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Scientific Reports Jul 2024Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation...
Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer's disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aβ) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aβ-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN- , A- /TN+ , and A- /TN- . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aβ-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aβ-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aβ-PET rate of change only in the A+ /TN- group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aβ and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aβ plaque formation and tau aggregate accumulation only in the presence of Aβ pathology.
Topics: Humans; Alzheimer Disease; Receptors, Immunologic; Membrane Glycoproteins; Biomarkers; Female; Male; Aged; Longitudinal Studies; tau Proteins; Neuroimaging; Aged, 80 and over; Amyloid beta-Peptides; Positron-Emission Tomography; Plaque, Amyloid; Microglia
PubMed: 38961148
DOI: 10.1038/s41598-024-66211-w -
Scientific Reports Jul 2024Alzheimer's disease (AD), the predominant form of dementia, is a growing global challenge, emphasizing the urgent need for accurate and early diagnosis. Current clinical...
Alzheimer's disease (AD), the predominant form of dementia, is a growing global challenge, emphasizing the urgent need for accurate and early diagnosis. Current clinical diagnoses rely on radiologist expert interpretation, which is prone to human error. Deep learning has thus far shown promise for early AD diagnosis. However, existing methods often overlook focal structural atrophy critical for enhanced understanding of the cerebral cortex neurodegeneration. This paper proposes a deep learning framework that includes a novel structure-focused neurodegeneration CNN architecture named SNeurodCNN and an image brightness enhancement preprocessor using gamma correction. The SNeurodCNN architecture takes as input the focal structural atrophy features resulting from segmentation of brain structures captured through magnetic resonance imaging (MRI). As a result, the architecture considers only necessary CNN components, which comprises of two downsampling convolutional blocks and two fully connected layers, for achieving the desired classification task, and utilises regularisation techniques to regularise learnable parameters. Leveraging mid-sagittal and para-sagittal brain image viewpoints from the Alzheimer's disease neuroimaging initiative (ADNI) dataset, our framework demonstrated exceptional performance. The para-sagittal viewpoint achieved 97.8% accuracy, 97.0% specificity, and 98.5% sensitivity, while the mid-sagittal viewpoint offered deeper insights with 98.1% accuracy, 97.2% specificity, and 99.0% sensitivity. Model analysis revealed the ability of SNeurodCNN to capture the structural dynamics of mild cognitive impairment (MCI) and AD in the frontal lobe, occipital lobe, cerebellum, temporal, and parietal lobe, suggesting its potential as a brain structural change digi-biomarker for early AD diagnosis. This work can be reproduced using code we made available on GitHub.
Topics: Alzheimer Disease; Humans; Magnetic Resonance Imaging; Neural Networks, Computer; Deep Learning; Neuroimaging; Brain; Image Processing, Computer-Assisted
PubMed: 38961114
DOI: 10.1038/s41598-024-60611-8 -
The Journal of Neuroscience : the... Jul 2024
Review
Topics: Alzheimer Disease; Humans; Amyloid beta-Peptides; Cerebrovascular Disorders; Animals; Cerebrovascular Circulation
PubMed: 38960709
DOI: 10.1523/JNEUROSCI.0663-24.2024 -
Magnetic Resonance in Medical Sciences... Jul 2024We developed new deep learning-based hierarchical brain segmentation (DLHBS) method that can segment T1-weighted MR images (T1WI) into 107 brain subregions and calculate...
PURPOSE
We developed new deep learning-based hierarchical brain segmentation (DLHBS) method that can segment T1-weighted MR images (T1WI) into 107 brain subregions and calculate the volume of each subregion. This study aimed to evaluate the repeatability and reproducibility of volume estimation using DLHBS and compare them with those of representative brain segmentation tools such as statistical parametric mapping (SPM) and FreeSurfer (FS).
METHODS
Hierarchical segmentation using multiple deep learning models was employed to segment brain subregions within a clinically feasible processing time. The T1WI and brain mask pairs in 486 subjects were used as training data for training of the deep learning segmentation models. Training data were generated using a multi-atlas registration-based method. The high quality of training data was confirmed through visual evaluation and manual correction by neuroradiologists. The brain 3D-T1WI scan-rescan data of the 11 healthy subjects were obtained using three MRI scanners for evaluating the repeatability and reproducibility. The volumes of the eight ROIs-including gray matter, white matter, cerebrospinal fluid, hippocampus, orbital gyrus, cerebellum posterior lobe, putamen, and thalamus-obtained using DLHBS, SPM 12 with default settings, and FS with the "recon-all" pipeline. These volumes were then used for evaluation of repeatability and reproducibility.
RESULTS
In the volume measurements, the bilateral thalamus showed higher repeatability with DLHBS compared with SPM. Furthermore, DLHBS demonstrated higher repeatability than FS in across all eight ROIs. Additionally, higher reproducibility was observed with DLHBS in both hemispheres of six ROIs when compared with SPM and in five ROIs compared with FS. The lower repeatability and reproducibility in DLHBS were not observed in any comparisons.
CONCLUSION
Our results showed that the best performance in both repeatability and reproducibility was found in DLHBS compared with SPM and FS.
PubMed: 38960679
DOI: 10.2463/mrms.mp.2023-0124 -
American Journal of Epidemiology Jul 2024We explored state-level indicators of structural racism on internalizing symptoms of depressive affect among US adolescents. We merged 16 indicators of state-level...
We explored state-level indicators of structural racism on internalizing symptoms of depressive affect among US adolescents. We merged 16 indicators of state-level structural racism with 2015-19 Monitoring the Future surveys (N=41,258) examining associations with loneliness, self-esteem, self-derogation, and depressive symptoms using regression analyses. Students racialized as Black in states with bans on food stamp eligibility and temporary assistance for drug felony conviction had 1.37 times the odds of high depressive symptoms (95% C.I. 1.01-1.89) compared to students in states without bans. In contrast, students racialized as White living in states with more severe disenfranchisement of people convicted of felonies had lower odds of high self-derogation (OR=0.89, 95% C.I. 0.78-1.02) and high depressive symptoms (OR=0.83, 95% C.I. 0.70-0.99) compared to states with less severe disenfranchisement. These findings demonstrate the need to address the legacy of structural racism at the state level to reduce mental distress for US youth.
PubMed: 38960643
DOI: 10.1093/aje/kwae164 -
Advances in Protein Chemistry and... 2024In Alzheimer's disease, the microtubule-associated protein, Tau misfolds to form aggregates and filaments in the intra- and extracellular region of neuronal cells.... (Review)
Review
In Alzheimer's disease, the microtubule-associated protein, Tau misfolds to form aggregates and filaments in the intra- and extracellular region of neuronal cells. Microglial cells are the resident brain macrophage cells involved in constant surveillance and activated by the extracellular deposits. Purinergic receptors are involved in the chemotactic migration of microglial cells towards the site of inflammation. From our recent study, we have observed that the microglial P2Y12 receptor is involved in phagocytosis of full-length Tau species such as monomers, oligomers and aggregates by actin-driven chemotaxis. This study shows the interaction of repeat-domain of Tau (Tau) with the microglial P2Y12 receptor and the corresponding residues for interaction have been analyzed by various in-silico approaches. In the cellular studies, Tau was found to interact with microglial P2Y12R and induces its cellular expression confirmed by co-immunoprecipitation and western blot analysis. Furthermore, the P2Y12R-mediated Tau internalization has demonstrated activation of microglia with an increase in the Iba1 level, and Tau becomes accumulated at the peri-nuclear region for the degradation.
Topics: Humans; Tauopathies; tau Proteins; Microglia; Receptors, Purinergic P2Y12; Animals; Receptors, G-Protein-Coupled
PubMed: 38960483
DOI: 10.1016/bs.apcsb.2024.04.001 -
Advances in Protein Chemistry and... 2024Alzheimer's disease is progressive neurodegenerative disease characterize by the presence of extracellular accumulation of amyloid-β plaques and intracellular deposits... (Review)
Review
Alzheimer's disease is progressive neurodegenerative disease characterize by the presence of extracellular accumulation of amyloid-β plaques and intracellular deposits of neurofibrillary tangles of Tau. Apart from axonal depositions pathological aggregated Tau protein is known to secrete into extracellular spaces and propagate through seeding mechanism. Microglia, the immune cells of the brain display modest ability to internalize the extracellular Tau and degrade it through endolysosomal pathway. However, the excessive burden of pathoproteins weakens the phagocytic ability of microglia. Extracellular supplementation of omega-3 fatty acids (n-3) may regulate the phagocytosis of microglia as they mediate the anti-inflammatory polarization of microglia through membrane lipid compositions changes. The internalization of extracellular Tau in the microglia is regulated by cortical membrane-associated actin remodeling driven by interplay of actin-binding proteins. On the other hand, Tau display capability bind and interact with various actin-binding protein owing to the presence of proline-rich domain in the structure and regulate their activation. In this study, we hypothesize that internalization of Tau in the presence of omega-3 fatty acids would propagate the Tau-mediated activation of actin-binding proteins as well as extracellular matrix and in turn modulate cortical actin remodeling for phagocytosis.
Topics: tau Proteins; Humans; Extracellular Matrix Proteins; Alzheimer Disease; Phagocytosis; Animals; Fatty Acids, Omega-3; Microglia
PubMed: 38960482
DOI: 10.1016/bs.apcsb.2024.04.002 -
Psychiatry Investigation Jun 2024To address the gap in timely diagnosis of dementia due to limited screening tools, we investigated the validity and reliability of the Hellocog, computerized...
OBJECTIVE
To address the gap in timely diagnosis of dementia due to limited screening tools, we investigated the validity and reliability of the Hellocog, computerized neuropsychological test based on tablets for screening dementia. The higher the probability score on the Hellocog, the higher the likelihood of dementia.
METHODS
This study included 100 patients with dementia and 100 individuals with normal cognition who were aged 60 years or older and free of other major psychiatric, neurological, or medical conditions. They administered the Hellocog on a tablet under the supervision of a neuropsychologist. To determine test-retest reliability, 20 took the Hellocog again after 4 weeks. Diagnostic performance was assessed using the receiver operator characteristics (ROC) analysis.
RESULTS
The Hellocog showed adequate internal consistency (Cronbach's alpha=0.69) and good test-retest reliability (intraclass correlation coefficient=0.86, p<0.001). Participants with dementia scored higher on the Hellocog than those with normal cognition (p<0.001), confirming its high criterion validity. Strong correlations with the Mini-Mental Status Examination (MMSE) score and the total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-TS) highlight the concurrent validity of the Hellocog. The area under the ROC curve for dementia of the Hellocog was excellent (0.971) and comparable to that of the MMSE and CERAD-TS. The sensitivity and specificity for dementia were 0.945 and 0.872%, respectively, which were slightly better than those of the MMSE and CERAD-TS.
CONCLUSION
Hellocog stands out as a valid and reliable tool for self-administered dementia screening, with promise for improving early detection of dementia.
PubMed: 38960443
DOI: 10.30773/pi.2023.0388 -
Psychiatry Investigation Jun 2024Subjective cognitive decline (SCD) refers to self-reported memory loss despite normal cognitive function and is considered a preclinical stage of Alzheimer's disease....
OBJECTIVE
Subjective cognitive decline (SCD) refers to self-reported memory loss despite normal cognitive function and is considered a preclinical stage of Alzheimer's disease. This study aimed to examine the mediating effects of depression and Instrumental Activities of Daily Living (IADL) on the association between the scoring of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Subjective Cognitive Decline Questionnaire (SCD-Q).
METHODS
A sample of 139 community-dwelling older adults aged 65-79 with normal cognitive function completed the SCD-Q, a comprehensive neuropsychological battery, and functional/psychiatric scales. We conducted 1) a correlation analysis between SCD-Q scores and other variables and 2) a path analysis to examine the mediating effects of depression and IADL on the relationship between CDR-SB and SCD-Q.
RESULTS
CDR-SB was found to be indirectly associated with SCD-Q, with depressive symptoms mediating this relationship. However, no direct association was observed between SCD-Q and CDR-SB. Additionally, IADL was not associated with SCD-Q and did not mediate the relationship between CDR-SB and SCD-Q. The model fit was acceptable (minimum discrepancy function by degrees of freedom divided [CMIN/DF]=1.585, root mean square error of approximation [RMSEA]=0.065, comparative fit index [CFI]=0.955, Tucker-Lewis index [TLI]=0.939).
CONCLUSION
Our results suggest that SCD-Q is influenced by depressive symptoms, but not by IADL. The role of depressive symptoms as a mediator between CDR-SB and SCD-Q indicates that psychological factors may contribute to the perception of SCD. Therefore, interventions targeting depression may mitigate the concerns associated with SCD and reduce feelings of worse performance compared to others of the same age group.
PubMed: 38960435
DOI: 10.30773/pi.2023.0403 -
Mechanisms of Ageing and Development Jul 2024This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders....
This comprehensive review elucidates the critical role of antioxidants to mitigate oxidative stress, a common denominator in an array of neurodegenerative disorders. Oxidative stress-induced damage has been linked to the development of diseases such as Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis. This article examines a wide range of scientific literature and methodically delineates the several methods by which antioxidants exercise their neuroprotective benefits. It also explores into the complex relationship between oxidative stress and neuroinflammation, focusing on how antioxidants can alter signaling pathways and transcription factors to slow neurodegenerative processes. Key antioxidants, such as vitamins C and E, glutathione, and polyphenolic compounds, are tested for their ability to combat reactive oxygen and nitrogen species. The dual character of antioxidants, which operate as both direct free radical scavengers and regulators of cellular redox homeostasis, is investigated in terms of therapeutic potential. Furthermore, the study focuses on new antioxidant-based therapy techniques and their mechanisms including Nrf-2, PCG1α, Thioredoxin etc., which range from dietary interventions to targeted antioxidant molecules. Insights into ongoing clinical studies evaluating antioxidant therapies in neurodegenerative illnesses offer an insight into the translational potential of antioxidant research. Finally, this review summarizes our present understanding of antioxidant processes in neurodegenerative illnesses, providing important possibilities for future study and treatment development.
PubMed: 38960099
DOI: 10.1016/j.mad.2024.111961