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Nature Neuroscience Jul 2024Age is a major nonmodifiable risk factor for ischemic stroke. Central nervous system-associated macrophages (CAMs) are resident immune cells located along the brain...
Age is a major nonmodifiable risk factor for ischemic stroke. Central nervous system-associated macrophages (CAMs) are resident immune cells located along the brain vasculature at the interface between the blood circulation and the parenchyma. By using a clinically relevant thromboembolic stroke model in young and aged male mice and corresponding human tissue samples, we show that during aging, CAMs acquire a central role in orchestrating immune cell trafficking after stroke through the specific modulation of adhesion molecules by endothelial cells. The absence of CAMs provokes increased leukocyte infiltration (neutrophils and CD4 and CD8 T lymphocytes) and neurological dysfunction after stroke exclusively in aged mice. Major histocompatibility complex class II, overexpressed by CAMs during aging, plays a significant role in the modulation of immune responses to stroke. We demonstrate that during aging, CAMs become central coordinators of the neuroimmune response that ensure a long-term fine-tuning of the immune responses triggered by stroke.
PubMed: 38961228
DOI: 10.1038/s41593-024-01695-3 -
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 -
British Journal of Anaesthesia Jul 2024The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion,...
BACKGROUND
The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis.
METHODS
Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg over 30 min+0.5 g kg h for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70-80 mm Hg.
RESULTS
At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] μM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all P<0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both P<0.01), and increased plasma ascorbate (20 000 [300] μM; P<0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate.
CONCLUSIONS
Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.
PubMed: 38960833
DOI: 10.1016/j.bja.2024.04.058 -
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 -
Journal of Atherosclerosis and... Jul 2024Increased arterial stiffness is associated with the severity of cerebral small-vessel disease (SVD) and may predict incident dementia. This study investigated the...
AIMS
Increased arterial stiffness is associated with the severity of cerebral small-vessel disease (SVD) and may predict incident dementia. This study investigated the predictive value of brachial-ankle pulse wave velocity (ba-PWV) for dementia and cognitive decline.
METHODS
Data were obtained from a Japanese cohort of 478 patients who underwent ba-PWV measurement. Magnetic resonance imaging (MRI) was used to evaluate SVD severity. The Mini-Mental State Examination (MMSE) and the Japanese version of the Montreal Cognitive Assessment (MoCA-J) were used to assess the cognitive function. The primary outcome was the incidence of dementia. The secondary outcome was cognitive change during three years of follow-up.
RESULTS
The median age was 71 years old, 61% were men, and the median ba-PWV was 1787 cm/s. Dementia was diagnosed in 23 patients during a mean follow-up of 4.8 years. A Cox proportional hazard regression analysis revealed that the highest quartile (ba-PWV ≥ 2102 cm/s) was associated with a significantly higher risk of dementia than the first to third quartiles (ba-PWV ≤ 2099 cm/s) after adjusting for risk factors, the mean blood pressure, the MoCA-J score, and SVD severity (adjusted HR, 3.40; 95% CI, 1.24-9.34; P=0.018). Longitudinal cognitive changes in 192 patients indicated that ba-PWV was negatively related to changes in the MoCA-J score (r=-0.184, P=0.011). The decline in the MoCA-J score in the highest quartile was greater than that in the first to third quartiles after adjusting for risk factors, SVD severity, and baseline MoCA-J score (P=0.017).
CONCLUSIONS
ba-PWV was associated with incident dementia and cognitive decline, independent of age, risk factors, the baseline cognitive function, and the SVD severity.
PubMed: 38960633
DOI: 10.5551/jat.65042 -
BMJ (Clinical Research Ed.) Jul 2024
Topics: Humans; Hypothyroidism; Dementia; Thyroxine; Female
PubMed: 38960619
DOI: 10.1136/bmj.q1426 -
Journal of Neurology, Neurosurgery, and... Jul 2024Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause...
BACKGROUND AND OBJECTIVE
Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.
METHODS
We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.
RESULTS
We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 ( gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.
CONCLUSIONS
While previous studies have dismissed a causal role of in ALS, our results strongly support as a novel ALS-causing gene.
PubMed: 38960585
DOI: 10.1136/jnnp-2024-333834 -
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