric tool and a cross‐sectional survey to assess the attitudes, buries and motivations to dementia testing. The content of the questionnaire was based on (1) a literature review, (2) the Perceptions Regarding Investigational Screening for Memory in Primary Care (PRISM‐PC) Questionnaire (M. Boustani et al., 2008), (3) a board of Clinical expert opinions. Two hundred eight (208) people enrolled in this cross sectional study. Participants came from Greece, ages ranged from 18‐70 (M = 35.5, SD = 5.7). and the majority of the sample was female (93.3%). Psychometric properties were assessed through construct validity (principal component analysis) and internal consistency (Cronbach’s alpha).

Result

Exploratory factor analyses revealed the presence of four factors. The first factor labelled as “Perceived harms of testing”, the second “Acceptance of testing”, the third “Perceived benefits of testing”) and the fourth factor “Need of knowledge”. The reliability of each factor separately was satisfactory to very satisfactory (.70‐.87). Cronbach’s alpha coefficient for all the final 25 items of the initial questionnaire was good (Cronbach’s α = 0.82), suggesting very satisfactory internal consistency.

Conclusion

This is the first study that created a questionnaire for measuring the attitudes of Greek people towards dementia and genetic screening. Capturing data via this questionnaire might help clinicians, policymakers, and health services researchers in dementia understand better peoples’ perspectives related to the pros and cons of dementia screening and develop effective counseling programs and prevention strategies.
First‐in‐Human (FIH), Single‐ and Multiple‐Ascending‐Dose (SAD/MAD) studies in healthy subjects of E2511, a novel tropomyosin receptor kinase a (TrkA) positive allosteric modulator (PAM)
Authors: Aceves Pau , Hall Nancy , Dayal Satish , Yagi Takuya , Chang Julia , Mikamoto Masaki , Ringheim Garth E , Takesuya Tomioka , Hiramatsu Naoki , Gordon Robert , Giorgi Luigi
Published: June 2023

Background

Cholinergic innervation is affected in multiple neurodegenerative diseases associated with cognitive dysfunction. Loss of cholinergic neurons in Alzheimer’s disease (AD) is correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons. The activation of NGF‐induced trophic signaling via TrkA could be a promising therapy for neurodegenerative diseases including AD. E2511 is a novel small molecule TrkA biased PAM that has shown reinnervative effects on cholinergic neurons in nonclinical studies (without NGF‐associated hyperalgesia). The main objectives of the E2511 FIH Phase 1 studies (SAD [completed] and MAD [ongoing]) are to evaluate the safety, tolerability and pharmacokinetics in healthy subjects.

Methods

: Both SAD and MAD are randomized, double‐blind and placebo‐controlled studies. The SAD evaluated 5 cohorts (n = 8/cohort) in adults and 1 cohort in elderly subjects (n = 5). Food effect was evaluated in one SAD cohort. Safety was evaluated through the review of adverse events, physical examinations, clinical laboratory tests, vital signs, electrocardiogram and electroencephalograms. Blood samples were collected for determination of plasma E2511 concentrations. Repeat dosing with E2511 (once daily for 14 days) is under evaluation in the MAD study.

Results

: Single doses of E2511 were safe and well‐tolerated across the investigated doses in adult and elderly subjects. There were no dose‐dependent nor severe treatment‐emergent adverse events (TEAEs). There were no clinically significant changes in the evaluated safety parameters on E2511 compared to placebo. Pharmacokinetic results show that E2511 was rapidly absorbed (tmax: 1 hour). Plasma half‐life was 3.2 hours. Plasma exposures (Cmax and AUC) increased dose proportionally over the investigated dose range. Food led to a decrease of 19% in Cmax and 15% in AUC compared to fasted conditions. Plasma exposures in elderly and younger adult subjects were comparable. Evaluation of E2511 safety, tolerability and PK/PD following multiple doses is ongoing.

Conclusion

E2511 presented an adequate safety and PK profile in healthy adults and elderly subjects. These results support further development of E2511 as a disease‐modifying therapy for neurodegenerative diseases.
Effects of acquisition protocol on advanced diffusion MRI measures
Authors: Mishra Virendra R , Sreenivasan Karthik , Cordes Dietmar , Ritter Aaron
Published: June 2023

Background

Several studies have suggested that advanced diffusion MRI (dMRI) measures derived through the analytic techniques of diffusion kurtosis imaging (DKI) and neurite orientation density and dispersion imaging (NODDI) might provide better sensitivity to predict the progression of Alzheimer’s disease (AD) when compared to conventional single tensor diffusion tensor imaging. Two popular simultaneous multislice (SMS) sequences, namely Alzheimer’s Disease Neuroimaging Initiative (ADNI)‐3 and Human Connectome Protocol (HCP) are currently widely used in the acquisition of such advanced dMRI data. Since HCP sequences require a custom connectome scanner, several variants of HCP protocol compatible with clinical MRI are in wide use. Before such techniques are used widely across the globe to understand AD, it is imperative to understand whether the absolute WM measures derived through such advanced dMRI measures are reproducible and whether harmonization of dMRI across sites employing different acquisition protocols is applicable. In this study, we hypothesize that higher spatial and angular resolution dMRI data will result in higher quantification of DKI and NODDI metrics, as compared with comparatively lower spatial resolution advanced ADNI‐3 sequences.

Method

A 32‐year‐old healthy male participant was scanned over five weeks, both with Advanced ADNI‐3 protocol (114 directions, 2mm3 isotropic, b‐values = 500s/mm2, 1000s/mm2, and 2000s/mm2) and 2 variants of the HCP sequence (1.5mm3 and 2mm3) both with 3 b‐values (500s/mm2, 1000s/mm2, and 2500s/mm2) and 213 directions on a 3T Skyra scanner. Total scan time for the ADNI‐3 sequence was 11:37 minutes, 2mm3 CCF sequence was 18:41 minutes, and 1.5mm3 CCF sequence was 23:13 minutes. Various DKI and NODDI measures were computed on all repetitions in‐house. JHU atlas of WM tracts was used as a mask to extract values along each tract at each run separately.

Result

As shown in Figs 1‐4, dMRI‐derived measures were underestimated for most of the WM tracts for the ADNI‐3 sequence, although they had less variance across different runs. Second, NODDI measures were more reproducible across most WM tracts when compared to DKI measures across protocols.

Conclusion

Acquisition parameters affect the absolute quantification of advanced dMRI measures. Our data suggest that the pooling of dMRI data across various protocols should be performed with caution
Fukushimura Brain Bank ‐Nursing home based brainbank project in Japan‐
Authors: Kaneda Daita , Ogawa Norihiro , Kanesaka Takeshi , Hishida Chie , Sakurai Keita , Akatsu Hiroyasu , Yamamoto Sakon , Yamamoto Takayuki , Yoshio Hashizume
Published: June 2023

Background

The Fukushimura (welfare village), located in Toyohashi city, Japan, is a unique complex of various nursing home facilities including dementia homes, Day‐care houses, homes for disabled and mentally retarded, and the Fukushimura Hospital. This village is totally managed by private sector, the Sawarabi Medical Cooperative. About 800 elderly people reside in this area. The hospital plays a pivotal role within the village and acts as the central facility for each nursing homes.

Fukushimura BrainBank (FBB) was established in 1990. The neuropathological investigation of FBB was initially conducted by Kenji Kosaka, who initially reported cortical Lewy bodies. Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants.

Method

Clinical information and neuroimaging analyses has been described in daily practice. For banking CNS specimens, the brains are separated into two hemispheres, one for neuropathological analyses with using several antibodies for beta‐amyloid, phosphorylated tau, alpha‐synuclein, and TDP‐43. Modified gallyas‐silver staining is applied for evaluating argyrophilic grain disease. The other hemispheres are stored for frozen sections. All the medical records and radiological images from the nursing home to hospital are stored in the research institute, which make it possible for the researchers to access the psychological symptoms observed by carers in the long duration of the disease.

Result

The number of autopsy became over 35 cases per year. Most of the patients had dementia or chronic devastating cerebrovascular diseases. Of note, geriatric residents with mentally retardation or cerebral palsy from childhood were included. At the end of 2021, more than 800 of frozen brains with detailed medical record are stored in FBB and readily available for research. The neuropathology database share the same coding system for Japanese Brain Bank Network for Neuroscience Research (JBBNNR). We already have over 20 collaborators and supply our samples for more than 30 research institutes in Japan.

Conclusion

The challenge of FBB will play a unique and important role to clarify cliniconeuropathological correlation of the nursing home residential with various geriatric conditions with 3D(Disability, Dementia, and Developmental disorders).