bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased medial temporal lobe functional connectivity is critical in Alzheimer’s disease: evidences from longitudinal analyses across the whole cognitive continuum
Authors: Chauveau Léa , Landeau Brigitte , Dautricourt Sophie , Delarue Marion , Hébert Oriane , la Sayette Vincent De , Chetelat Gael , de Flores Robin
Published: December 2023

Background

The medial temporal lobe is extensively connected to the whole brain through two functional networks: the anterior‐temporal (AT) and posterior‐medial (PM) systems. While both increased and decreased functional connectivity (FC) have been reported in Alzheimer’s disease (AD), the specific changes in each network and their clinical relevance throughout AD stages remain to be elucidated. To fill this gap, we aimed to provide a comprehensive overview of AT‐ and PM‐FC changes, and links with AD imaging‐biomarkers, clinical severity and dementia onset, using longitudinal data covering the whole cognitive continuum.

Method

Longitudinal data were acquired in 209 cognitively unimpaired (CU) adults aged 19‐85 (n = 56 Aβ‐ over 60), 26 Aβ+ patients with mild cognitive impairment (MCI) (n = 18 AD‐converters), and 26 Aβ+ AD‐demented patients, all followed up to 4 years. All underwent resting‐state (rs)‐fMRI, T1‐w MRI, Florbetapir‐ and FDG‐PET. Connectivity maps were generated from seed‐to‐voxels analyses applied to rs‐fMRI using individual ROIs (AT = perirhinal cortex, PM = parahippocampal cortex). The networks were defined by comparing baseline CU Aβ‐ AT to PM maps (and vice‐versa) using paired permutation t‐tests with FWE correction. Mean FC was then extracted from these masks for each participant. Generalized additive and linear mixed models were run to assess AT‐ and PM‐FC changes across the whole cognitive continuum, and their relationships with i)‐amyloid uptake, ii)‐glucose metabolism, iii)‐hippocampal volume and iv)‐cognitive deficit within participants>60yo, and v)‐AD‐conversion time in MCI patients.

Result

Results showed that AT‐FC linearly increased from younger to Aβ+ AD‐demented adults while PM‐FC decreased along the healthy lifespan and then remained stable across the AD continuum (Aβ+ individuals). Higher AT‐FC was associated with i)‐higher amyloid uptake, ii)‐lower glucose metabolism, iii)‐smaller hippocampal volume, iv)‐lower MMSE/Mattis scores and v)‐faster AD‐dementia onset. No such relationships were found with PM‐FC.

Conclusion

By encompassing the whole cognitive continuum and assessing longitudinal changes, we highlighted that AT‐ and PM‐FC alterations differ in aging and AD. While reduced PM connectivity seems restricted to age‐related processes (corroborated by no correlation with AD‐signature changes), increased AT connectivity seems to result from specific AD‐related mechanisms. Importantly, we evidenced that AT hyper‐connectivity appears critical in AD and might predict clinical and pathological outcomes.
Volume of the posterior and not anterior hippocampus predicts spatial memory performance in Alzheimer´s Disease
Authors: Kara Esra , Toelke Sophia , Onur Oezguer A.
Published: December 2023

Background

Hippocampal volume atrophy is one of the most acknowledged supportive biomarkers for Alzheimer´s disease (AD). However, how hippocampal volumes along the anterior‐posterior axis mediate memory in aging and dementia is still subject of ongoing research. This study aimed to investigate the difference in volume of the hippocampus and its anterior and posterior subregions in a healthy young and senior control group as well as in mild cognitive impairment (MCI) due to AD and its ability to predict performance in spatial memory tasks.

Method

Thirteen healthy young controls (24.9 ± 2.8 years), fourteen healthy senior controls (66.6 ± 8.2 years) as well as fifteen MCI patients (71.1 ± 6.0 years) with biomarkers typical for AD were included in this study. Subject‐specific manual tracing of hippocampi according to the EADC‐ADNI Harmonized Protocol for Hippocampal Segmentation (HarP) was performed on high‐resolution T1‐weighted MRI. Following the segmentation into anterior and posterior hippocampal parts, volumetry of anterior, posterior and total hippocampus was computed. Every subject performed a combined spatial memory and object recognition paradigm. Brain‐behavior correlations were conducted in order to explore prediction of spatial memory performance.

Result

Volume measures of the hippocampi significantly differentiated healthy from pathological aging. Larger volume of posterior hippocampus in MCI patients correlated with higher performance scores in the spatial memory task (mean percentage of successfully retrieved object locations) whereas total and anterior hippocampal volume did not predict performance in the spatial memory task.

Conclusion

These results support a functional hippocampal anterior‐posterior differentiation in memory processes and further stress the importance of integrating the dissociation of the hippocampus along its long‐axis concerning functional connectivity in memory processes and dementia.
Deletion of miR‐155 in microglia enhances their response to neurodegeneration and mitigates cognitive impairment in a mouse model of Alzheimer’s disease
Authors: Yin Zhuoran , Herron Shawn , Silveira Sebastian , Kleemann Kilian , Gauthier Christian , Mallah Dania , Cheng Caterina , Margeta Milica , Pitts Kristen , Barry Jen‐Li , Subramanian Ayshwarya , Shorey Hannah , Brandao Wesley N , Durao Ana , Delpech Jean Christophe , Madore Charlotte , Jedrychowski Mark P , Ajay Amrendra K. , Gopal Murugaiyan , Hersh Samuel Walter , Ikezu Seiko , Ikezu Tsuneya , Butovsky Oleg
Published: December 2023

Background

Microglia, the resident brain immune cells, play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA‐155 (miR‐155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear.

Methods

We used RNAseq and immunohistochemistry (n = 6‐8 per sex per group) to investigate the gene expression profile and AD pathology. We further utilized single‐cell RNAseq (n = 5 per group) to identify microglial clusters. Whole‐tissue proteomics (n = 4) was applied to detect the protein changes in brain milieu. Moreover, we used spontaneous alternation and forced alternation tests to evaluate the cognition (n = 33‐36).

Result

We report that microglial deletion of miR‐155 induces a pre‐MGnD activation state via interferon‐g (IFNg) signaling and blocking IFNg signaling attenuates MGnD induction and microglial phagocytosis. Single‐cell RNAseq analysis of microglia from AD mouse model identifies Stat1 and Clec2d as pre‐MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque‐associated synaptic degradation, and improves cognition.

Conclusion

Our study demonstrates a novel miR‐155‐mediated regulatory mechanism of MGnD and the beneficial role of IFNg‐responsive pre‐MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR‐155 and IFNg as potential therapeutic targets for AD.
Associations of orthostatic hypotension and frailty with dementia and mortality in older adults: a cohort study
Authors: Xia Xin , Tazzeo Clare , Jönsson Linus , Qiu Chengxuan , Rizzuto Debora , Laukka Erika J , Okoye Chukwuma , Grande Giulia , Fratiglioni Laura , Vetrano Davide Liborio
Published: December 2023

Background

Orthostatic hypotension (OH) has been considered a frailty marker and is associated with a higher risk of dementia and mortality. We sought to assess whether OH is associated with dementia and mortality in older adults while taking onto account frailty.

Method

We conducted a population‐based cohort study of 2703 dementia‐free individuals (mean age: 73.7; 63.3% females) from the Swedish National Study on Aging and Care in Kungsholmen, regularly followed from 2001‐2004 to 2016‐2019. OH was defined as systolic/diastolic blood pressure drops ≥20/10 mmHg one minute after standing up from a supine position. Fried’s frailty phenotype was used to assess frailty/pre‐frailty. Dementia was diagnosed following the DSM‐IV criteria. Individuals were cross‐classified into four groups based on their OH and frailty status and followed until dementia diagnosis, death, or dropout, whichever came first. Flexible parametric survival models with follow‐up time as the time scale were applied to estimate the associations of OH and frailty with dementia and mortality, adjusting for age, sex, education, vascular risk factors, and comorbidities. We also tested the interaction between OH and frailty on dementia or mortality risk on the multiplicative and additive scales.

Result

During the follow‐up period, 418 (15.5%) individuals developed dementia, and 933 (34.5%) died without dementia. Compared with OH‐free and robust people, robust people with OH (adjusted HR = 1.90; 95% CI = 1.27‐2.86) had a higher risk of developing dementia. Pre‐frail/frail people without OH (HR = 1.67; 95% CI = 1.22‐2.28) and pre‐frail/frail people with OH (HR = 2.36; 95% CI = 1.62‐3.42) also had a higher dementia risk. Robust people with OH did not have a higher mortality hazard (HR = 1.11; 95% CI = 0.83‐1.48), but pre‐frail/frail people without OH (HR = 1.25; 95% CI = 1.04‐1.51) and pre‐frail/frail people with OH (HR = 1.55; 95% CI = 1.23‐1.94) had a higher mortality hazard than robust and OH‐free people. There was no evident interaction between OH and frailty on dementia or mortality risk on either the multiplicative or additive scale.

Conclusion

Older adults with OH, whether robust or frail, may have a higher dementia risk than those without OH. Robust older adults with OH do not seem to have a higher mortality rate than robust older adults without OH.
INPP5D is associated with tau seeding and tau pathogenesis
Authors: Oblak Adrian L , Soni Disha , Lee‐Gosselin Audrey , Lin Peter Bor‐Chian , Reeves Cristian A Lasagna
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common type of dementia characterized by extracellular amyloid deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau aggregates. GWAS studies have identified variants in several inflammatory genes as significant risk factors for AD, highlighting that neuroinflammation is a critical, underlying pathological component in AD. INPP5D, a family member of Src homology 2 domain containing inositol 5' polyphosphatases (SHIPs), is an AD risk gene related to innate immunity in late‐onset AD (LOAD). Inpp5d plays a role in regulating signal transduction initiated by immune cell surface receptors. INPP5D binds receptor ITIMs, competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P¬2, thereby limiting downstream signaling. We previously reported that Inpp5d expression is increased in LOAD and is positively correlated with amyloid burden. However, the relationship of Inpp5d in tau pathology remains unclear. We hypothesize that inhibiting INPP5D will release the break and increase microglial function.

Methods

To assess the role of Inpp5d in tau pathology, we performed a fluorescence resonance energy transfer (FRET) assay on human‐AD brains obtained from NCRAD. We also crossed a mouse model deficient in Inpp5d (Inpp5d+/−) with a PS19 model of tau pathology and measured tau phosphorylation and transcriptomics. Primary microglia were utilized to measure microglial internalization of Tau.

Results

In human AD‐ brains, increased tau seeding was positively correlated with Inpp5d expression. Furthermore, in PS19 mice, Inpp5d protein expression was upregulated and positively correlated with phosphorylated tau (S202, Thr205). Utilizing the NanoString nCounter assay, we found an upregulation of the immune‐related and cell migration related genes in PS19.Inpp5d+/‐ mice compared to PS19 mice. Primary microglia from Inpp5d+/− mice released increased tau internalization compared to WT microglia.

Conclusion

Our findings confirmed that elevated Inpp5d expression in human‐AD subjects is recapitulated in PS19 mice and correlated with increased tau pathology. In PS19.Inpp5d+/‐ mice we found alterations in immune related and cell migration related pathways suggesting that Inpp5d modulates the disease progression through these pathways. Furthermore, pathogenesis may be modulated through increased internalization of tau. Together these results suggest that therapeutic interventions aimed at reducing Inpp5d may be beneficial in tauopathies.
The role of transcranial direct current stimulation in improving learning and memory performances of patients with mild cognitive impairment and mild Alzheimer’s disease: a functional magnetic resonance imaging study
Authors: Joshi Himanshu , Roy Ashika Anne , Havanur Setu , Rangarajan Subhashini K , Sreeraj Vanteemar S , Sinha Preeti , Narayanan Mariyappa , Janakiprasad Keshav K , Alladi Survana , Sinha Sanjib , Saini Jitender , PT Sivakumar , Varghese Mathew , Venkatasubramanian Ganesan , John John P
Published: December 2023

Background

Transcranial direct current stimulation (tDCS) is a safe non‐invasive brain stimulation (NIBS) procedure which helps to stimulate a particular region of interest by modulating the neuronal firing rate, thereby modulating the cognitive functioning. The tDCS intervention is known to show improvement on memory recall and recognition in patients with mild cognitive impairment (MCI) and mild Alzheimer’s Disease (mild AD)

Method

We investigated the effect of anodal stimulation at the left dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation at the right supra‐orbital area in patients with MCI (n = 18) and mild AD (n = 20) (Refer Table 1), after due approval from Institute Ethics Committee NIMHANS. Both baseline and post‐intervention assessments for a single patient were administered by the different assessors allocated randomly using NIMHANS neuropsychological battery for elderly (NNB‐E). Two resting state functional magnetic resonance imaging (rsfMRI) acquisitions, before and after the ten sessions of tDCS, each session lasting 20 minutes. A spherical mask of 5 mm diameter was chosen a priori on the left middle frontal gyrus (LMFG) as a seed for performing seed based functional connectivity (sbFC) analysis using default preprocessing pipeline and pre‐post analysis setup in CONN 18b toolbox.

Result

The combined sample of patients with MCI and mild AD showed significant improvement in word list learning trial 3 (pre tDCS 5.85 (1.59); post tDCS 6.63 (1.67); Z = 3.586, p<0.0001) and delayed recall (pre tDCS 1.50 (1.88); post tDCS 2.45 (2.33); Z = 3.656, p<0.0001) scores using NNB‐E. The sbFC analysis showed significantly reduced functional connectivity between left MFG (the region of anodal stimulation) and posterior cingulate cortex (PCC) as well as precuneus cortex (cluster‐level extent threshold p‐FDR <0.05) after tDCS. Post‐hoc tests showed that these reductions after tDCS intervention were also found to be significantly associated with attention and auditory verbal learning memory scores (Refer Figure 1 and Table 2).

Conclusion

The tDCS intervention helped reducing the functional connectivity at rest, which was responsible for compensatory neuronal processes found in early AD. These findings unravel the therapeutic role of tDCS by enhancing auditory verbal memory performance and altering the functional connectivity at PCC and precuneus cortex in earlier stages of AD.
Molecular analysis of nasal secretion to identify Alzheimer’s disease
Authors: Nicoló Marion San , Wunderlich Hilary , Peters Oliver , Grimmer Timo , Frölich Lutz , Metzler Richard , Schaepe Arno , Mertzig Sabine , Hallermayer Klaus , Waltenberger Harald , Heydler Thomas , Haack Mareike
Published: December 2023

Background

Increasing clinical evidence shows significant drainage of cerebrospinal fluid (CSF) and its metabolites along the olfactory route into the nose. Nasal secretion‐based analysis of key Alzheimer biomarkers was compared to CSF‐based analysis in different cohorts.

Method

We conducted a multicenter, prospective cohort study involving patients with cognitive impairment and availability of CSF measurement of the 4 AD‐specific proteins. Cohorts were defined based on CSF biomarker classification following NIA‐AA ATN research diagnostic framework and clinical findings. Nasal secretion (NS) was collected from the vicinity of the olfactory cleft. [NosetestAD] was performed for subsequent in vitro analysis.

Result

For this analysis, 39 patients with cognitive impairment were included at 3 university clinics in Germany. The nasal sampling procedure [noseabsorb] is painless (VAS 2 ±1.7) and yields a high sample volume (mean 450 μl). [NosetestAD] allows for precise quantification in size and relative protein amount of AD biomarkers pTau181, total Tau, Amyloid‐ß1‐40 and Amyloid‐ß1‐42. By using an automated protein separation and immunodetection system, we are able to generate a protein specific biomarker signature for all 4 AD‐associated proteins (pTau, tTau, Aß42,Aß40) characterizing parameters such as oligomerization state and relative protein amount. Further, a highly significant discrimination of amyloid pathology (A+ vs. A‐) was achieved with an AUC of 0.94 and p‐value <0.001.

Conclusion

Nasal secretion constitutes a safe, minimally invasive access to CSF. Therefore, it is highly suitable for detection and monitoring of AD relevant biomarkers. Within a cohort of patients with cognitive impairment A+ patients can be distinguished from A‐ patients based on their diseases state specific individual protein‐specific biomarker signatures and the different levels of oligomeric or monomeric structures. Thus, our proprietary diagnostic platform, detects and assesses a broad panel of brain derived biomarkers simultaneously and allows for intraindividual monitoring and possibly disease staging in nasal secretion.
TDP‐43 dysregulation and STMN‐2 mis‐splicing upon proteasomal inhibition in potential iPSC‐derived neuronal ALS model
Authors: Ritsma Laila , Bsibsi Malika , Popalzij Abeera , Sancerni Sara Compte , de Kraa Esther , Magnani Dario , Turner Amanda , Oosterveen Tony , Fisher David F , Iovino Mariangela , Vlaming Marijn
Published: December 2023

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. Many ALS cases are associated with nuclear‐to‐cytosolic mislocalization and phosphorylation of the transactivation response DNA binding protein (TDP)‐431. This is caused by several mutations such as M337V in the TAR DNA binding protein (TARDBP) gene1. In addition, proteasomal degradation is often affected, resulting in aggregation of TDP‐432. TDP‐43 is involved in many mRNA processes, and its depletion results in mis‐splicing of the neuronal growth associated factor, stathmin 2 (STMN‐2)3. This mis‐splicing contributes to axonal degeneration. To model the ALS phenotypes in vitro, proteasomal inhibition is often used to trigger TDP‐43‐associated phenotypes2.

Methods

In this report we assessed if homozygous or heterozygous CRISPR‐edited TPD‐43 M337V mutations in induced pluripotent stem cell (iPSC)‐derived glutamatergic neurons, generated by bit.bio using the opti‐ox technology4‐5, alone, or in combination with an MG‐132 proteasomal inhibition trigger, would result in TDP‐43 mislocalization and/or STMN‐2 splicing, and could therefore be used as an ALS‐relevant disease model. This was assessed in highly mature (DIV21), and less mature (DIV7) neurons.

Results

Immunocytochemistry, high‐content imaging, and automated image analysis were used for visualization, localization, and quantification of proteins of interest in individual cells. Here, increase in TDP‐43 mislocalization, phosphorylation (and aggregation) was observed upon acute proteasomal inhibition in all cell lines compared to their respective untreated sample, with more extreme phenotypes on DIV7. More interestingly, the homozygous M337V cell line D5 showed showed TDP‐43 associated phenotypes in untreated conditions at DIV7. Digital droplet PCR was used to evaluate mRNA expression, using absolute quantification of nucleic acid molecules. This showed decrease of full length STMN‐2 and the generation of truncated STMN‐2 upon MG‐132 treatment in most cell lines. Additionally, preliminary functional data generated using Multi Electrode Arrays (MEA) showed that all neuronal lines demonstrated formation of synchronous activity at late stage of maturation, suggesting these neurons are electrophysiologically active and amenable to functional studies.

Conclusion

These results suggest that wildtype and mutant clones show TDP‐43 dysregulation and mis‐splicing of STMN‐2 upon acute proteasomal inhibition, thus establishing an ALS relevant phenotype that can be used for in vitro drug discovery.
Transcranial Magnetic Stimulation improves language and language network functional connectivity in a patient with logopenic Primary Progressive Aphasia
Authors: Touroutoglou Alexandra , Katsumi Yuta , Jones Amelia , Hochberg Daisy , Quimby Megan , Wong Bonnie , Carvalho Nicole , Brickhouse Michael , Dickerson Brad C. , Eldaief Mark C.
Published: December 2023

Background

Primary progressive aphasia (PPA) refers to a group of neurodegenerative disorders characterized by early language impairments. Neuroimaging evidence suggests that language networks anchored in prefrontal, temporal and parietal cortices are selectively affected in these syndromes. Focal neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), are able to change resting‐state functional connectivity in a network‐specific manner.

Method

Here, we characterized the language network of a patient with logopenic PPA and targeted this network in an individualized manner with high frequency (20Hz) rTMS and with sham rTMS. We used detailed language testing and resting‐state functional connectivity MRI as outcome measures.

Result

The patient’s language performance improved following active but not sham rTMS. This was accompanied by increased functional connectivity in the patient’s individually characterized language network after active but not sham rTMS.

Conclusion

This case report supports further controlled clinical trials of individually‐targeted rTMS in PPA.
Hsp40 molecular chaperones are potent regulators of tau seeding and accumulation
Authors: Esquivel Abigail R. , Hill Shannon E. , Blair Laura J.
Published: December 2023

Background

The misfolding of the microtubule associated protein tau is associated with Alzheimer’s disease and other tauopathies. In tauopathies, aberrant tau spreads through synaptically connected regions of the brain by templating the misfold of endogenous tau. Work from our group and others has identified molecular chaperones as regulators of tau accumulation and toxicity, but many tau regulators have yet to be identified.

Method

We performed a screen of members from seven major chaperone families using Tau RD P301S FRET Biosensor cells. Hits were assessed by secondary knockdown studies in cultured cells and validated in tau expressing primary neurons. Additional in vitro experiments to dissect the mechanism of activity are ongoing, which will be followed by in vivo studies.

Result

Our data support the use of Tau RD P301S FRET Biosensor cells as a robust screening tool to identify known and novel tau regulators. The Hsp40 family is enriched with tau regulators, including some not previously known to affect tau. Studies are ongoing to determine how these proteins alter tau levels.

Conclusion

Multiple members of the Hsp40 family regulate tau accumulation.
Developing Training for MyChart Use for Older Persons with Mild Cognitive Impairment
Authors: Loizos Maria , Chin Shehan , Umpierre Mari , Inala Sanjana , Sewell Margaret , Neugroschl Judith A. , Sano Mary
Published: December 2023

Background

MyChart, a mechanism for sharing personal health information and communication among patients and healthcare providers is well received but underutilized by older adults, especially those with Mild Cognitive Impairment (MCI). Difficulty using or accessing technology coupled with rapid changes in portals may negatively impact a patient’s ability to effectively manage their health concerns. We report the initial phase of a study in older adults using focus groups to 1) determine the nature of user difficulties and knowledge gaps, and explore the preferred training methods (in person, virtual, manual), 2) develop a MyChart training module based on focus group data, and 3) assess the feasibility of providing training to improve MyChart use amongst older adults with MCI.

Method

We conducted three focus groups with older adults with MCI. Groups were held from August‐November 2022 and consisted of 15 participants both familiar and unfamiliar with MyChart. Focus groups were conducted virtually, and participants were asked open ended questions regarding user difficulties, knowledge gaps, and preferred training methods. Sessions were recorded, transcribed, and later analyzed utilizing thematic analysis. Focus groups continued until saturation was reached.

Result

We approached 84 ADRC participants to get 15 needed to reach saturation. 1) Technology and Health: participants acknowledged technology could be used positively to control health 2) MyChart: participants reported positive view of MyChart as a way to communicate with doctors and manage medical information 3) Difficulty with MyChart: participants stated there was no clear way to get help if needed to make appointments or find medical information 4) Learning technology: participants reported a preference for verbal teaching methods such as a video (over solely manualized teaching) that could be slowed down and stressed the importance of repetition of information.

Conclusion

The use of direct patient feedback was positive in that we discovered that older adults with MCI are open to use MyChart to monitor their health but have clear preferences on how to learn and get support with the technology.
Analysis of human endogenous retrovirus in Alzheimer’s disease and Frontotemporal dementia affected tissues
Authors: Fort‐Aznar Laura ,   Unitat d’Alzheimer i altres trastorns cognitius
Published: December 2023

Background

Human Endogenous Retroviruses (HERVs), normally dormant within the eukaryotic genome, can be awaken by environmental factors that may induce neurodegeneration via brain inflammation and epigenetic dysregulation. We investigated different HERVs transcripts using blood and post‐mortem brain samples from genetic and sporadic Alzheimer’s disease (gAD and sAD) and Frontotemporal Dementia (sFTD and gFTD) patients, using quantitative PCR (RT‐qPCR) and microarray techniques. Only HERV‐K env transcript was upregulated in sporadic AD in blood. Genome‐wide DNA methylation data analysis revealed hypermethylation in several genes involved in HERVs machinery, including APOBEC3, CDK6, E2F5, PRODH and SLC4A8 in AD and FTD when compared to healthy controls in post‐mortem brain tissue. In summary, our preliminary findings suggest that HERVs may be implicated in AD and FTD neuropathogenesis.

Method

RNA samples were obtained from sAD (n = 63), gAD (n = 10), sFTD (n = 46), gFTD (n = 15) and healthy controls (n = 39). Post‐mortem tissue (prefrontal cortex) from sAD (n = 10), gAD (n = 10), sFTD (n = 10), gFTD (n = 15) and healthy controls (n = 17). Quantification of different HERVs were measured by qRT‐PCR. Transcript levels within each of the samples were quantitated and normalized using the reference genes actin and GAPDH. 64 subjects were studied with Infinium MethylationEPIC array. Samples comprised healthy controls (n = 5), sAD (n = 5), gAD (n = 5), gFTD (n = 15) and sFTD (n = 10).

Result

HERV‐K env transcript was increased in blood from sAD compared to healthy controls (p = 0.0044). No other HERV transcript was found to be significantly upregulated in sporadic and genetic AD and FTD. Microarray analysis from AD and FTD patients revealed hypermethylation in APOBEC3, E2F5, in all groups and CDK6, PRODH and SLC4A8 in FTD when compared to healthy controls in post‐mortem brain tissue.

Conclusion

In this study we found that HERV‐K env transcript was upregulated in sAD from blood, which could be useful as a potential clinical biomarker. Future studies targeting the env protein should be performed to confirm the results found in this preliminary study. Hypermethylation of different genes involved in HERVs machinery suggest a different pathomechanism between AD and FTD that might help to differentiate them. Future functional studies for APOBEC3, CDK6, E2F5, PRODH and SLC4A8 could reveal the underlying biological mechanism leading to HERV activation.
Soluble biomarkers of Alzheimer’s disease in plasma vary according to quantity of blood CNS derived extracellular vesicles
Authors: Boyer Emilien , Kienlen‐Campard Pascal , Hanseeuw Bernard J
Published: December 2023

Background

Hallmark proteins pathogenic in Alzheimer’s disease (AD), amyloid and tau, can now be quantified in plasma samples using single‐molecule array (SIMOA). However, proteins are not only circulating in plasma, but are also present in nervous system‐derived extracellular vesicles (NDBEs) secreted by neurons in the plasma. We aim to quantify plasmatic NBDEs to evaluate whether their number or content are modified in symptomatic AD.

Method

Plasma samples were obtained in clinically normal (CN) participants (N = 76, sex ratio F/M = 1.5, mean age 57.5 ± 16.3, Apoε4 positive n = 31, Apoε4 negative n = 43). Quantification of amyloid 42 – 40 peptides and total‐Tau protein was achieved with SIMOA multiplex analysis. For relative quantification of NDBEs circulating in plasma, we used DELFIA ELISA immunoassay with anti‐neuronal cell adhesion molecule (NCAM1) antibody. EVs content analysis was done with SIMOA Neurology 3‐plex A multiplex (t‐tau, Aβ42 and Aβ40).

Result

We observed that the relative amount of NDBEs in plasma was correlated with circulating Aβ42 (p < 0.0001, R² 0.2699) and t‐tau (p < 0.0001, R² 0.2753) such that greater numbers of NBDEs were associated with lower concentrations of proteins in circulating plasma. Content in Aβ42, Aβ40 and t‐Tau of NDBEs was higher in individuals with high amount of NDBEs circulating (Aβ42 (p < 0.05, R² = 0.18), Aβ40 (p < 0.05, R² = 0.18) and t‐tau (p < 0.03, R² = 0.17)).

Conclusion

The number of NBDEs is negatively associated with the concentrations of these proteins, suggesting that these proteins are encapsulated in NBDEs. Latest results regarding NDBEs content seems to confirm this hypothesis with significant higher biomarkers concentrations in individuals with high amount of plasmatic NDBEs.
Older adults participation and adoption among a lifestyle‐based multidomain dementia prevention program
Authors: Pérez Ana Laura Isidro , Martínez‐Galindo Joyce Graciela , Salinas‐Contreras Rosa Maria , Sosa‐Ortiz Ana Luisa
Published: December 2023

Background

Older adult participation in lifestyle‐based programs has been described round 80%. (Lee et al., 2018). Participation at dementia prevention programs has been influenced by age, gender, marital status, and interest in receiving health education (Coley et al., 2021). The aim of this study is to evaluate the participation and adoption of lifestyle changes of older adults in a multidomain dementia prevention program from the LatAm Fingers Initiative, in Mexico

Method

healthy cognitive older adults between 60 to 77 years old were recruited. 148 pre‐screenings were done to complete a 100 participants sample, all of them were randomized between Systematic (SIG) (supervised participation) or Flexible FIG (educational advises) Lifestyle Intervention groups (50 per group). Participation is defined as attendance to educational session for physical, nutritional, cognitive and cardiovascular health plus attendance to physical activities, diary diet delivery, and 48 levels per week of cognitive online activities through 6‐months. Participation was classified as low, moderate, and high.

Result

Mean age was 70.06 (±5.4) years old, and 70.8% participants were females. From 48 participants of the systematic group (SIG) there were two dropouts because problems for traveling, and work. 45% of the SIG, are participating on the four intervention domains. 40 participants are currently at the physical activity intervention. From them high participation and adoption of physical activity was 52.5%, moderate participation was 37.5% and low, 10%. From Nutritional intervention are 26 participants who showed high participation at 57.7%, 11.5% moderate and 30.8%, low. The 21 participants that are at the Cognitive intervention stage, 33.3% had high participation, 52.4% moderate and 14.3% low participation. From the 18 participants at the health intervention stage, 94.4% participants had high participation and 5.6% low.

Conclusion

from this preliminary data, we found that the in the SIG the participation rates, are moderate to high. Physical, nutritional, and cardiovascular health activities showed more than 50% of participation rate. Also, nutritional domain showed the lowest percentage of participation among the four interventions.
Comparing approaches based on the global functional organization of the brain versus local connectivity to predict tau‐PET across the Alzheimer’s disease phenotypic spectrum
Authors: Corriveau‐Lecavalier Nick , Botha Hugo , Schumacher Julia , Dicks Ellen , Barnard Leland R , Lee Jeyeon , Sintini Irene , Gunter Jeffrey L. , Kamykowski Michael G. , Graff‐Radford Jonathan , Ramanan Vijay K , Fields Julie A. , Machulda Mary M. , Boeve Brad F. , Lowe Val J. , Kantarci Kejal , Knopman David S. , Whitwell Jennifer L , Josephs Keith A , Petersen Ronald C. , Jack Clifford R. , Jones David T.
Published: December 2023

Background

Predictive models of tau‐PET accumulation have largely relied on the functional connectome to estimate its spatial patterns in Alzheimer’s disease (AD). Patterns of global functional organization represent a promising avenue as they encapsulate many biological properties relevant to neurodevelopment, cognition and degeneration. We compared approaches based on local connectivity (from task‐free fMRI) and global organization (from FDG‐PET) to predict regional tau‐PET across AD phenotypes.

Method

We included 430 cognitively unimpaired (CU) individuals (214 A+T‐, 216 A+T+) and 62 amnestic mild cognitive impairment (aMCI), 64 amnestic AD, 21 dysexecutive AD (dAD), 41 logopenic progressive aphasia (LPA) and 49 posterior cortical atrophy (PCA) patients (all A+T+) from the Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Groups (referred to as “Mayo cohort”). The connectivity approach consisted of assessing the relationship between a region’s tau level and its functional connectivity to the region of highest tau (epicenter). The global organization approach consisted of 1) performing a principal component analysis on 3000 FDG‐PET images that did not overlap with the Mayo cohort, 2) projecting FDG‐PET images of the Mayo cohort onto the low‐dimensional space generated in Step 1 and extracting corresponding weighted values across the first 100 components, 3) using these weighted values as predictors of regional tau‐PET in a linear model and determining optimal parameters based on predicted R
2 values, and 4) using the parameters from the model built in Step 3 to predict tau‐PET in the ADNI cohort (n = 86) (Fig.2).

Result

The connectivity‐based approach yielded adjusted R
2 values ranging from 0.19‐0.45 across diagnostic groups (Fig.1). The global organization approach yielded averaged adjusted R
2 and predicted R
2 values of 0.71 and 0.63, respectively, in the Mayo cohort. Out‐of‐sample median R
2 in the ADNI cohort was 0.41 (range 0.10‐0.60) (Fig.3).

Conclusion

An unbiased approach based on the global functional organization of the brain and using an imaging modality widely used in clinical settings outperformed a connectome‐based one to predict regional tau‐PET across the AD phenotypic spectrum. Patterns of tau accumulation may better relate to the large‐scale physiology of the brain underlying specific mental functions rather than local connectivity factors.
Immigrant health paradox: Do immigrants have lower risks of dementia than non‐immigrants? A systematic review and meta‐analysis
Authors: Lillard‐Green Arion M , Hosssain M. Mahbub , Hong Y. Alicia
Published: December 2023

Background

With rising immigration rates around the globe, there is growing interest in the “immigrant health paradox”. Voluntary immigrants tend to have healthier profiles compared to their native‐born counterparts, especially within the early years after migration. Conversely, most immigrants experience structural racism and barriers to health and social services in the process of acculturation. Limited research is focused on cognitive health of older immigrants and existing evidence on whether immigrants have lower rates of dementia or cognitive impairment compared to native‐born remains inconclusive. The current study aims to address this literature gap with a systematic review and meta‐analysis.

Method

The literature search and review was guided with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISM). Major databases of PubMed, CINAHL, Global Health, PsycInfo, and Web of Science were searched. Studies that reported prevalence or incidence of dementia or cognitive impairment comparing immigrants and native‐born were included. A random‐effects meta‐analytic model with the DerSimonian‐Laird approach was used to calculate the pooled relative risk (RR) of dementia.

Results

A total of 26 articles were included in this review, of which 14 were reported from North America, 11 were from EU countries, and one from Australia. The included studies represented a total of 12.42 million participants. The pooled RR of dementia was 1.10 (95% confidence interval [CI]: 0.78 – 1.53) among immigrants compared to natives with high heterogeneity (I2 = 99.6%; 95% CI: 99.6% ‐ 99.7%). Stratified analyses suggested that studies based on medical records reported lower risks of dementia in immigrants, whereas most studies based on surveys reported higher risks of dementia in immigrants.

Conclusion

This study represents one of the first meta‐analyses of dementia risks comparing immigrants to non‐immigrants. The lower risks of dementia in immigrants documented in medical records may be due to the fact that immigrants are less likely to seek diagnosis or treatment of dementia due to social and cultural barriers in the new country. Immigrants are a diverse population and immigration experience varies in different groups and across countries. We call for more research on rigorous studies on dementia risks in immigrants.
Prevention of release of amyloid beta 1‐42 fibrils by inhibiting Hsc70
Authors: Çamoğlu Tugay , Yurttaş Zuhal , Dursun Erdinc , Gezen‐Ak Duygu
Published: December 2023

Background

Amyloid beta 1‐42(Aβ1‐42) peptide is famous for its fibrils in amyloid plaques, which are pathological findings of Alzheimer’s disease(AD). The fibrils can amplify themselves like prions by using monomeric peptides as substrates. Therefore, neurons can uptake and release the fibrils, and this process can cause pathology to spread throughout the brain. In addition, hsc70‐mediated tau release by exocytosis has been shown. Therefore, in this study, we examined whether Hsc70 also mediates the release of Aβ1‐42 fibrils(F‐Aβ1‐42).

Method

SH‐SY5Y cell was used in the study. Hsc70 dominant negative mutant, D10N, overexpressed with 72 hours plasmid transfection. MOCK plasmid and untransfected cells were used as controls. Hsp70 inhibitor VER‐155008(VER) was applied to other cell groups, and DMSO and untreated cells were controls. F‐Aβ1‐42 was labeled with Alexa Fluor‐488 and fragmented with ultrasonication before applying to the cells. We found that the cells took up fibrils within 6 hours. Therefore, VER, DMSO, D10N, MOCK and untreated cell groups were treated with fibrils, and incubated for 6 hours. Then, the cells were washed to remove extracellular fibrils and incubated for additional 18 hours. Supernatants were collected and measured with a fluorometer. 2 to 0,001 µM fluorescent‐labeled Aβ1‐42 fibrils were measured to make standard graphics.

Result

We showed that SH‐SY5Y cells effectively uptake and release F‐Aβ1‐42. VER application did not significantly affect to release of F‐Aβ1‐42 compared to DMSO and the control groups(p>0,05). However, F‐Aβ1‐42 release was significantly increased in D10N overexpressing cells compared to MOCK and untransfected cells(p<0,05).

Conclusion

In this study, we have shown that release of F‐Aβ1‐42 can be prevented by intervention to the pathway that Hsc70 takes roles. Why the release was decreased with D10N but not with VER treatment may be caused by the fact that VER inhibits Hsp70 chaperon class, while D10N targets only Hsc70. These results showed that Hsc70 especially could take a role in the release of F‐Aβ1‐42. Recently, some drugs aiming at clearing extracellular F‐Aβ1‐42 were approved by the FDA. Our findings can provide a new target working in a different pathway for AD treatment. This study was supported by Istanbul University‐Cerrahpaşa BAP (Project ID:33479).
24 hour rest‐activity rhythms and cognition in community dwelling older adults
Authors: Zhang Meina , Hoth Karin F , Linkenmeyer Carinda , Moon Chooza
Published: December 2023

Background

Cognitive decline associated with aging is a growing public health concern as individuals are living longer with chronic medical conditions. Rest activity rhythm (RAR) describes the pattern of physical activity and sleep period in 24 hours. Compared with younger people, older adults are more likely to maintain a sedentary lifestyle with altered RAR. Although there is no doubt that physical activity plays a vital role in health outcomes, little is known about how RAR is linked to cognitive functioning in late life. This study investigated the association between RAR and cognitive performance among older adults.

Method

Sixty community dwelling older adults aged 70±7.3 years (mean ± standard deviation) wore Phillips actigraphy spectrum plus 2 for two weeks. RAR parameters were analyzed using cosinor approach, such as amplitude (difference between the peak and lowest activity levels), mesor (mean activity level), pseudo‐F‐statistic (the robustness of RAR), and acrophase (peak activity time). A comprehensive neuropsychological battery was used to assess cognition (i.e., Brief Visuospatial Memory Test – Revised (BVMT‐R), California Verbal Learning Test – II, Boston Naming Test, Wechsler Adult Intelligence Scale‐IV Coding, and Trail Making Test A and B). Multiple linear regression models were built to explore associations between different RAR measures and each cognitive task adjusting for age, gender, and years of education.

Result

We found positive associations between RAR amplitude (p = 0.01), mesor (p = 0.008), acrophase (p = 0.006), pseudo F‐statistic (p = 0.002) and visual memory (BVMT‐R). Similarly, positive associations were found between amplitude (p = 0.006), mesor (p = 0.005), acrophase (p = 0.005), pseudo F‐statistic (p = 0.002) and psychomotor processing speed (Coding). Greater pseudo‐F statistics were associated with stronger performance on naming (BNT); p = 0.03). No association was found between RAR and other cognitive tasks.

Conclusions

Our findings provide evidence that some RAR characteristics are associated with cognitive performance among older adults, particularly visual memory, psychomotor processing speed, and naming ability. Further research should be undertaken using a large and diverse sample, prospective design, and inclusion of potentially confounding variables to confirm those associations.
Movement Digital Biomarkers for Functional and Cognitive Decline in Dementia
Authors: Abulikemu Subati , Crook‐Rumsey Mark , Carpio‐Chicote Ainara , Jeyasingh‐Jacob Julian , Shah Harshvi , Bugg Josh , Daniels Sarah , Sharp David J , Haar Shlomi
Published: December 2023

Background

Digital biomarkers based on accurate tracking of motor behaviour can provide a cost‐effective, objective, and robust measure for disease progression in dementia, changes in care needs, and the effect of interventions. Most of our brain is involved in the planning and execution of movement. Hence, quantifying and monitoring movement can produce powerful indicators of both motor and cognitive decline. In this project, we develop an intelligent system that computes and tracks movement‐based digital biomarkers of dementia.

Methods

The project is established in a controlled and ecologically valid mock apartment – the Living Lab – situated in the UK DRI Care Research and Technology Centre. We collected patients’ performance in a set of physical tasks and activities of daily living (ADL) with a depth‐based motion capture system, along with neurocognitive measures using Addenbrooke’s Cognitive Examination III and Cognitron. We first conducted temporal and spatial synchronisations of data collected from six Microsoft Azure Kinect cameras to produce high‐precision three‐dimensional joint coordinates that provide dynamic postural representations. These were then used to compute digital kinematic markers. This was followed by an assessment of the efficacy of the biomarkers in characterising people affected by dementia. We examined the association between the biomarkers with motor and cognitive function and overall efficiency in performing ADL.

Results

Our preliminary analysis showed that patients and healthy controls can be distinguished by the distribution of extracted features (an example feature – spinal curvature – is shown in Figure 1) in structured tasks and free behaviour. The variance of the distribution was correlated with performance in clinical assessments.

Conclusion

Our analysis suggests the feasibility of digital biomarkers in characterising functional limitations and cognitive decline. Successfully validated biomarkers can be integrated into remote health monitoring systems at home, care‐homes, and clinics, with the potential to revolutionise prognostic prediction and functional assessment of dementia.