bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction of a new synchronization index by correlating Leg Movements and overall activity distinguishes subjects with normal cognitive functioning from those with MCI: Preliminary results
Authors: Conde‐Lara Federico Menéndez , Rodríguez‐Torres Erika E. , Rosales‐Lagarde Alejandra , Cubero‐Rego Lourdes
Published: June 2023

Background

Exploratory data analysis was performed, looking after correlations of Leg Movement (LMs) against the 22 full‐EEG polysomnography during sleep. The EEG signals were recorded with the 19 derivations from the traditional International 10/20 electrode placement, chin electromyography (EMG), and electrooculogram (EOG). Nine subjects were considered: six in the Mild Cognitive Impairment (MCI) group, and three controls (CTRL). In line with the hypothesis about phasic activity reorganizing cerebral processing, lower correlations were expected for MCI, during REM sleep.

Method

For each subject, the first rotation (PC1) of the Principal Component Analysis (PCA) decomposition of the data (22 channels) was generated. This accounts for the direction of the maximal variance. The proportion of variance explained by PC1 was very high (Table 2). In view of this, pairing the LMs and the PC1 time series allowed for reliable comparisons. As expected, there was no linear relation between the LMs and each of the channels: out of 198 pairs (22 for each subject), the maximal correlation coefficient was 0.0194. Therefore, it was natural to look for nonlinear relationships. The metric considered, was the total variation, at 5‐second intervals. The total variation corresponds with the arclength of the graph and is a measure of variability of a time series. For each subject, correlation coefficients were calculated for the total variations for LM versus PC1.

Result

The mean coefficients for the CTRL group were higher than those for the MCI group for all the sleep epochs (Table 1). The difference was highest for REM sleep. In Table 2, the coefficients of the PC1 for each subject and variable (PC1) are presented (variations of one subject, Fig. 1).

Conclusion

Due to the small size of the sample, it is not possible to draw any actual conclusions. However, anecdotal evidence was found for differences in synchronic activity between groups. This was most notorious for REM sleep, with decreased correlations for the MCI group. It would be of interest to replicate this study with a much larger sample.
A feasibility study of a brief person‐centered dementia training to promote more empowered staffing teams
Authors: Gholizadeh Shadi , Popolizio Elizabeth M. , Wile Michelle , Smith Erica C.
Published: June 2023

Background

As a growing number of people with dementia are opting to age at home, the need for well‐trained, dementia‐knowledgeable nonmedical care teams has increased. An important and understudied member of the in‐home care team is the scheduler/staffing coordinator (SC). The SC often identifies an appropriate professional caregiver/care partner (CP) for the person with dementia, liaises between the CP and the client or client’s family, and provides informal coaching to the CP as challenges arise. The objectives were to: 1) develop a brief person‐centered dementia training program for SCs that is tailored to their role and 2) assess SC’s perspectives on the relevance and accessibility of the training.

Method

A small group (N = 10) of SCs across three states and two in‐home care companies attended a four‐part dementia training covering 1) dementia types, symptoms, and experience, 2) behavioral and mood expressions of dementia, 3) mobility and approach considerations in dementia, and 4) engagement and person‐centered care for people with dementia. The SCs completed pre‐ and post‐training questions asking about training needs, confidence in coaching CPs and confidence in finding an appropriate client/care partner match. They were also asked to comment on the relevance and accessibility of the training.

Result

Prior to training, SCs reported a desire to learn more about triggers in dementia; best practices for communication with CPs that consider cultural, social, and language differences; and tips for helping CPs who are feeling emotionally dysregulated or overwhelmed. There was a wider range of reported confidence in coaching CPs and finding an appropriate match. The SCs overall found the training to be relevant and reported being highly satisfied with the content. Suggestions to improve the training included shortening the training and simplifying the language.

Conclusion

SCs have a strong interest in increasing their knowledge about dementia, especially in terms of how to 1) best support CPs experiencing care challenges and 2) facilitate optimal client and CP matches. Future research can explore the impact of the training in a larger sample on outcomes including job satisfaction and self‐efficacy, burnout, and overall dementia knowledge as well as matching and coaching behaviors.
Daily heart rate variability biofeedback practice sessions affect plasma Αβ40 and Αβ42 levels in healthy younger and older adults: A randomized clinical trial (N = 108)
Authors: Min Jungwon , Rouanet Jeremy P. , Martini Alessandra Cadete , Nashiro Kaoru , Yoo Hyun Joo , Porat Shai , Cho Christine , Wan Junxiang , Cole Steve W , Head Elizabeth , Nation Daniel A. , Thayer Julian F , Mather Mara
Published: June 2023

Background

Genetic mutations affecting β‐amyloid (Αβ) production suggest that decreasing Αβ levels in healthy adults could prevent AD. However, evidence for behavioral interventions that decrease Αβ levels is lacking. The current study examined whether heart rate variability (HRV) biofeedback affects plasma Αβ levels. This intervention involves breathing slowly at a pace that maximizes the amplitude of heart rate oscillations. During slow paced breathing, the vagus nerve receives strong signals from stretch receptors in blood vessels and the lungs. These afferent signals stimulate ascending vagus nerve signaling that activate ‘safety’ signaling pathways, suppressing stress and arousal pathways in the brain and body. Experiencing adversity increases production of Aβ and risk of AD. We hypothesized that, in healthy adults, daily sessions involving slow paced breathing during HRV biofeedback could decrease Aβ by suppressing these adversity‐related processes.

Method

Healthy adults (N = 54 age 18‐35; N = 54 age 55‐80) practiced HRV biofeedback daily for five weeks. They were randomized to use slow paced breathing and HRV biofeedback to increase heart rate oscillations (Osc+ condition) or to use personalized strategies and HRV biofeedback to try to decrease heart rate oscillations (Osc‐ condition). Pre‐ and post‐intervention plasma Aβ40 and Aβ42 levels were quantified blind to condition. Gene expression analysis of peripheral blood samples of the 54 younger adults using bioinformatics‐based analyses of genome‐wide RNA profiles examined activity of pro‐inflammatory, neuroendocrine, and antiviral transcription control pathways relevant to the conserved transcriptional response to adversity (CTRA). We predicted that reductions in the CTRA across the 5‐week trial would be associated with reduced plasma Aβ.

Result

Both younger and older adults showed significant differences between Osc+ and Osc‐ conditions in change in plasma Aβ40 and Aβ42 levels (Figure 1). The Osc+ condition decreased Αβ while the Osc‐ condition increased Αβ. Individual changes in plasma Aβ from pre‐ to post‐intervention were associated with changes in expression of the CTRA in the predicted direction.

Conclusion

HRV biofeedback affects plasma Aβ and these effects are associated with changes in expression of genes upregulated during adversity. Future longer‐term studies should test whether reducing plasma Αβ via the Osc+ intervention reduces risk of developing AD.
Comparison of diagnostic routines for suspected Alzheimer’s Disease patients between US‐American and German health care providers
Authors: Menne Felix , Schipke Carola G.
Published: June 2023

Background

Thorough diagnostics are a prerequisite for the optimal treatment of Alzheimer’s Disease. Biomarker‐based diagnostics are now standard within a research framework. On the contrary, data on diagnostic workups applied by physicians in their everyday clinical practice is scarce.

Method

Two surveys were conducted on the diagnostic actions taken by physicians when faced with patients with AD suspicion. The sample consisted of German (n = 500) and American (n = 100) health care providers, both specialists and non‐specialists.

Result

German specialists more often conduct neuropsychological testing themselves than their American colleagues (p<0.001). Likewise, in German non‐specialists, neuropsychological testing elsewhere is recommended almost twice as often compared to US physicians (p<0.0001). In contrast, US non‐specialists perform lumbar punctures for CSF analysis themselves twelve times more often than their German colleagues (p<0.0001). Furthermore, they are more than three times as likely to recommend CSF analysis elsewhere than German non‐specialists (p<0.0001). Similarly, US non‐specialists significantly more often recommend patients to have a PET scan with a 4.7‐fold difference (p = 0.0007).

Conclusion

Diagnostic routines for suspected AD patients are in large parts alike between German and US‐American health care providers. However, when it comes to gathering neurobiological evidence through the means of biomarker‐based CSF or PET diagnostics, German doctors significantly less perform and prescribe these measures.
Weight increases and decreases show distinct association with Alzheimer’s Disease in different age and APOE‐ε4 status
Authors: Li Anqi , Du Jing , Cai Yue , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Background

High and low body mass index (BMI) may increase the risk of Alzheimer’s disease (AD) in mid‐life (age<65) and late‐life (age≥65) respectively. However, it is still not fully understood about the associations of BMI changes with AD progression as well as how APOE‐ε4 allele modulates their relationships in mid‐life and late‐life. In this study, we aimed to determine how BMI changes and APOE‐ε4 allele relate to longitudinal β‐amyloid (Aβ) accumulation, tau aggregation, neurodegeneration and cognitive decline in mid‐life and late‐life.

Method

We examined 325 cognitively unimpaired and 391 mild cognitive impairment Alzheimer’s Disease Neuroimaging Initiative participants with longitudinal 18F‐florbetapir (FBP) Aβ PET and BMI measurements. Among of them, 486, 707 and 710 had longitudinal 18F‐fluorodeoxyglucos (FDG) PET, adjusted hippocampal volume (aHCV) and memory scores, and 246 participants had follow‐up 18F‐flortaucipir (FTP) tau PET data measured at a median of 5.5 years post baseline FBP scan. We investigated the associations of BMI slopes with longitudinal changes of AD typical summary cortical region FBP PET and FDG PET, aHCV and memory scores, and follow‐up Temporal‐metaROI FTP PET in different Aβ status (Aβ‐ and Aβ+), APOE‐ε4 status (carriers and non‐carriers), age (mid‐life and late‐life).

Result

We found faster BMI decreases accelerated the rates of Aβ accumulation (Fig.1D, standardized β (βstd) = ‐0.29, p = 0.002), hypometabolism (Fig.3D, βstd = 0.24, p = 0.03), hippocampal atrophy (Fig.3H, βstd = 0.29, p = 0.002), and memory decline (Fig.4D, βstd = 0.28, p = 0.005), and induced marginally higher follow‐up tau deposition (Fig.2D, βstd = ‐0.26, p = 0.09) in Aβ+ late‐life APOE‐ε4 non‐carriers but not in APOE‐ε4 carriers. In contrast, BMI increases were related to faster (Fig.1C, βstd = 0.80, p < 0.001) rates of Aβ accumulation in Aβ+ mid‐life APOE‐ε4 carriers but not in APOE‐ε4 non‐carriers.

Conclusion

These findings suggest that weight increase in mid‐life APOE‐ε4 carriers and weight loss in late‐life APOE‐ε4 non‐carriers are environmental risk factors of AD, highlighting the importance of tracking BMI data in Aβ+ individuals.
Plasma lipid signature as an indicator of the risk and rate of progression from mild cognitive impairment to Alzheimer’s disease
Authors: Dakterzada Faride , Jové Mariona , Pamplona Reinald , Piñol‐Ripoll Gerard
Published: June 2023

Background

Our knowledge about the importance of lipids in progression and the rate of progression from Mild Cognitive Impairment (MCI) to AD is limited. Our objective was to determine plasma lipids that could be implicated in the progression or rate of progression from MCI to AD.

Method

We analyzed the plasma lipid profile of MCI patients (N = 90) by liquid chromatography coupled with mass spectrometry. The association of lipids with progression was studied by logistic regression and a Cox regression model was used to assess lipids associated with the speed of progression. We adjusted our analyses for age, sex, CSF core AD biomarkers, APOE4 status, and Mini‐Mental State Examination (MMSE).

Result

Forty‐seven (52%) MCI patients progressed to AD during follow‐up (58 ± 12.5 months). Regression analysis detected that presence of APOE4 allele and high levels of four lipids – two as risk factors (p = 0.002) and two as protectors (p = 0.002 and p = 0.003)– were associated with progression (AUC 0.972, p < 0.001). The effect of these lipids in separating progressive from non‐progressive patients was significant when compared with the regression model without them (AUC 0.729 vs 0.972, z = 4.595, |z|>2.575, p < 0.01). Seven lipids were associated with the rate of progression, of which two were associated with a shorter time to progression (OR 9.88, 99% CI [3.08 –31.71], p < 0.001 and OR 34.81, CI 99% [4.88 – 248.3], p < 0.001) and five with a longer time to progression (OR 0.34, 99% CI [0.135 – 0.870], p = 0.003; OR 0.164, CI 99% [0.056 – 0.479], p < 0.001; OR 0.153, 99% CI [0.056 – 0.419], p < 0.001; OR 0.148, CI 99% [0.034 – 0.644], p = 0.001; and OR 0.029, 99% CI [0.007 – 0.131], p < 0.001).

Conclusion

Our results suggest that lipid dysregulation could have an important role in progression and rate of progression from MCI to AD. Our data also indicate that AD lipid alterations could have clinical implications as circulating biomarkers of progression and progression speed.
Possibility of stimulation of cerebral angiogenesis and neurogenesis with transcatheter intracerebral laser photobiomodulation therapy during dementia in patients with Alzheimer’s disease and in patients with distal cerebral atherosclerosis
Authors: Maksimovich Ivan V
Published: June 2023

Background

The research is dedicated to stimulation of cerebral angiogenesis and neurogenesis with Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) in patients with dementia during Alzheimer’s disease (AD) and patients with distal forms of cerebral atherosclerosis.

Materials & Methods

350 patients with dementia were examined.

We carried out determination of CDR, Tomography Dementia Rating scale (TDR), MMSE, cerebral CT, MRI, SG, rheoencephalography (REG), cerebral MUGA.

48 (13.71%) patients with AD aged 34‐80 (mean age 67.5) were selected: 17 men (35.42%), 31 women (54.58%). According to their dementia severity, the patients were subdivided: preclinical stage (TDR‐0) ‐ 4, mild stage (TDR‐1) ‐ 16, moderately severe stage (TDR‐2) ‐ 21, severe stage (TDR‐3) ‐ 7.

302 (86.29%) patients with distal cerebral atherosclerosis aged 58‐81 (mean age 78) were selected: 226 men (74.83%), 76 women (25.17%). According to their dementia severity, the patients were subdivided: mild stage (СDR‐1) ‐ 284 (94.04%), moderately severe stage (СDR‐2) ‐ 18 (5.96%).

At hospital, all the patients underwent PBMT.

Results

All 48 (100%) patients with AD showed improved cerebral microcirculation and 10‐20% increase in the volume of cerebral temporal lobes, which indicates cerebral neurogenesis development and tissue regeneration. The process was accompanied by a decreased level of dementia and restoration of cognitive functions. Consequently, the patients were transferred to milder TDR groups. Depending on the initial dementia severity, the resulting positive effect was observed during 2‐10 years.

All 302 (100%) patients with distal cerebral atherosclerosis showed improved cerebral microcirculation and declining cerebral involutional changes, which indicates neurogenesis development and tissue regeneration. The process was accompanied by a decreased dementia level and cognitive functions restoration. The resulting positive effect was observed for over 10 years.

Conclusions

Despite differences in the etiology of AD and distal cerebral atherosclerosis, PBMT is an effective treatment for dementia in these diseases. The method improves the blood supply of the brain; it stimulates neurogenesis and tissue structures restoration, which leads to an improvement in mental and cognitive functions. The resulting effect persists for a long time.
Clinical relevance of disrupted topological organization of anatomical connectivity in behavioral variant frontotemporal dementia
Authors: Chu Min , Liu Li , Nie Binbin , Chen Kewei , Wu Liyong
Published: June 2023

Background

Abnormalities of neurodegenerative disease are not only involved in individual brain regions but also characterized by the alterations of a balance of connectomes. Graph theory is a novel approach to examine the balance of connectomes. However, the clinical relevance of white matter connectome changes in behavioral variant of frontotemporal dementia (bvFTD) is not well understood.

Methods

In this study, we used DTI image data from 24 patients with bvFTD and 28 normal controls to exploratory investigate the clinical relevance of white matter topological alterations.

Results

The topological organization was disrupted in patients with bvFTD both globally and locally, some of which were correlated with the severity of behavior symptoms reflected as frontal behavior inventory (FBI), clinical statuses including the mini‐mental state examination (MMSE) and frontotemporal lobar degeneration‐clinical dementia rating scale (FTLD‐CDR). Notably, the nodal parameters of the lost hub regions including bilateral dorsolateral superior frontal gyrus, right orbital inferior frontal gyrus, left insula and left anterior cingulate gyrus were associated with the severity of cognitive and behavioral symptoms.

Conclusion

Topological measures would be a potential marker to explore the disease severity, mapping the large‐scale structural connectome of the brain will help to understand emergent cognitive behaviors in the disease condition of bvFTD.
Molecular activation of gliovascular signaling precedes blood‐brain barrier disruption and neuronal loss in a mouse model of tauopathy
Authors: Komuro Yutaro , Minaeva Olga , Moncaster Juliet A , Hua Ning , Carmichael S. Thomas , Goldstein Lee E , Hinman Jason
Published: June 2023

Background

Increasing evidence points to disruption of the blood‐brain barrier (BBB) as an inciting event in the pathogenesis of Alzheimer’s disease. The contribution of tau‐mediated pathways driving blood‐brain dysfunction are comparatively understudied.

Method

Using the P301S mouse model of tauopathy, we employed dynamic contrast enhanced MRI (DCE‐MRI) and quantitative spatial analysis using gadolinium‐based mass spectrometry imaging to demonstrate widespread BBB dysfunction in late stage tauopathy. To identify molecular pathways regulating intercellular signaling between neurons and gliovascular support cells that are dysregulated in advance of BBB disruption, we developed a cell‐specific viral approach for transcriptional profiling of novel pathways within the multicellular environment of the neurovascular unit (NVU) in tauopathy. Viral constructs using cell‐type specific promoters (hSynapsin, GFAP, or PDGFRb) to drive expression of antigen‐tagged ribosomes (TRAP) were used to study variance in spatial and temporal gene expression patterns in NVU cell types in P301S transgenic mice prior to widespread BBB disruption.

Result

Regional disruption of BBB integrity involving the hippocampus, lateral temporal, and frontal cortices is prominent in 11 month‐old P301S mice. Cell‐specific profiling of early symptomatic 6 month‐old P301S mice identified a defined gene expression profile antecedent to BBB disruption in NVU cells comprised of 29 shared and 3299 unique genes across all cell types. In this early symptomatic stage of tauopathy, pericytes (1021 genes) and astrocytes (1717 genes) were remarkably more transcriptionally active than neurons (561 genes). Gene ontology analysis indicates that multiple molecular programs driving neuronal differentiation, neurite outgrowth, and synaptogenesis are expressed in gliovascular cells in the prodromal stage.

Conclusion

The specific and temporally regulated coordination of pathways in pericytes and astrocytes in advance of BBB dysfunction implicates the neurovascular unit as a potential driver in the development of tauopathy. This suggests a paradigm exists for gliovascular rescue of neurodegeneration and implicates numerous novel perivascular molecular pathways in the pathogenesis of tauopathy and Alzheimer’s disease.
Peripheral immunity is associated with the risk of incident dementia
Authors: Zhang Ya‐Ru
Published: June 2023

Background

Central immunity components especially microglia in dementia have been well studied and corresponding immunotherapy gradually caught the attention. However, few studies focused on peripheral immunity and dementia.

Method

To address the issue, we examined the longitudinal association between incident dementia and peripheral immunity markers encompassing immune cell counts, and their derived ratios including neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), systemic immune‐inflammation index (SII) and lymphocyte‐to‐monocyte ratio (LMR), utilizing data of 361653 participants from the UK Biobank (UKB).

Result

During a median follow‐up of 8.99 years, 4239 participants developed dementia. The results revealed that increased innate immunity markers were associated with higher dementia risk (per SD increment hazard ratio [HR]; 95% confidence interval [CI] 1.14; 1.09‐1.19 for neutrophils, 1.16; 1.11‐1.20 for NLR and 1.11; 1.07‐1.16 for SII), while increased adaptive immunity markers were associated with lower dementia risk (0.93; 0.90‐0.97 for lymphocytes and 0.94; 0.90‐0.98 for LMR).

Conclusion

Our study pinpoints the differential role of innate and adaptive immunity in dementia incidence, which may provide some new perspectives in etiology and therapy of dementia.
Study the potential of PS23 probiotics in Alzheimer’s disease model mice
Authors: Chang Ching‐Hwa , Shih Jui‐Hsin , Tsai Ying‐Chieh , Hsieh Hsiu‐Mei
Published: June 2023

Background

Alzheimer’s disease (AD) is the most common form of dementia that affects memory, thinking, and behaviors. Studies have proved that there is a bidirectional communication in the gut‐brain axis. Recently, increasing evidence indicate the association between gut dysbiosis and AD, and studies show that probiotics can affect gut dysbiosis through the gut‐brain axis. Lactobacillus paracasei PS23 is a probiotic isolated from healthy human feces, and several studies suggest it can ameliorate cognitive decline, aging progression, and depression. Whether PS23 show effect on AD remains to be explored.

Method

We applied the PS23 one week before and four weeks after the Aβ injection into the mouse hippocampal CA1 region. A series of behavior tasks were performed to analyze the cognition and anxiety of mice. We also investigated whether probiotic PS23 changed the gut microbiota composition and gene expression in mouse hippocampus.

Result

PS23 showed a tendency in improving the short‐term memory and spatial learning ability of an Aβ‐injected acute AD model mice. In addition, synapse protection and anti‐inflammation were observed after PS‐23 treatment. The gut microbiota composition showed some bacteria strains were different after Aβ injection and oral administration of PS23. How the alteration in microbiota associates with AD is under characterization. In addition, the alteration in hippocampal gene expression profile will be used to further elucidate the molecular mechanism of PS23 in the AD model mice.

Conclusion

Results of this project suggest that PS23 might have benefit in improving the short‐term memory and spatial learning of an Aβ‐injected acute AD model mice through anti‐inflammation, which could provide some options in the strategy for AD prevention or therapy.
Chronic glial activation causes cholinergic cell loss in the basal forebrain during pathological aging
Authors: Gamage Rashmi Vasundhara , Childs Ryan , Hornas Gintara , Wagnon Ingrid Marguerite , Niedermayer Garry , Muench Gerald Wolfgang , Gyengesi Erika
Published: June 2023

Background

Neuroinflammation, described by chronic glial reactivation lead to gradual neurodegeneration during pathological aging, contributing to disorders like Alzheimer’s disease (AD). Cholinergic cell loss in the basal forebrain (BF) including the medial septum (MS) is associated with AD; however the underlying mechanism is still unknown. Hence, this study investigated the effects of aging and chronic neuroinflammation on the MS cholinergic cell numbers and morphology.

Method

Aged, 12 and 24 months WT and GFAP‐IL6 mice (presenting IL‐6 overexpression under the GFAP promoter, resulting in chronic glial activation) were used. Immunohistochemistry combined with unbiased stereology and 3D morphology analysis were used to estimate the number and morphology of Iba1+ microglia and ChAT+ cholinergic cells in the MS. Transcriptomic analysis of the MS was performed using qPCR.

Result

Stereological estimation of MS microglia number displayed a significant 25% increase in GFAP‐IL6 mice compared to control WT (12M). A significant 30% increase was obtained for GFAP‐IL6 (24M) mice compared to control (24M). Furthermore, a significant 23% increase in microglia was described for GFAP‐IL6 (24M) compared to the GFAP‐IL6 (12M) mice. A significant 28% and 38% decrease in microglial 3D surface area, and volume respectively were observed between WT and GFAP‐IL (12M) mice, as well as 26% and 34% decrease respectively between WT (12M) and (24M), resembling reactive microglial morphology. Meanwhile, cholinergic cell number displayed a significant 31% decrease in GFAP‐IL6 (12M) mice compared to WT (12M). While a significant 30% decrease was displayed in GFAP‐IL6 (24M) mice compared to WT (24M) mice. There was a tendency for the cholinergic cell number to decrease with ageing among control and GFAP‐IL6 cohorts. Cholinergic cell morphology displayed significant 58% and 67% reduction in the 3D dendritic field surface area, and volume respectively between WT (12M) and GFAP‐IL (12M) mice, as well as 41% and 46% decrease respectively between WT (12M) and (24M), displaying patterns like neuronal degeneration.

Conclusion

These findings demonstrate a significant impact of both aging and chronic glial activation alone on cholinergic cell number and morphology in the MS, resembling the cholinergic cell loss in AD, which can exacerbate throughout ageing leading to neurodegenerative impairments.
A comprehensive array of gray matter labels for the MIITRA atlas: Interoperability with complementary atlases
Authors: Niaz Mohammad Rakeen , Ridwan Abdur Raquib , Wu Yingjuan , Zhang Shengwei , Bennett David A , Arfanakis Konstantinos
Published: June 2023

Background

A comprehensive array of gyral‐based,cytoarchitecture‐based,and functional connectivity‐based gray matter labels were constructed in the Multichannel Illinois Institute of Technology & Rush university Aging (MIITRA) atlas space in order to enhance the functionality of the atlas and its interoperability with complementary atlases.

Method

T1w images from the 400 older adults included in the construction of the MIITRA atlas (50%male;64.9‐98.9 years of age) were processed with Freesurfer’s standard recon‐all pipeline. The Freesurfer outputs for all images were manually edited. Parcellations from Yeo,Desikan‐Killiany,HCP‐MMP,Brainnetome,Brodmann,Destrieux,Campbell,Flechsig,Mindboggle,Kleist,Smith,and EconomoCT atlases were projected onto the surface of each image and then converted to volumetric labels. The T1w images were also nonlinearly registered using ANTs‐SyN to the MNI152‐6thgen,MNI‐Colin,and the MNI‐2009b templates, and volumetric labels from Harvard‐Oxford,Julich,AAL3,Buckner,CoBrALab,CAREN,Striatum‐subdivision and Hippocampal‐subfields atlases were warped to the space of each image. The ANTs‐derived transformations applied on individual T1w images to build the MIITRA T1w template were used to map the corresponding gray matter labels from raw space to exact physical locations in the final MIITRA space. The performance of the MIITRA gray matter labels in segmentation of the gray matter of a separate group of 100 older adult individuals was evaluated in terms of label overlap, geometry, and dissimilarity when comparing the MIITRA labels warped to each individual’s space, to the respective reference labels from the source atlases.

Result

Examples of the gray matter labels in MIITRA space are shown in Figure1. The measures of overlap between the warped and reference labels for each set of labels were generally high, with an average Dice coefficient of 0.78±0.3, average Jaccard coefficient of 0.59±0.27(Fig.2), sensitivity of 0.74±0.1, and specificity of 0.86±0.35(Fig.3). The label geometry showed a high correlation both in terms of the average volume of each label(correlation coefficient = 0.997,p‐value<10−10) and in terms of the average surface area of each label(correlation coefficient = 0.991,p‐value<10−10)(Fig.4). The values of dissimilarity were low, with an average volume error of 0.38±0.2(Fig.5).

Conclusion

The gray matter labels in the MIITRA, in combination with the high‐resolution T1w template of the atlas, allowed segmentation of the gray matter of older adults that is in good agreement with the reference labels from the source atlases.
The effects of cognitive and physical exercise interventions on cognition in Huntington’s disease: A systematic review
Authors: Huynh Katharine , Nategh Leila , Jamadar Sharna , Georgiou‐Karistianis Nellie , Lampit Amit
Published: June 2023

Background

Cognitive and physical exercise interventions demonstrate efficacy in improving cognition in several populations but have not been reviewed in Huntington’s disease (HD). This systematic review aims to examine the effects of cognitive and physical interventions in HD.

Method

Electronic databases (MEDLINE, EMBASE, PsycINFO, CENTRAL) were searched from inception through till 10 May 2021 for interventional studies of cognitive or physical exercise interventions in HD, with any control or no control. Clinical trial registries, theses databases and organisational websites were additionally searched. The primary outcome was change on objective measures of cognition. Additional outcomes included change in psychosocial, functional and neuroimaging outcomes. Risk of bias for each outcome domain was assessed independently by two reviewers using the Cochrane RoB 2 and ROBINS‐I tools. As studies reported multiple eligible outcomes in cognitive and psychosocial domains, composite effect sizes were calculated as standardized mean differences (Hedges’ g) with 95% CI.

Result

Fifteen studies (three cognitive, five physical, seven multidomain interventions) were included. There were five randomized controlled trials, two non‐randomized controlled trials and eight single arm studies. Most studies were therefore considered at serious risk of bias due to confounding. Interventions that included cognitive training (alone or combined with exercise) tended to report larger cognitive effect sizes, whereas studies of physical exercise (alone or combined with cognitive rehabilitation or stimulation) reported negligible benefits. Studies of multidomain interventions had larger effects on psychosocial functioning. Functional outcomes were only available from studies of multidomain interventions, which had negligible benefits. Across interventions, structural brain changes were reported in cortical and subcortical regions, but regions of interest and analyses were heterogeneous. No studies reported functional brain changes.

Conclusion

Our review indicates that cognitive training may benefit cognition in HD, while multidomain interventions may improve psychosocial function. Cognitive and physical interventions may promote structural brain changes, but functional brain changes are unclear. Larger randomised controlled trials are required to confirm the effects of cognitive or physical interventions in HD.
Associations of lifespan cognitive reserve with mild cognitive impairment and dementia among older adults with low literacy: A population‐based cohort study
Authors: Li Yuanjing , Ren Yifei , Cong Lin , Hou Tingting , Song Lin , Wang Mingqi , Wang Xiang , Shi Lin , Dekhtyar Serhiy , Wang Yongxiang , Du Yifeng , Qiu Chengxuan
Published: June 2023

Background

Educational attainment in early life represents a major contributor to cognitive reserve (CR). High CR capacity derived from lifespan enriching factors could delay cognitive decline. We sought to investigate the longitudinal associations of CR capacity with mild cognitive impairment (MCI) and dementia among older adults with no or low literacy.

Method

This population‐based cohort study included 2141 rural participants (age≥60 years; 59.5% women; 84.8% illiteracy or elementary school) in the Shandong Yanggu Study of Aging and Dementia who were free of dementia at baseline (August‐December 2014) and who undertook follow‐up examinations in March‐September 2018. CR capacity was estimated by integrating early‐life education attainment, adulthood occupation and marital status, and late‐life physical activity and social support, and categorized into low, intermediate, and high levels using tertiles. MCI and amnestic MCI were defined according to the Petersen’s criteria that integrated clinical assessment with neuropsychological tests. Dementia and Alzheimer’s disease (AD) were diagnosed according to the DSM‐IV and NIA‐AA criteria, respectively. Data were analyzed using the structural equation and Cox proportional‐hazards models.

Result

During an average of 3.7 (SD = 0.4) years of follow‐up, 102 of the 2141 dementia‐free participants were diagnosed with dementia, including 75 with AD. Compared to the low CR level, intermediate and high CR levels were associated with multi‐adjusted hazards ratios (HRs) (95% confidence intervals [CIs]) of 0.59 (0.37–0.94) and 0.47 (0.26–0.85) for dementia and 0.53 (0.31–0.92) and 0.38 (0.17–0.83) for AD, respectively. In addition, out of the 1727 MCI‐free participants at baseline, 330 developed MCI at follow‐up, including 270 with aMCI. Intermediate and high CR levels (vs. low) were associated with multi‐adjusted HRs (95% CIs) of 0.70 (0.53–0.92) and 0.60 (0.45–0.81) for MCI and 0.65 (0.48–0.87) and 0.58 (0.42–0.79) for amnestic MCI, respectively.

Conclusion

In Chinese rural elderly, high CR capacity is associated with reduced risks of MCI, amnestic MCI, dementia, and AD. This suggests that the effect of CR capacity in delaying the onset of MCI and dementia exists even among rural older adults with no or very low literacy.
Association between amyloid, tau and cerebral small vessel disease
Authors: Cai Yuan , Liu Wanting , Fan Xiang , Wu Kuan‐Jung , Shi Lin , Au Lisa Wing Chi , Lam Bonnie Y.K. , Abrigo Jill , Mok Vincent C.T. , Ko Ho
Published: June 2023

Background

Controversy exists with respect to the etiological role of cerebral small vessel disease (CSVD) in Alzheimer’s disease (AD). We thus evaluated the association between white matter hyperintensity (WMH), an MRI marker of CSVD, with brain amyloid β (Aβ) and tau burden and their plasma markers among subjects with varying severity levels of cognitive impairment.

Methods

We recruited 84 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had varying severity levels of cognitive impairment: 10 healthy controls [HC], 32 with subjective cognitive decline [SCD], 26 with mild cognitive impairment [MCI] and 16 with dementia. All subjects underwent structural MRI, 11C‐ PIB, and 18F‐T807 positron emission tomography (PET), to measure WMH volume, and pathological Aβ deposition (A+) and tau burden (T+), respectively. WMH volume was quantified by automatic segmentation using AccuBrain® IV 1.1. Plasma levels of Aβ40, Aβ42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181) and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays among 71 subjects.

Results

The mean age of the subjects was 67.5. 34 (40.8%) were male. No significant associations were found between WMH volume and global 11C‐PIB or 18F‐T807 standardized uptake value ratio (SUVR) on PET. Interestingly, we found that increasing WMH volume significantly correlated with higher plasma p‐tau181 level (β = 0.10; 95% C.I.: 0.012 – 0.188; P = 0.03). There were no associations between WMH volume and plasma Aβ40, Aβ42, t‐tau or NfL levels.

Conclusion

Brain WMH volume was associated with plasma p‐tau181 level but not with PET tau positivity in the brain. Our results suggest that CSVD burden may contribute to elevated plasma phosphorylated tau in AD, and such change may precede PET‐detectable elevated tau burden in the brain.
Longitudinal brain atrophy rates in presymptomatic genetic frontotemporal dementia
Authors: Poos Jackie M. , Grandpierre Leonie D.M. , van der Ende Emma L. , Panman Jessica L. , Papma Janne M. , Seelaar Harro , van den Berg Esther , van ’t Klooster Ronald , Bron Esther E , Steketee Rebecca M.E. , Vernooij Meike W , Pijnenburg Yolande A.L. , van Swieten John C. , Rombouts Serge A.R.B. , Jiskoot Lize C.
Published: June 2023

Background

In light of upcoming clinical trials for genetic frontotemporal dementia (FTD), it is important to identify at what age brain atrophy rates start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We aimed to investigate longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD, using normative brain volumetry software.

Method

34 GRN, eight MAPT, and 14 C9orf72 presymptomatic mutation carriers underwent longitudinal volumetric T1‐weighted MRI of the brain with a one‐ to two‐year interval (mean number of scans = 3.5, SD = 1.6). Images were automatically analyzed with Quantib® ND which consisted of volume measurements (CSF and grey + white matter) of lobes (left, right, and combined), cerebellum, and hippocampus. All volumes were compared to reference centile curves based on a large population‐derived sample of non‐demented individuals (n = 4951). Mixed‐effects models were fitted to analyze atrophy rates of the different gene groups as a function of age, and were corrected for sex, head coil, and scanner software version.

Result

Atrophy rates of the total brain, frontal lobe, and temporal lobe differed between gene groups (all p<0.002). GRN mutation carriers declined faster than the reference centile curves for all brain areas, though relative volumes remained between 5th and 75th percentile between the ages of 45 – 70. In MAPT mutation carriers, frontal lobe volume was already at the 5th percentile at age 45, and showed further decline between the ages 50‐60. Temporal lobe volume started in the 50th percentile at age 45, but showed fastest decline over time compared to other brain structures. Frontal, temporal, parietal and cerebellar volume already started below the 5th percentile compared to the reference centile curves at age 45 for C9orf72 mutation carriers, but there was minimal decline over time until the age of 60.

Conclusion

We provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease‐tracking and staging biomarkers in genetic FTD.
Associations of patient‐specific resting state variability with CSF and clinical biomarkers: Data from Alzheimer’s disease clinical trials
Authors: Gobbi Susanna , Scelsi Marzia A. , Delmar Paul , Bittner Tobias , Klein Gregory , Magon Stefano
Published: June 2023

Background

Changes of brain functional connectivity assessed using MRI in patients with Alzheimer’s disease (AD) have been previously reported. However, factors contributing to the variability among patients have not been sufficiently investigated. Here, we investigated the association of patient‐specific resting state parameters with CSF markers and clinical measures.

Method

We analyzed the baseline rs‐fMRI of 158 patients (87 female, age 50‐89) with mild AD collected in the Marguerite RoAD trial of gantenerumab in mild AD (NCT02051608) and 132 cognitively unimpaired adults (88 female, age 56‐90) from ADNI. We investigated the within‐ and between‐subjects’ variability in five brain networks (Sensory Motor, Cerebellar, Visual, Default Mode and Cognitive Control), inferred from the two groups using a Bayesian probabilistic model (PROFUMO, Harrison‐Smith‐2015; Harrison‐Woolrich‐2020). We computed spatial maps, BOLD amplitude changes, and spatial (temporal) functional connectivity between‐ and within‐networks for each subject. Those metrics were compared between groups using T‐tests. In AD patients we used linear models to investigate associations of the extracted metrics with CSF markers (Amyloid Beta 42, p‐Tau217, pTAU/Abeta 1‐42 ratio and Neurogranin) and cognitive scores (ADAS‐Cog 13, MMSE and ADCS‐ADL), while controlling for age, sex and MRI‐scanner type. All results were corrected for multiplicity using FDR.

Result

On average the signal amplitude was lower in the Cognitive Control and the Sensory Motor (p < 0.0001) networks in AD patients compared to cognitively unimpaired adults. Interestingly, in AD patients the lower amplitude observed in the cognitive control network was associated with cognitive decline (β = 0.02, p = 0.01). Moreover, significant associations were observed in AD patients between lower signal amplitude and higher CSF levels of ABeta 42 (β = ‐0.02, p = 0.036) and cognitive decline (β = 0.02, p = 0.008) (Fig.2). AD group showed on average reduced functional connectivity compared to the healthy one. Furthermore, the within‐AD patients’ analysis showed weak between‐ and strong within‐networks connectivity (T‐test, q < 0.05, Fig.1).

Conclusion

In patients with mild AD, the signal amplitude and connectivity in the cognitive control and DMN networks were associated with both CSF level of ABeta42 and cognitive scores.
A lightweight unsupervised approach for adverse health detection and digital biomarker discovery in people living with dementia
Authors: Bijlani Nivedita , Nilforooshan Ramin , Barnaghi Payam , Kouchaki Samaneh
Published: June 2023

Background

Sensor‐based remote health monitoring of persons living with dementia (PLwD) can be used to gain insights into their health and monitor the progression of their condition, with minimal intrusion. This helps minimize preventable hospital admissions, while allowing researchers to improve their understanding of dementia. Existing approaches for detecting activity and behavioural anomalies in PLwD are challenged by noise in data, lack of annotated datasets, multivariate data, scalability, data drift and explainability.

Method

We propose and evaluate a solution based on the Matrix Profile, an exact, ultra‐fast distance‐based anomaly detection algorithm, specifically the Contextual Matrix Profile (CMP), to detect anomalies that may indicate unusual activity and onset of UTI. Daily household movement data collected via passive infrared (PIR) sensors are used to generate CMPs from location‐wise sensor counts, duration and change in hourly movement patterns. We create CMP‐based multivariate anomaly detection models to generate a single daily normalized anomaly score for each patient. We discover digital biomarkers of anomalies and evaluate our method vs. three state‐of‐the‐art algorithms.

Result

CMP‐based models yield up to 85% recall with only a 5% alert rate, when evaluated on a subset of 9363 days from 15 participant households with 41 clinically validated incidences of urinary tract infections (UTI) and hospitalization, collected by the UK Dementia Research Institute between August 2019 and July 2021. Our multidimensional CMP model offers the best balance of recall vs. anomalies raised, with excellent generalisation. We discover that bathroom early AM activity (midnight to 6 am) is the prime cross‐patient digital biomarker of anomalies. This validates findings in literature that unusual bathroom activity is a clinically significant feature in UTI for dementia. We also demonstrate a cross‐patient view of anomaly patterns.

Conclusion

We address the need for anomaly detection and scoring using multivariate time series sensor data in remote health monitoring. The CMP allows configurability, ability to denoise and detect patterns, and explainability to clinical practitioners. With higher sensitivity, fewer alerts and better overall performance than state‐of‐the‐art methods, and the ability to discover digital biomarkers of anomalies, the CMP is a clinically meaningful unsupervised anomaly detection technique for dementia and beyond.
Integrated Mass Spectrometry‐based Pipeline for Characterization of Tau in Human Alzheimer’s Brain: Development and Comparison of Sample Preparation Methods
Authors: Azevedo Rita , Villain Nicolas , Boluda Susana , Fenaille François , Lamari Foudil , Becher Francois
Published: June 2023

Background

Tau protein aggregation into neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer’s disease (AD) and related tauopathies [1]. Though the mechanism of tau destabilization is not fully understood, tau protein exhibits several allele‐specific isoforms and post‐translational modifications (PTMs) specific to tau aggregates [2]. To explore in‐depth tau species in brain tissues of AD patients, we developed novel pipelines based on different tau fractions retrieved by buffer solubility, Filter Aided Sample Preparation (FASP) or immunoprecipitation, before high‐resolution mass spectrometry (HRMS) analysis.

Method

As a proof of concept, we used frozen brain samples from two AD patients (0.6‐1.2 g per replicate, middle frontal gyrus). The samples were divided and homogenized, ultracentrifuged at 180.000xg for 30min and solubilized in different buffers successively (2 replicates): (1) Sark

Method

low‐salt buffer, 10% Triton X‐100, sarkosyl buffer, and urea buffer; (2) RIPA

Method

high‐salt buffer (twice), RIPA buffer and urea buffer; and, (3) GnH

Method

guanidine hydrochloride and urea buffer. Then, we performed an antibody‐free approach by FASP or immunoprecipitation with a panel of commercial tau antibodies and analyzed on reversed‐phase capillary liquid chromatography, coupled with a qExactive HRMS.

Result

HRMS demonstrated that the RIPA method performed better than the other methods for Tau analysis: coverage of 63% (full‐length, 2N4R) and 342 tau peptide‐spectrum matches (PSMs) (Sark: 49% and 183 PSMs; GnH: 41% and 169 PSMs). PTM‐modified tau species (phosphorylated, methylated, and acetylated) were primarily seen using the RIPA method (59 PSMs; Sark: 19 PSMs, GnH: 21 PSMs). Immunoprecipitation improved tau coverage and PTM detection compared to FASP.

Conclusion

These findings highlight the best performance of the RIPA method followed by immunoprecipitation for the study of AD brain tau allele‐specific isoforms and PTMs using HRMS. Better characterization of Tau molecular profile in the brain of AD patients opens the gate for a better understanding of AD pathogenesis and represents an opportunity in the biomarker field.

[1] Mroczko, B. et al. Int J Mol Sci 2019, 20, E4661, https://doi.org/10.3390/ijms20194661.

[2] Boyarko, B.; Hook, V. Front. Neurosci. 2021, 15, 702788, https://doi.org/10.3389/fnins.2021.702788.