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Cell Reports Jun 2024Cell functions rely on intracellular transport systems distributing bioactive molecules with high spatiotemporal accuracy. The endoplasmic reticulum (ER) tubular network...
Cell functions rely on intracellular transport systems distributing bioactive molecules with high spatiotemporal accuracy. The endoplasmic reticulum (ER) tubular network constitutes a system for delivering luminal solutes, including Ca, across the cell periphery. How the ER structure enables this nanofluidic transport system is unclear. Here, we show that ER membrane-localized reticulon 4 (RTN4/Nogo) is sufficient to impose neurite outgrowth inhibition in human cortical neurons while acting as an ER morphoregulator. Improving ER transport visualization methodologies combined with optogenetic Ca dynamics imaging and in silico modeling, we observed that ER luminal transport is modulated by ER tubule narrowing and dilation, proportional to the amount of RTN4. Excess RTN4 limited ER luminal transport and Ca release, while RTN4 elimination reversed the effects. The described morphoregulatory effect of RTN4 defines the capacity of the ER for peripheral Ca delivery for physiological releases and thus may constitute a mechanism for controlling the (re)generation of neurites.
PubMed: 38955182
DOI: 10.1016/j.celrep.2024.114357 -
Alzheimer's & Dementia : the Journal of... Jun 2024The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in... (Review)
Review
INTRODUCTION
The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization of patients with co-occurring Alzheimer's disease (AD) and LBD since the early clinical or even preclinical stage.
METHODS
We reviewed studies with an in vivo biomarker-based diagnosis of AD-LBD copathology.
RESULTS
Studies in large cohorts of cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect the coexistence of AD and LB pathology in approximately 20%-25% of them, independently of the primary clinical diagnosis. Compared to those with pure AD, AD-LBD patients showed worse global cognition, especially in attentive/executive and visuospatial functions, and worse motor functions. In cognitively unimpaired individuals, concurrent AD-LBD pathologies predicted longitudinal cognitive progression with faster worsening of global cognition, memory, and attentive/executive functions.
DISCUSSION
Future research studies aiming for a better precision medicine approach should develop SAAs further to reach a quantitative evaluation or staging of each underlying pathology using a single biofluid sample.
HIGHLIGHTS
α-Synuclein seed amplification assays (SAAs) provide a specific marker for Lewy body disease (LBD). SAAs allow for the in vivo identification of co-occurring LBD in patients with Alzheimer's disease (AD). AD-LBD coexist in 20-25% of cognitively impaired elderly individuals, and ∼8% of those asymptomatic. Compared to pure AD, AD-LBD causes a faster worsening of cognitive functions. AD-LBD is associated with worse attentive/executive, memory, visuospatial and motor functions.
PubMed: 38955137
DOI: 10.1002/alz.14039 -
Computer Methods and Programs in... Jun 2024Alzheimer's disease dementia (ADD) is well known to induce alterations in both structural and functional brain connectivity. However, reported changes in connectivity...
BACKGROUND AND OBJECTIVE
Alzheimer's disease dementia (ADD) is well known to induce alterations in both structural and functional brain connectivity. However, reported changes in connectivity are mostly limited to global/local network features, which have poor specificity for diagnostic purposes. Following recent advances in machine learning, deep neural networks, particularly Graph Neural Network (GNN) based approaches, have found applications in brain research as well. The majority of existing applications of GNNs employ a single network (uni-modal or structure/function unified), despite the widely accepted view that there is a nontrivial interdependence between the brain's structural connectivity and the neural activity patterns, which is hypothesized to be disrupted in ADD. This disruption is quantified as a discrepancy score by the proposed "structure-function discrepancy learning network" (sfDLN) and its distribution is studied over the spectrum of clinical cognitive decline. The measured discrepancy score is utilized as a diagnostic biomarker and is compared with state-of-the-art diagnostic classifiers.
METHODS
sfDLN is a GNN with a siamese architecture built on the hypothesis that the mismatch between structural and functional connectivity patterns increases over the cognitive decline spectrum, starting from subjective cognitive impairment (SCI), passing through a mid-stage mild cognitive impairment (MCI), and ending up with ADD. The structural brain connectome (sNET) built using diffusion MRI-based tractography and the novel, sparse (lean) functional brain connectome (ℓNET) built using fMRI are input to sfDLN. The siamese sfDLN is trained to extract connectome representations and a discrepancy (dissimilarity) score that complies with the proposed hypothesis and is blindly tested on an MCI group.
RESULTS
The sfDLN generated structure-function discrepancy scores show high disparity between ADD and SCI subjects. Leave-one-out experiments of SCI-ADD classification over a cohort of 42 subjects reach 88% accuracy, surpassing state-of-the-art GNN-based classifiers in the literature. Furthermore, a blind assessment over a cohort of 46 MCI subjects confirmed that it captures the intermediary character of the MCI group. GNNExplainer module employed to investigate the anatomical determinants of the observed discrepancy confirms that sfDLN attends to cortical regions neurologically relevant to ADD.
CONCLUSION
In support of our hypothesis, the harmony between the structural and functional organization of the brain degrades with increasing cognitive decline. This discrepancy, shown to be rooted in brain regions neurologically relevant to ADD, can be quantified by sfDLN and outperforms state-of-the-art GNN-based ADD classification methods when used as a biomarker.
PubMed: 38954916
DOI: 10.1016/j.cmpb.2024.108290 -
Scientific Reports Jul 2024Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization...
Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen's criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval.
PubMed: 38956440
DOI: 10.1038/s41598-024-65364-y -
Nature Communications Jul 2024
PubMed: 38956107
DOI: 10.1038/s41467-024-49938-y -
Nature Communications Jul 2024Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers...
Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with CN Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.
Topics: Humans; Amyloid beta-Peptides; White People; Male; Female; Alzheimer Disease; Longitudinal Studies; Aged; Peptide Fragments; Biomarkers; Black or African American; Middle Aged; Aged, 80 and over; Black People
PubMed: 38956096
DOI: 10.1038/s41467-024-49859-w -
Nature Communications Jul 2024Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking....
Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.
Topics: Humans; Iron; Brain; Exome Sequencing; Male; Female; Mendelian Randomization Analysis; Genome-Wide Association Study; Parkinson Disease; Middle Aged; Genetic Predisposition to Disease; Aged; Nerve Tissue Proteins; Adult; Alzheimer Disease
PubMed: 38956042
DOI: 10.1038/s41467-024-49702-2 -
The International Journal of Pharmacy... Jul 2024Previous studies have examined the psychological burden of caregivers of patients with dementia. However, although many caregivers struggle to assist patients with...
OBJECTIVES
Previous studies have examined the psychological burden of caregivers of patients with dementia. However, although many caregivers struggle to assist patients with dementia with medication management, the relationship between assisting such patients with taking their medicines and the caregiver psychological burden is understudied. Therefore, this study identified the association between caregivers' psychological burden and assisting patients with dementia with taking medication.
METHODS
A cross-sectional survey was conducted among caregivers of patients with dementia in Japan. The survey questionnaire included questions that assessed the symptoms of patients with dementia, their status of taking medication through medication assistance from caregivers, and caregivers' psychological burden using the Kessler Psychological Distress Scale and the Japanese version of the Perceived Stress Scale.
KEY FINDINGS
A total of 57 caregivers participated in the study. Higher Kessler Psychological Distress Scale scores were significantly associated with unsuccessful assistance with taking regular medication (β = 0.35, 95% confidence interval [CI]: 2.23-12.0, P < .05), depressive symptoms (β = 0.26, 95% CI: 0.10-8.53, P < .05), and irritability (β = 0.38, 95% CI: 2.71-11.5, P < .05). Likewise, higher scores on the Japanese version of the Perceived Stress Scale were significantly associated with irritability (β = 0.37, 95% CI: 1.87-12.5, P < .05) among patients with dementia.
CONCLUSION
The findings suggest that caregiver psychological burden is associated with unsuccessful assistance with taking regular medication for patients with dementia.
PubMed: 38954838
DOI: 10.1093/ijpp/riae029 -
Clinical and Experimental Nephrology Jul 2024The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to...
BACKGROUND
The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to explore the association between CKD-MBD and cognitive function in patients on hemodialysis.
METHODS
Hemodialysis patients aged ≥ 65 years without diagnosed dementia were included. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). CKD-MBD markers, serum magnesium, intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), fibroblast growth factor (FGF)-23, and soluble α-klotho were measured.
RESULTS
Overall, 390 patients with a median age of 74 (interquartile range, 70-80) years, mean serum magnesium level of 2.4 ± 0.3 mg/dL, and median MoCA and MMSE scores of 25 (22-26) and 28 (26-29), respectively, were analyzed. MoCA and MMSE scores were significantly higher (preserved cognitive function) in the high-magnesium group than in the low-magnesium group according to the unadjusted linear regression analysis (β coefficient [95% confidence interval (CI)] 1.05 [0.19, 1.92], P = 0.017 for MoCA; 1.2 [0.46, 1.94], P = 0.002 for MMSE) and adjusted multivariate analysis with risk factors for dementia (β coefficient [95% CI] 1.12 [0.22, 2.02], P = 0.015 for MoCA; 0.92 [0.19, 1.65], P = 0.014 for MMSE).
CONCLUSIONS
Higher serum magnesium levels might be associated with preserved cognitive function in hemodialysis patients. Conversely, significant associations were not observed between cognitive function and intact PTH, 25-OHD, FGF-23, or soluble α-klotho levels.
PubMed: 38954308
DOI: 10.1007/s10157-024-02528-0 -
AAPS PharmSciTech Jul 2024Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ) neurotoxicity in Balb/c...
Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aβ intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aβ. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aβ in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aβ aggregate acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aβ toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.
Topics: Animals; Amyloid beta-Peptides; Mice; Silybin; Mice, Inbred BALB C; Peptide Fragments; Neuroprotective Agents; Male; Brain; Particle Size; Nanoparticles; Reactive Oxygen Species; Disease Models, Animal; Alzheimer Disease; Acetylcholinesterase
PubMed: 38954224
DOI: 10.1208/s12249-024-02859-x