@article {pmid38655852,
year = {2024},
author = {Kelechi, TJ and Layne, D and Mueller, M and Madisetti, M and Balasubramanian, S},
title = {Feasibility and Preliminary Impact of a Web-Based Mind Body Intervention for Older Dementia Caregivers.},
journal = {Western journal of nursing research},
volume = {},
number = {},
pages = {1939459241247926},
doi = {10.1177/01939459241247926},
pmid = {38655852},
issn = {1552-8456},
abstract = {BACKGROUND: Mind-body interventions focused on intentional breathing and movement have been found to mitigate the negative effects of caregiving such as such as stress, psychosocial distress, and emotional distress associated for persons living with Alzheimer's disease and related dementias.

OBJECTIVE: The objective was to assess the feasibility and acceptability and preliminary impacts of our 12-week mind body intervention "Gentle Yoga and Yogic Breathing" for caregivers of persons living with dementia on health outcomes including mutuality, depression and anxiety, loneliness and social support, quality of life, and physical function.

METHODS: We conducted a single-group cohort study in which 20 caregivers were enrolled. Data were collected at baseline and at the 12-week post-intervention endpoint.

RESULTS: The intervention was acceptable; 75% (n = 15/20) completed the study; 16 completed post-study questionnaires. Very few experienced technical issues; 31% (n = 3) most commonly reported as poor internet connectivity, 75% (n = 12/16) perceived a health benefit, 88% (n = 14/16) perceived improved day-to-day mood, and 100% (n = 16/16) would recommend the intervention to other caregivers. Although there was minimal change from baseline to 12 weeks, for health outcomes, there were very small improvements noted in anxiety and overall health. There were no reported adverse events.

CONCLUSION: The intervention was well received and is feasible and acceptable for future studies of stress and health management interventions for caregivers of persons living with dementia.Registered with https://www.ClinicalTrials.gov (NCT03853148).},
}

@article {pmid38655803,
year = {2024},
author = {Temkin-Greener, H and Hua, Y and Cai, S},
title = {Assisted living residents with dementia: Disparities in mental health services pre and during COVID-19.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.18926},
pmid = {38655803},
issn = {1532-5415},
support = {RF1AG063811/AG/NIA NIH HHS/United States ; RF1AG073052/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Little is known about mental health among Medicare beneficiaries with Alzheimer's disease or related dementias (ADRD) who reside in assisted living (AL) communities. The COVID-19 pandemic may have curtailed ambulatory care access for these residents, but telehealth may have expanded it. We examined in-person and telehealth use of ambulatory mental health visits among AL residents with ADRD, pre and during the COVID pandemic, focusing on race/ethnicity and Medicare/Medicaid dual status.

METHODS: A CY2018 cohort of AL residents with ADRD was identified. Outcome was any quarterly in-person or telemedicine mental health visit based on national CY2019-2020 Medicare claims. Key independent variables were individual race/ethnicity and dual status and the AL-level proportion of dual residents. We estimated a linear probability model with random effects and robust standard errors. Quarterly indicators captured service use before and after the onset of the pandemic.

RESULTS: The study included 102,758 fee-for-service Medicare beneficiaries with ADRD in 13,400 ALs. One in five residents had any mental health visits prior to the COVID-19 pandemic. Black residents, and those with dual Medicare/Medicaid eligibility, were significantly less likely to use mental health services prior to and during the pandemic. There were no significant differences in visits via telemedicine by race/ethnicity or individual dual status. Residents in AL communities with a higher proportion of duals had a lower likelihood of visits before and during the pandemic.

CONCLUSIONS/IMPLICATIONS: Mental health service use among AL residents with ADRD was low and declining prior to the pandemic. Telehealth allowed for mental health visits to continue during the pandemic, albeit at a lower level. Residents in ALs with a higher proportion of duals were less likely to have in-person or telehealth visits. The results suggest that some ALs may find it difficult to assure mental health service provision to this vulnerable population.},
}

@article {pmid38655549,
year = {2024},
author = {Graves, LV and Tarraf, W and Gonzalez, K and Bondi, MW and Gallo, LC and Isasi, CR and Daviglus, M and Lamar, M and Zeng, D and Cai, J and González, HM},
title = {Characterizing cognitive profiles in diverse middle-aged and older Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging (HCHS/SOL).},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12592},
pmid = {38655549},
issn = {2352-8729},
abstract = {INTRODUCTION: We investigated cognitive profiles among diverse, middle-aged and older Hispanic/Latino adults in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) cohort using a cross-sectional observational study design.

METHODS: Based on weighted descriptive statistics, the average baseline age of the target population was 56.4 years, slightly more than half were women (54.6%), and 38.4% reported less than a high school education. We used latent profile analysis of demographically adjusted z scores on SOL-INCA neurocognitive tests spanning domains of verbal memory, language, processing speed, and executive function.

RESULTS: Statistical fit assessment indices combined with clinical interpretation suggested five profiles: (1) a Higher Global group performing in the average-to-high-average range across all cognitive and instrumental activity of daily living (IADL) tests (13.8%); (2) a Higher Memory group with relatively high performance on memory tests but average performance across all other cognitive/IADL tests (24.6%); (3) a Lower Memory group with relatively low performance on memory tests but average performance across all other cognitive/IADL tests (32.8%); (4) a Lower Executive Function group with relatively low performance on executive function and processing speed tests but average-to-low-average performance across all other cognitive/IADL tests (16.6%); and (5) a Lower Global group performing low-average-to-mildly impaired across all cognitive/IADL tests (12.1%).

DISCUSSION: Our results provide evidence of heterogeneity in the cognitive profiles of a representative, community-dwelling sample of diverse Hispanic/Latino adults. Our analyses yielded cognitive profiles that may assist efforts to better understand the early cognitive changes that may portend Alzheimer's disease and related dementias among diverse Hispanics/Latinos.

HIGHLIGHTS: The present study characterized cognitive profiles among diverse middle-aged and older Hispanic/Latino adults.Latent profile analysis of neurocognitive test scores was the primary analysis conducted.The target population consists of middle-aged and older Hispanic/Latino adults enrolled in the Hispanic Community Health Study/Study of Latinos and ancillary Study of Latinos - Investigation of Neurocognitive Aging.},
}

@article {pmid38655427,
year = {2024},
author = {Yazdanpanah, F and Jackson, AC and Sanaie, N and Sharifi, F and Shamshirgaran, SM and Bahramnezhad, F},
title = {The epidemiology and treatment outcomes of COVID-19 patients admitted to an intensive care unit in an Iranian hospital in Neyshabur city.},
journal = {Health science reports},
volume = {7},
number = {4},
pages = {e2049},
pmid = {38655427},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: The COVID-19 pandemic and the infection of numerous individuals from diverse societies have emerged as major global challenges. Given the limited resources in intensive care units, effective bed management and resource allocation require a deep understanding of the disease. This study aimed to assess the epidemiology and treatment outcomes of COVID-19 patients admitted to an intensive care unit in an Iranian hospital in Neyshabur city.

METHODS: This cross-sectional study was conducted on COVID-19 patients hospitalized in intensive care units in Razavi Khorasan, Iran in 2021. Census sampling was used to include all intensive care units. Of the initial 480 cases, 54 cases were excluded based on the exclusion criteria, leaving 426 cases for the study. Data were collected with the help of a data collection form that was designed by the researcher and its content validity and reliability were measured with Cronbach's alpha coefficient (α = 89%.). Data were analyzed with SPSS version 20 software. Descriptive and inferential statistics were used to analyze the data. Mean, standard deviation, and interquartile range indicators were used for descriptive statistics, and absolute frequency and relative frequency (percentage) were used to show numbers and ratios.

RESULTS: The mean (SD) age of the patients was 66.33 (15.05) years, and 49.3% were female. The results showed that arterial blood oxygen saturation, respiratory rate, and Alzheimer's disease were significant variables for predicting mortality. Furthermore, arterial blood oxygen saturation, respiratory rate, and the need for transfusion of blood products were significant variables in predicting hospitalization and the risk of acute respiratory distress syndrome (ARDS).

CONCLUSION: This study demonstrated that arterial blood oxygen saturation, respiratory rate, and Alzheimer's disease are crucial variables for predicting death. Furthermore, arterial blood oxygen saturation and respiratory rate are significant factors in predicting the risk of ARDS.},
}

@article {pmid38655218,
year = {2024},
author = {Wolf, A and Ravienna, K and Salobrar-Garcia, E},
title = {Editorial: Early indicators of cognitive decline, Alzheimer's disease, and related dementias captured by neurophysiological tools.},
journal = {Frontiers in psychology},
volume = {15},
number = {},
pages = {1393724},
pmid = {38655218},
issn = {1664-1078},
}

@article {pmid38655129,
year = {2024},
author = {Wang, H and Li, Q and Liu, Y},
title = {Multi-response Regression for Block-missing Multi-modal Data without Imputation.},
journal = {Statistica Sinica},
volume = {34},
number = {2},
pages = {527-546},
pmid = {38655129},
issn = {1017-0405},
abstract = {Multi-modal data are prevalent in many scientific fields. In this study, we consider the parameter estimation and variable selection for a multi-response regression using block-missing multi-modal data. Our method allows the dimensions of both the responses and the predictors to be large, and the responses to be incomplete and correlated, a common practical problem in high-dimensional settings. Our proposed method uses two steps to make a prediction from a multi-response linear regression model with block-missing multi-modal predictors. In the first step, without imputing missing data, we use all available data to estimate the covariance matrix of the predictors and the cross-covariance matrix between the predictors and the responses. In the second step, we use these matrices and a penalized method to simultaneously estimate the precision matrix of the response vector, given the predictors, and the sparse regression parameter matrix. Lastly, we demonstrate the effectiveness of the proposed method using theoretical studies, simulated examples, and an analysis of a multi-modal imaging data set from the Alzheimer's Disease Neuroimaging Initiative.},
}

@article {pmid38655109,
year = {2024},
author = {Inui, K and Takeuchi, N and Borgil, B and Shingaki, M and Sugiyama, S and Taniguchi, T and Nishihara, M and Watanabe, T and Suzuki, D and Motomura, E and Kida, T},
title = {Age and sex effects on paired-pulse suppression and prepulse inhibition of auditory evoked potentials.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1378619},
pmid = {38655109},
issn = {1662-4548},
abstract = {Responses to a sensory stimulus are inhibited by a preceding stimulus; if the two stimuli are identical, paired-pulse suppression (PPS) occurs; if the preceding stimulus is too weak to reliably elicit the target response, prepulse inhibition (PPI) occurs. PPS and PPI represent excitability changes in neural circuits induced by the first stimulus, but involve different mechanisms and are impaired in different diseases, e.g., impaired PPS in schizophrenia and Alzheimer's disease and impaired PPI in schizophrenia and movement disorders. Therefore, these measures provide information on several inhibitory mechanisms that may have roles in clinical conditions. In the present study, PPS and PPI of the auditory change-related cortical response were examined to establish normative data on healthy subjects (35 females and 32 males, aged 19-70 years). We also investigated the effects of age and sex on PPS and PPI to clarify whether these variables need to be considered as biases. The test response was elicited by an abrupt increase in sound pressure in a continuous sound and was recorded by electroencephalography. In the PPS experiment, the two change stimuli to elicit the cortical response were a 15-dB increase from the background of 65 dB separated by 600 ms. In the PPI experiment, the prepulse and test stimuli were 2- and 10-dB increases, respectively, with an interval of 50 ms. The results obtained showed that sex exerted similar effects on the two measures, with females having stronger test responses and weaker inhibition. On the other hand, age exerted different effects: aging correlated with stronger test responses and weaker inhibition in the PPS experiment, but had no effects in the PPI experiment. The present results suggest age and sex biases in addition to normative data on PPS and PPI of auditory change-related potentials. PPS and PPI, as well as other similar paradigms, such as P50 gating, may have different and common mechanisms. Collectively, they may provide insights into the pathophysiologies of diseases with impaired inhibitory function.},
}

@article {pmid38655107,
year = {2024},
author = {Mohanty, R and Ferreira, D and Westman, E},
title = {Multi-pathological contributions toward atrophy patterns in the Alzheimer's disease continuum.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1355695},
pmid = {38655107},
issn = {1662-4548},
abstract = {INTRODUCTION: Heterogeneity in downstream atrophy in Alzheimer's disease (AD) is predominantly investigated in relation to pathological hallmarks (Aβ, tau) and co-pathologies (cerebrovascular burden) independently. However, the proportional contribution of each pathology in determining atrophy pattern remains unclear. We assessed heterogeneity in atrophy using two recently conceptualized dimensions: typicality (typical AD atrophy at the center and deviant atypical atrophy on either extreme including limbic predominant to hippocampal sparing patterns) and severity (overall neurodegeneration spanning minimal atrophy to diffuse typical AD atrophy) in relation to Aβ, tau, and cerebrovascular burden.

METHODS: We included 149 Aβ + individuals on the AD continuum (cognitively normal, prodromal AD, AD dementia) and 163 Aβ- cognitively normal individuals from the ADNI. We modeled heterogeneity in MRI-based atrophy with continuous-scales of typicality (ratio of hippocampus to cortical volume) and severity (total gray matter volume). Partial correlation models investigated the association of typicality/severity with (a) Aβ (global Aβ PET centiloid), tau (global tau PET SUVR), cerebrovascular (total white matter hypointensity volume) burden (b) four cognitive domains (memory, executive function, language, visuospatial composites). Using multiple regression, we assessed the association of each pathological burden and typicality/severity with cognition.

RESULTS: (a) In the AD continuum, typicality (r = -0.31, p < 0.001) and severity (r = -0.37, p < 0.001) were associated with tau burden after controlling for Aβ, cerebrovascular burden and age. Findings imply greater tau pathology in limbic predominant atrophy and diffuse atrophy. (b) Typicality was associated with memory (r = 0.49, p < 0.001) and language scores (r = 0.19, p = 0.02). Severity was associated with memory (r = 0.26, p < 0.001), executive function (r = 0.24, p = 0.003) and language scores (r = 0.29, p < 0.001). Findings imply better cognitive performance in hippocampal sparing and minimal atrophy patterns. Beyond typicality/severity, tau burden but not Aβ and cerebrovascular burden explained cognition.

CONCLUSION: In the AD continuum, atrophy-based severity was more strongly associated with tau burden than typicality after accounting for Aβ and cerebrovascular burden. Cognitive performance in memory, executive function and language domains was explained by typicality and/or severity and additionally tau pathology. Typicality and severity may differentially reflect burden arising from tau pathology but not Aβ or cerebrovascular pathologies which need to be accounted for when investigating AD heterogeneity.},
}

@article {pmid38654932,
year = {2024},
author = {Ingannato, A and Bagnoli, S and Mazzeo, S and Giacomucci, G and Bessi, V and Ferrari, C and Sorbi, S and Nacmias, B},
title = {Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia.},
journal = {Frontiers in endocrinology},
volume = {15},
number = {},
pages = {1375302},
pmid = {38654932},
issn = {1664-2392},
mesh = {Humans ; *Glial Fibrillary Acidic Protein/blood ; Female ; Male ; *Neurofilament Proteins/blood ; *tau Proteins/blood ; Aged ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; *Alzheimer Disease/blood/diagnosis ; Middle Aged ; Phosphorylation ; Dementia/blood/diagnosis ; Apolipoproteins E/blood/genetics ; Aged, 80 and over ; Follow-Up Studies ; },
abstract = {BACKGROUND: Plasma biomarkers are preferable to invasive and expensive diagnostic tools, such as neuroimaging and lumbar puncture that are gold standard in the clinical management of Alzheimer's Disease (AD). Here, we investigated plasma Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NfL) and Phosphorylated-tau-181 (pTau 181) in AD and in its early stages: Subjective cognitive decline (SCD) and Mild cognitive impairment (MCI).

MATERIAL AND METHODS: This study included 152 patients (42 SCD, 74 MCI and 36 AD). All patients underwent comprehensive clinical and neurological assessment. Blood samples were collected for Apolipoprotein E (APOE) genotyping and plasma biomarker (GFAP, NfL, and pTau 181) measurements. Forty-three patients (7 SCD, 27 MCI, and 9 AD) underwent a follow-up (FU) visit after 2 years, and a second plasma sample was collected. Plasma biomarker levels were detected using the Simoa SR-X technology (Quanterix Corp.). Statistical analysis was performed using SPSS software version 28 (IBM SPSS Statistics). Statistical significance was set at p < 0.05.

RESULTS: GFAP, NfL and pTau 181 levels in plasma were lower in SCD and MCI than in AD patients. In particular, plasma GFAP levels were statistically significant different between SCD and AD (p=0.003), and between MCI and AD (p=0.032). Plasma NfL was different in SCD vs MCI (p=0.026), SCD vs AD (p<0.001), SCD vs AD FU (p<0.001), SCD FU vs AD (p=0.033), SCD FU vs AD FU (p=0.011), MCI vs AD (p=0.002), MCI FU vs AD (p=0.003), MCI FU vs AD FU (p=0.003) and MCI vs AD FU (p=0.003). Plasma pTau 181 concentration was significantly different between SCD and AD (p=0.001), MCI and AD (p=0.026), MCI FU and AD (p=0.020). In APOE ϵ4 carriers, a statistically significant increase in plasma NfL (p<0.001) and pTau 181 levels was found (p=0.014). Moreover, an association emerged between age at disease onset and plasma GFAP (p = 0.021) and pTau181 (p < 0.001) levels.

DISCUSSION AND CONCLUSIONS: Plasma GFAP, NfL and pTau 181 are promising biomarkers in the diagnosis of the prodromic stages and prognosis of dementia.},
}

Humans
*Glial Fibrillary Acidic Protein/blood
Female
Male
*Neurofilament Proteins/blood
*tau Proteins/blood
Aged
*Biomarkers/blood
*Cognitive Dysfunction/blood/diagnosis
*Alzheimer Disease/blood/diagnosis
Middle Aged
Phosphorylation
Dementia/blood/diagnosis
Apolipoproteins E/blood/genetics
Aged, 80 and over
Follow-Up Studies

@article {pmid38654824,
year = {2024},
author = {Joshi, R and Brezani, V and Mey, GM and Guixé-Muntet, S and Ortega-Ribera, M and Zhuang, Y and Zivny, A and Werneburg, S and Gracia-Sancho, J and Szabo, G},
title = {IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.03.08.582968},
pmid = {38654824},
abstract = {The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D:IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer's Disease, notably apolipoprotein-e . Lastly, using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 as a target of IRF3 that is relevant across various neuroinflammatory disorders. Together, our results identify IRF3 as an important regulator of LPS-mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.},
}

@article {pmid38654595,
year = {2024},
author = {Srivastava, A and Kumar, G and Kumar, P and Srikrishna, S and Chandra, P and Singh, VP},
title = {Thiazole-Based Silver Ion Sensor for Sequential Colorimetric Visualization of Epinephrine in the Brain Tissues of an Alzheimer's Disease Model of Mouse.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.4c00229},
pmid = {38654595},
issn = {2576-6422},
abstract = {A thiazole-based probe, N'-((2-aminothiazol-5-yl)methylene)benzohydrazide (TBH), has been efficiently synthesized and characterized for the selective and sensitive detection of the neurotransmitter epinephrine (EP). The sensing strategy is based on the use of TBH for sequential colorimetric sensing of Ag[+] and EP via in situ formation of Ag nanoparticles (Ag NPs) from the TBH-Ag[+] complex. The generated Ag NPs lead to a bathochromic shift in absorption maximum and a change in color of the solution from light brown to reddish brown. TBH-Ag[+] shows remarkable selectivity toward EP versus other drugs, common cations, anions, and some biomolecules. Moreover, TBH-Ag[+] has a low detection limit for EP at 1.2 nM. The coordination of TBH-Ag[+] has been proposed based on Job's plot, Fourier transform infrared spectroscopy (FT-IR), high-resolution mass spectrometry (HRMS), [1]H NMR titration, X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray analysis (EDAX), and density functional theory (DFT) studies. The composition and morphology of the generated Ag NPs have been analyzed by XPS, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The proposed sensing mechanism for EP has been supported by XPS of Ag after the reaction. Further, the sensitivity of TBH-Ag[+] toward EP in brain tissues of an Alzheimer's disease model of mouse has been evaluated. A thorough comparison was done for evaluation of the proposed method.},
}

@article {pmid38654513,
year = {2024},
author = {Baumeister, H and Vogel, JW and Insel, PS and Kleineidam, L and Wolfsgruber, S and Stark, M and Gellersen, HM and Yakupov, R and Schmid, MC and Lüsebrink, F and Brosseron, F and Ziegler, G and Freiesleben, SD and Preis, L and Schneider, LS and Spruth, EJ and Altenstein, S and Lohse, A and Fliessbach, K and Vogt, IR and Bartels, C and Schott, BH and Rostamzadeh, A and Glanz, W and Incesoy, EI and Butryn, M and Janowitz, D and Rauchmann, BS and Kilimann, I and Goerss, D and Munk, MH and Hetzer, S and Dechent, P and Ewers, M and Scheffler, K and Wuestefeld, A and Strandberg, O and van Westen, D and Mattsson-Carlgren, N and Janelidze, S and Stomrud, E and Palmqvist, S and Spottke, A and Laske, C and Teipel, S and Perneczky, R and Buerger, K and Schneider, A and Priller, J and Peters, O and Ramirez, A and Wiltfang, J and Heneka, MT and Wagner, M and Düzel, E and Jessen, F and Hansson, O and Berron, D},
title = {A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awae118},
pmid = {38654513},
issn = {1460-2156},
abstract = {Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.},
}

@article {pmid38654507,
year = {2024},
author = {Peng, Y and Chen, Q and Xue, YH and Jin, H and Liu, S and Du, MQ and Yao, SY},
title = {Ginkgo biloba and Its Chemical Components in the Management of Alzheimer's Disease.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-42},
doi = {10.1142/S0192415X24500277},
pmid = {38654507},
issn = {1793-6853},
abstract = {The pathogenesis of Alzheimer's disease (AD), a degenerative disease of the central nervous system, remains unclear. The main manifestations of AD include cognitive and behavioral disorders, neuropsychiatric symptoms, neuroinflammation, amyloid plaques, and neurofibrillary tangles. However, current drugs for AD once the dementia stage has been reached only treat symptoms and do not delay progression, and the research and development of targeted drugs for AD have reached a bottleneck. Thus, other treatment options are needed. Bioactive ingredients derived from plants are promising therapeutic agents. Specifically, Ginkgo biloba (Gb) extracts exert anti-oxidant, anticancer, neuroplastic, neurotransmitter-modulating, blood fluidity, and anti-inflammatory effects, offering alternative options in the treatment of cardiovascular, metabolic, and neurodegenerative diseases. The main chemical components of Gb include flavonoids, terpene lactones, proanthocyanidins, organic acids, polysaccharides, and amino acids. Gb and its extracts have shown remarkable therapeutic effects on various neurodegenerative diseases, including AD, with few adverse reactions. Thus, high-quality Gb extracts are a well-established treatment option for AD. In this review, we summarize the insights derived from traditional Chinese medicine, experimental models, and emerging clinical trials on the role of Gb and its chemical components in the treatment of the main clinical manifestations of AD.},
}

@article {pmid38654447,
year = {2024},
author = {Morais-Ribeiro, R and Almeida, FC and Coelho, A and Oliveira, TG},
title = {Differential atrophy along the longitudinal hippocampal axis in Alzheimer's disease for the Alzheimer's Disease Neuroimaging Initiative.},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.16361},
pmid = {38654447},
issn = {1460-9568},
support = {U01 AG024904/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the hippocampus. Since hippocampal studies have highlighted a differential subregional regulation along its longitudinal axis, a more detailed analysis addressing subregional changes along the longitudinal hippocampal axis has the potential to provide new relevant biomarkers. This study included structural brain MRI data of 583 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitively normal (CN) subjects, mild cognitively impaired (MCI) subjects and AD patients were conveniently selected considering the age and sex match between clinical groups. Structural MRI acquisitions were pre-processed and analysed with a new longitudinal axis segmentation method, dividing the hippocampus in three subdivisions (anterior, intermediate, and posterior). When normalizing the volume of hippocampal sub-divisions to total hippocampus, the posterior hippocampus negatively correlates with age only in CN subjects (r = -.31). The longitudinal ratio of hippocampal atrophy (anterior sub-division divided by the posterior one) shows a significant increase with age only in CN (r = .25). Overall, in AD, the posterior hippocampus is predominantly atrophied early on. Consequently, the anterior/posterior hippocampal ratio is an AD differentiating metric at early disease stages with potential for diagnostic and prognostic applications.},
}

@article {pmid38654375,
year = {2024},
author = {Vandermeulen, L and Geric, I and Fumagalli, L and Kreir, M and Lu, A and Nonneman, A and Premereur, J and Wolfs, L and Policarpo, R and Fattorelli, N and De Bondt, A and Van Den Wyngaert, I and Asselbergh, B and Fiers, M and De Strooper, B and d'Ydewalle, C and Mancuso, R},
title = {Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {19},
number = {1},
pages = {37},
pmid = {38654375},
issn = {1750-1326},
support = {HBC.2018.2290//Agentschap Innoveren en Ondernemen/ ; },
mesh = {*Microglia/metabolism ; *Alzheimer Disease/metabolism/genetics ; Humans ; *Oligonucleotides, Antisense/pharmacology ; Animals ; Mice ; Membrane Glycoproteins/metabolism/genetics ; Apolipoproteins E/genetics/metabolism ; Receptors, Immunologic/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Gene Expression Regulation/drug effects ; Disease Models, Animal ; },
abstract = {BACKGROUND: Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer's disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs).

METHODS: In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo.

RESULTS: We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-β plaques in vivo in a model of AD.

CONCLUSIONS: This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo.},
}

*Microglia/metabolism
*Alzheimer Disease/metabolism/genetics
Humans
*Oligonucleotides, Antisense/pharmacology
Animals
Mice
Membrane Glycoproteins/metabolism/genetics
Apolipoproteins E/genetics/metabolism
Receptors, Immunologic/metabolism/genetics
Induced Pluripotent Stem Cells/metabolism
Gene Expression Regulation/drug effects
Disease Models, Animal

@article {pmid38654366,
year = {2024},
author = {Chen, TY and Zhu, JD and Tsai, SJ and Yang, AC},
title = {Exploring morphological similarity and randomness in Alzheimer's disease using adjacent grey matter voxel-based structural analysis.},
journal = {Alzheimer's research & therapy},
volume = {16},
number = {1},
pages = {88},
pmid = {38654366},
issn = {1758-9193},
support = {MOHW112-CDC-C-114-000111//Taiwan Centers for Disease Control/ ; Mt. Jade Young Scholarship Award//Ministry of Education/ ; 112W32101//Brain Research Center, National Yang Ming Chiao Tung University/ ; 112-2823-8-A49-001, 111-2634-F-A49-014, 112-2321-B-A49-013, 112-2321-B-A49-021, and 112-2634-F-A49-003//National Science and Technology Council/ ; V112C-054, V113C-144, and V113E-008-3//Taipei Veterans General Hospital/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; Male ; Female ; *Magnetic Resonance Imaging/methods ; Aged ; *Gray Matter/diagnostic imaging/pathology ; Brain/diagnostic imaging/pathology ; Aged, 80 and over ; Image Processing, Computer-Assisted ; Neuroimaging/methods ; },
abstract = {BACKGROUND: Alzheimer's disease is characterized by large-scale structural changes in a specific pattern. Recent studies developed morphological similarity networks constructed by brain regions similar in structural features to represent brain structural organization. However, few studies have used local morphological properties to explore inter-regional structural similarity in Alzheimer's disease.

METHODS: Here, we sourced T1-weighted MRI images of 342 cognitively normal participants and 276 individuals with Alzheimer's disease from the Alzheimer's Disease Neuroimaging Initiative database. The relationships of grey matter intensity between adjacent voxels were defined and converted to the structural pattern indices. We conducted the information-based similarity method to evaluate the structural similarity of structural pattern organization between brain regions. Besides, we examined the structural randomness on brain regions. Finally, the relationship between the structural randomness and cognitive performance of individuals with Alzheimer's disease was assessed by stepwise regression.

RESULTS: Compared to cognitively normal participants, individuals with Alzheimer's disease showed significant structural pattern changes in the bilateral posterior cingulate gyrus, hippocampus, and olfactory cortex. Additionally, individuals with Alzheimer's disease showed that the bilateral insula had decreased inter-regional structural similarity with frontal regions, while the bilateral hippocampus had increased inter-regional structural similarity with temporal and subcortical regions. For the structural randomness, we found significant decreases in the temporal and subcortical areas and significant increases in the occipital and frontal regions. The regression analysis showed that the structural randomness of five brain regions was correlated with the Mini-Mental State Examination scores of individuals with Alzheimer's disease.

CONCLUSIONS: Our study suggested that individuals with Alzheimer's disease alter micro-structural patterns and morphological similarity with the insula and hippocampus. Structural randomness of individuals with Alzheimer's disease changed in temporal, frontal, and occipital brain regions. Morphological similarity and randomness provide valuable insight into brain structural organization in Alzheimer's disease.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
Male
Female
*Magnetic Resonance Imaging/methods
Aged
*Gray Matter/diagnostic imaging/pathology
Brain/diagnostic imaging/pathology
Aged, 80 and over
Image Processing, Computer-Assisted
Neuroimaging/methods

@article {pmid38654300,
year = {2024},
author = {Kang, S and Jeon, S and Lee, YG and Ye, BS},
title = {Alteration of medial temporal lobe metabolism related to Alzheimer's disease and dementia with lewy bodies.},
journal = {Alzheimer's research & therapy},
volume = {16},
number = {1},
pages = {89},
pmid = {38654300},
issn = {1758-9193},
support = {HI14C1324//Korea Health Industry Development Institute/Republic of Korea ; 2022R1C1C2011227//Ministry of Science and ICT, South Korea/ ; },
mesh = {Humans ; *Lewy Body Disease/metabolism/diagnostic imaging ; *Alzheimer Disease/metabolism/diagnostic imaging ; Female ; Male ; Aged ; *Positron-Emission Tomography ; *Temporal Lobe/metabolism/diagnostic imaging ; *Fluorodeoxyglucose F18 ; *Neuropsychological Tests ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Association of medial temporal lobe (MTL) metabolism with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) has not been evaluated considering their mixed disease (MD).

METHODS: 131 patients with AD, 133 with DLB, 122 with MD, and 28 normal controls (NCs) underwent neuropsychological tests, assessments for parkinsonism, cognitive fluctuation (CF), and visual hallucinations (VH), and [18]F-fluorodeoxyglucose PET to quantify MTL metabolism in the amygdala, hippocampus, and entorhinal cortex. The effects of AD and DLB on MTL metabolism were evaluated using general linear models (GLMs). Associations between MTL metabolism, cognition, and clinical features were evaluated using GLMs or logistic regression models separately performed for the AD spectrum (NC + AD + MD), DLB spectrum (NC + DLB + MD), and disease groups (AD + DLB + MD). Covariates included age, sex, and education.

RESULTS: AD was associated with hippocampal/entorhinal hypometabolism, whereas DLB was associated with relative amygdalar/hippocampal hypermetabolism. Relative MTL hypermetabolism was associated with lower attention/visuospatial/executive scores and severe parkinsonism in both the AD and DLB spectra and disease groups. Left hippocampal/entorhinal hypometabolism was associated with lower verbal memory scores, whereas right hippocampal hypometabolism was associated with lower visual memory scores in both the AD spectrum and disease groups. Relative MTL hypermetabolism was associated with an increased risk of CF and VH in the disease group, and relative amygdalar hypermetabolism was associated with an increased risk of VH in the DLB spectrum.

CONCLUSIONS: Entorhinal-hippocampal hypometabolism and relative amygdala-hippocampal hypermetabolism could be characteristics of AD- and DLB-related neurodegeneration, respectively.},
}

Humans
*Lewy Body Disease/metabolism/diagnostic imaging
*Alzheimer Disease/metabolism/diagnostic imaging
Female
Male
Aged
*Positron-Emission Tomography
*Temporal Lobe/metabolism/diagnostic imaging
*Fluorodeoxyglucose F18
*Neuropsychological Tests
Aged, 80 and over
Middle Aged

@article {pmid38653878,
year = {2024},
author = {He, Y and Wang, Y and Li, X and Qi, Y and Qu, Z and Hu, Y},
title = {Lycium Barbarum Polysaccharides Improves Cognitive Functions in ICV-STZ-Induced Alzheimer's Disease Mice Model by Improving the Synaptic Structural Plasticity and Regulating IRS1/PI3K/AKT Signaling Pathway.},
journal = {Neuromolecular medicine},
volume = {26},
number = {1},
pages = {15},
pmid = {38653878},
issn = {1559-1174},
support = {No. 82260712//the National Natural Science Foundation of China/ ; No. 82260712//the National Natural Science Foundation of China/ ; No. 82260712//the National Natural Science Foundation of China/ ; No. 82260712//the National Natural Science Foundation of China/ ; No. 82260712//the National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Insulin Receptor Substrate Proteins/metabolism ; Male ; *Alzheimer Disease/chemically induced/drug therapy ; Mice ; *Signal Transduction/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Mice, Inbred C57BL ; *Phosphatidylinositol 3-Kinases/metabolism ; *Disease Models, Animal ; *Neuronal Plasticity/drug effects ; *tau Proteins/metabolism ; Streptozocin ; Neuroprotective Agents/therapeutic use/pharmacology ; Cognition/drug effects ; Amyloid beta-Peptides/metabolism ; Phosphorylation/drug effects ; Synapses/drug effects ; Insulin Resistance ; Brain/drug effects/metabolism/pathology ; },
abstract = {Lycium barbarum polysaccharide (LBP) have a certain curative effect on hypoglycemic and neuroprotective effects, but the specific mechanism is unclear and needs to be further explored. This study aimed to clarify the mechanisms of LBP in the treatment of ICV-STZ mice model of AD from the perspectives of insulin resistance, IRS1/PI3K/AKT signaling pathway, and synaptic protein expression. We used male C57BL/6J mice injected with STZ (3 mg/kg) in the lateral ventricle as an AD model. After treatment with LBP, the learning and memory abilities of ICV-STZ mice were enhanced, and the pathological changes in brain tissue were alleviated. LBP can regulate the expression of proteins related to the IRS1/PI3K/AKT signaling pathway and thereby reducing Aβ deposition and tau protein phosphorylation in the brain of ICV-STZ mice. In addition, LBP also can up-regulate the expression of synaptic proteins. The results indicated that LBP played a neuroprotective role by regulating the IRS1/PI3K/AKT pathway, inhibiting tau protein hyperphosphorylation and improving the expression levels of synapse-related proteins.},
}

Animals
*Insulin Receptor Substrate Proteins/metabolism
Male
*Alzheimer Disease/chemically induced/drug therapy
Mice
*Signal Transduction/drug effects
*Proto-Oncogene Proteins c-akt/metabolism
*Drugs, Chinese Herbal/therapeutic use/pharmacology
*Mice, Inbred C57BL
*Phosphatidylinositol 3-Kinases/metabolism
*Disease Models, Animal
*Neuronal Plasticity/drug effects
*tau Proteins/metabolism
Streptozocin
Neuroprotective Agents/therapeutic use/pharmacology
Cognition/drug effects
Amyloid beta-Peptides/metabolism
Phosphorylation/drug effects
Synapses/drug effects
Insulin Resistance
Brain/drug effects/metabolism/pathology

@article {pmid38653428,
year = {2024},
author = {Zaafar, D and Elghazawy, NH and Hassan, A and Mahmoud, MY and Bakr, AF and Arafa, RK},
title = {Unleashing new MTDL AChE and BuChE inhibitors as potential anti-AD therapeutic agents: In vitro, in vivo and in silico studies.},
journal = {International journal of biological macromolecules},
volume = {268},
number = {Pt 1},
pages = {131740},
doi = {10.1016/j.ijbiomac.2024.131740},
pmid = {38653428},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is challenging due to its irreversible declining cognitive symptoms and multifactorial nature. This work tackles targeting both acetylcholinesterase (AChE) and BuChE with a multitarget-directed ligand (MTDL) through design, synthesis, and biological and in silico evaluation of a series of twenty eight new 5-substituted-2-anilino-1,3,4-oxadiazole derivatives 4a-g, 5a-g, 9a-g and 13a-g dual inhibitors of the target biomolecules. In vitro cholinesterases inhibition and selectivity assay of the synthesized derivatives showed excellent nanomolar level inhibitory activities. Compound 5a, the most potent inhibitor, elicited IC50s of 46.9 and 3.5 nM against AChE and BuChE, respectively (SI = 0.07), 5 folds better than the known dual inhibitor Rivastagmine. In vivo and ex vivo investigation showed that 5a significantly inhibited MDA levels and increased GSH contents, thus, attenuating the brain tissue oxidative stress. Additionally, 5a significantly decreased AChE and BuChE levels and inhibited self-mediated β-amyloid aggregation in brains of treated rats. Histopathological and immunohistochemical evaluation demonstrated lessened damage and decreased caspase-3 and VEGF expression levels. In silico prediction of 5a's pharmacokinetics and toxicity profiles reflected promising results. Finally, 5a demonstrated tight binding interactions with the two target biomolecules upon docking along with stable complex formation with its bio-targets throughout the 100 ns MD trajectories.},
}

@article {pmid38653355,
year = {2024},
author = {Mey, M and Bhatta, S and Suresh, S and Labrador, LM and Piontkivska, H and Casadesus, G},
title = {Therapeutic benefits of central LH receptor agonism in the APP/PS1 AD model involve trophic and immune regulation and reproductive status dependent.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167165},
doi = {10.1016/j.bbadis.2024.167165},
pmid = {38653355},
issn = {1879-260X},
abstract = {The mechanisms that underly reproductive hormone effects on cognition, neuronal plasticity, and AD risk, particularly in relation to gonadotropin LH receptor (LHCGR) signaling, remain poorly understood. To address this knowledge gap and clarify the impact of circulating steroid hormones the therapeutic effects of CNS LHCGR activation, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV) and evaluated functional, structural, plasticity-related signaling cascades, Aβ pathology, and transcriptome differences in reproductively intact and ovariectomized (OVX) APP/PS1 AD female mice. Here we demonstrate that CNS hCG delivery restored function to wild-type levels only in OVX APP/PS1 mice. Spine density was increases in all hCG treated groups independently of reproductive status. Notably, increases in BDNF signaling, like cognition, were selectively upregulated only in the OVX hCG-treated group. RNA sequencing analyses identified a significant increase in peripheral myeloid and pro-inflammatory genes within the hippocampi of the OVX group that were completely reversed by hCG, identifying a potential mechanism underlying the selective therapeutic effect of LHCGR activation. Interestingly, in intact mice, hCG administration mimicked the effects of gonadectomy. Together, our findings indicate that CNS LHCGR agonism in the post-menopausal context is beneficial through trophic and immune mechanisms. Our findings also underscore the presence of a steroid-LHCGR mechanistic interaction that is unexplored yet potentially meaningful to fully understand "post-menopausal" brain function and CNS hormone treatment response.},
}

@article {pmid38653354,
year = {2024},
author = {Jácome, D and Cotrufo, T and Andrés-Benito, P and Lidón, L and Martí, E and Ferrer, I and Del Río, JA and Gavín, R},
title = {miR-519a-3p, found to regulate cellular prion protein during Alzheimer's disease pathogenesis, as a biomarker of asymptomatic stages.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167187},
doi = {10.1016/j.bbadis.2024.167187},
pmid = {38653354},
issn = {1879-260X},
abstract = {Clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. In this, diagnosis at asymptomatic stages of Alzheimer's disease (AD) remains a challenge since it can only be made at autopsy according to Braak NFT staging. Achieving the objective of detecting AD at early stages would allow possible therapies to be addressed before the onset of cognitive impairment. Many studies have determined that the expression pattern of some miRNAs is dysregulated in AD patients, but to date, none has been correlated with downregulated expression of cellular prion protein (PrP[C]) during disease progression. That is why, by means of cross studies of miRNAs up-regulated in AD with in silico identification of potential miRNAs-binding to 3'UTR of human PRNP gene, we selected miR-519a-3p for our study. Then, in vitro experiments were carried out in two ways. First, we validated miR-519a-3p target on 3'UTR-PRNP, and second, we analyzed the levels of PrP[C] expression after using of mimic technology on cell culture. In addition, RT-qPCR was performed to analyzed miR-519a-3p expression in human cerebral samples of AD at different stages of disease evolution. Additionally, samples of other neurodegenerative diseases such as other non-AD tauopathies and several synucleinopathies were included in the study. Our results showed that miR-519a-3p overlaps with PRNP 3'UTR in vitro and promotes downregulation of PrP[C]. Moreover, miR-519a-3p was found to be up-regulated exclusively in AD samples from stage I to VI, suggesting its potential use as a novel label of preclinical stages of the disease.},
}

@article {pmid38653353,
year = {2024},
author = {Huang, T and Gong, XK and Liang, Z and Yang, R and Wu, L and Yang, C and Wu, M and Wang, XC and Shu, XJ and Bao, J},
title = {Exercised-enriched blood plasma rescues hippocampal impairments and cognitive deficits in an Alzheimer's disease model.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167197},
doi = {10.1016/j.bbadis.2024.167197},
pmid = {38653353},
issn = {1879-260X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and moderate exercise holds promise in ameliorating the ongoing neurodegeneration and cognitive decline. Here, we investigated whether exercise-enriched blood plasm could yield a beneficial therapeutic effect on AD pathologies and cognitive decline in transgenic AD (P301S) mice. In this investigation, a cohort of 2-month-old C57BL/6 mice were granted continuous access to either a running wheel or a fixed wheel for 6 weeks. After that, their plasmas were extracted and subsequently injected intravenously into 4.5-month-old P301S mice biweekly over a 6-week period. A comprehensive methodology was then employed, integrating behavioral tests, pathology assessments, and biochemical analyses to unveil the potential anti-dementia implications of exercise-enriched blood plasma in P301S mice. Upon systemic administration, the findings revealed a noteworthy attenuation of hippocampus-dependent behavioral impairments in P301S mice. Conversely, blood plasma from sedentary counterparts exhibited no discernible impact. These effects were intricately associated with the mitigation of neuroinflammation, the augmentation of hippocampal adult neurogenesis, and a reduction of synaptic impairments following the administration of exercise-enriched blood plasma. These findings advance the proposition that administering exercise-enriched blood plasma may serve as an effective prophylactic measure against AD, opening avenues for further exploration and potential therapeutic interventions.},
}

@article {pmid38653305,
year = {2024},
author = {Saad, A and Turgut, F and Sommer, C and Becker, M and DeBuc, D and Barboni, M and Somfai, GM},
title = {The Use of the RETeval Portable Electroretinography Device for Low-Cost Screening: A Mini-Review.},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {241},
number = {4},
pages = {533-537},
doi = {10.1055/a-2237-3814},
pmid = {38653305},
issn = {1439-3999},
mesh = {Humans ; *Electroretinography/instrumentation/economics ; *Equipment Design ; *Retinal Diseases/diagnosis ; Equipment Failure Analysis ; Miniaturization ; Reproducibility of Results ; Sensitivity and Specificity ; Mass Screening/instrumentation/economics ; Vision Screening/instrumentation/economics ; Health Care Costs ; },
abstract = {Electroretinography (ERG) provides crucial insights into retinal function and the integrity of the visual pathways. However, ERG assessments classically require a complicated technical background with costly equipment. In addition, the placement of corneal or conjunctival electrodes is not always tolerated by the patients, which restricts the measurement for pediatric evaluations. In this short review, we give an overview of the use of the RETeval portable ERG device (LKC Technologies, Inc., Gaithersburg, MD, USA), a modern portable ERG device that can facilitate screening for diseases involving the retina and the optic nerve. We also review its potential to provide ocular biomarkers in systemic pathologies, such as Alzheimer's disease and central nervous system alterations, within the framework of oculomics.},
}

Humans
*Electroretinography/instrumentation/economics
*Equipment Design
*Retinal Diseases/diagnosis
Equipment Failure Analysis
Miniaturization
Reproducibility of Results
Sensitivity and Specificity
Mass Screening/instrumentation/economics
Vision Screening/instrumentation/economics
Health Care Costs

@article {pmid38653174,
year = {2024},
author = {Ikeda, K and Sugiura, Y and Nakao, H and Nakano, M},
title = {Thermodynamics of oligomerization and Helix-to-sheet structural transition of amyloid β-protein on anionic phospholipid vesicles.},
journal = {Biophysical chemistry},
volume = {310},
number = {},
pages = {107248},
doi = {10.1016/j.bpc.2024.107248},
pmid = {38653174},
issn = {1873-4200},
abstract = {Understanding oligomerization and aggregation of the amyloid-β protein is important to elucidate the pathological mechanisms of Alzheimer's disease, and lipid membranes play critical roles in this process. In addition to studies reported by other groups, our group has also reported that the negatively-charged lipid bilayers with a high positive curvature induced α-helix-to-β-sheet conformational transitions of amyloid-β-(1-40) upon increase in protein density on the membrane surface and promoted amyloid fibril formation of the protein. Herein, we investigated detailed mechanisms of the conformational transition and oligomer formation of the amyloid-β protein on the membrane surface. Changes in the fractions of the three protein conformers (free monomer, membrane-bound α-helix-rich conformation, and β-sheet-rich conformation) were determined from the fluorescent spectral changes of the tryptophan probe in the protein. The helix-to-sheet structural transition on the surface was described by a thermodynamic model of octamer formation driven by entropic forces including hydrophobic interactions. These findings provide useful information for understanding the self-assembly of amyloidogenic proteins on lipid membrane surfaces.},
}

@article {pmid38653150,
year = {2024},
author = {Sun, L and Wang, XM and Tang, Q and Xiao, Y and Xu, JB and Zhang, TT and Liu, YJ and Li, X and Gao, F},
title = {Lathyrane and premyrsinane Euphorbia diterpenes against Alzheimer's disease: Bioinspired synthesis, anti-cholinesterase and neuroprotection bioactivity.},
journal = {Bioorganic chemistry},
volume = {147},
number = {},
pages = {107377},
doi = {10.1016/j.bioorg.2024.107377},
pmid = {38653150},
issn = {1090-2120},
abstract = {The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 μM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 μM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.},
}

@article {pmid38653149,
year = {2024},
author = {Das, B and Tk Baidya, A and Chakrabarti, S and Chouhan, D and Thakur, B and Darreh-Shori, T and Chen, G and Tiwari, V and Kumar, R},
title = {Synthesis and biological evaluation of Halogen-Substituted novel α-Ketoamides as potential protein aggregation modulators in Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {147},
number = {},
pages = {107373},
doi = {10.1016/j.bioorg.2024.107373},
pmid = {38653149},
issn = {1090-2120},
abstract = {The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aβ) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from β,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aβ aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aβ aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10[-6] cm/s. In addition to its Aβ inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aβ induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.},
}

@article {pmid38652895,
year = {2024},
author = {Parvin, F and Haglund, S and Wegenast-Braun, B and Jucker, M and Saito, T and Saido, TC and Nilsson, KPR and Nilsson, P and Nyström, S and Hammarström, P},
title = {Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and App[NL-F] Mice.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00104},
pmid = {38652895},
issn = {1948-7193},
abstract = {Amyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aβ fibril structures in situ differ in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aβ-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and App[NL-F] have different fibril structures within Aβ-amyloid plaques depending on the AβPP-processing genotype. Co-staining with Aβ-specific antibodies showed that individual plaques from APP23 mice expressing AβPP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aβ40 fibrils, and the corona region is dominated by diffusely packed Aβ40 fibrils. Conversely, the AβPP knock-in mouse App[NL-F], expressing the AβPP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aβ42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by Aβ40 and was hence minuscule in App[NL-F]. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.},
}

@article {pmid38652732,
year = {2024},
author = {Zeng, W and Li, C and Wu, R and Yang, X and Wang, Q and Lin, B and Wei, Y and Li, H and Shan, G and Qu, L and Cang, C},
title = {Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.},
journal = {PLoS biology},
volume = {22},
number = {4},
pages = {e3002591},
doi = {10.1371/journal.pbio.3002591},
pmid = {38652732},
issn = {1545-7885},
abstract = {Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking. Here, we constructed lysosome-localized optogenetic actuators, named lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2, to achieve optogenetic manipulation of lysosomes. These new actuators enable light-dependent control of lysosomal membrane potential, pH, hydrolase activity, degradation, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy through the mTOR pathway, promotes Aβ clearance in an autophagy-dependent manner in cellular models, and alleviates Aβ-induced paralysis in the Caenorhabditis elegans model of Alzheimer's disease. Our lysosomal optogenetic actuators supplement the optogenetic toolbox and provide a method to dynamically regulate lysosomal physiology and function in living cells and animals.},
}

@article {pmid38652714,
year = {2024},
author = {Wu, D and Sun, JK and Chow, KH},
title = {Neuronal cell cycle reentry events in the aging brain are more prevalent in neurodegeneration and lead to cellular senescence.},
journal = {PLoS biology},
volume = {22},
number = {4},
pages = {e3002559},
pmid = {38652714},
issn = {1545-7885},
mesh = {Animals ; Humans ; *Cellular Senescence/genetics ; *Brain/metabolism/pathology ; *Aging/physiology/genetics ; *Cell Cycle/genetics ; Mice ; *Alzheimer Disease/pathology/genetics/metabolism ; *Neurons/metabolism/pathology ; Transcriptome/genetics ; Parkinson Disease/genetics/pathology/metabolism ; Gene Expression Profiling ; Male ; Dopaminergic Neurons/metabolism/pathology ; Neurodegenerative Diseases/genetics/metabolism/pathology ; Mice, Inbred C57BL ; Aged ; },
abstract = {Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization. Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model. An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.},
}

Animals
Humans
*Cellular Senescence/genetics
*Brain/metabolism/pathology
*Aging/physiology/genetics
*Cell Cycle/genetics
Mice
*Alzheimer Disease/pathology/genetics/metabolism
*Neurons/metabolism/pathology
Transcriptome/genetics
Parkinson Disease/genetics/pathology/metabolism
Gene Expression Profiling
Male
Dopaminergic Neurons/metabolism/pathology
Neurodegenerative Diseases/genetics/metabolism/pathology
Mice, Inbred C57BL
Aged

@article {pmid38652661,
year = {2024},
author = {Qiu, Y and Hou, Y and Gohel, D and Zhou, Y and Xu, J and Bykova, M and Yang, Y and Leverenz, JB and Pieper, AA and Nussinov, R and Caldwell, JZK and Brown, JM and Cheng, F},
title = {Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.},
journal = {Cell reports},
volume = {43},
number = {5},
pages = {114128},
doi = {10.1016/j.celrep.2024.114128},
pmid = {38652661},
issn = {2211-1247},
abstract = {Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.},
}

@article {pmid38652236,
year = {2024},
author = {Ayten, Ş and Bilici, S},
title = {Modulation of Gut Microbiota Through Dietary Intervention in Neuroinflammation and Alzheimer's and Parkinson's Diseases.},
journal = {Current nutrition reports},
volume = {},
number = {},
pages = {},
pmid = {38652236},
issn = {2161-3311},
abstract = {PURPOSE OF REVIEW: The gut microbiota plays a crucial role in the pathogenesis of neuroinflammation and Alzheimer's and Parkinson's diseases. One of the main modulators of the gut microbiota is the diet, which directly influences host homeostasis and biological processes. Some dietary patterns can affect neurodegenerative diseases' progression through gut microbiota composition, gut permeability, and the synthesis and secretion of microbial-derived neurotrophic factors and neurotransmitters. This comprehensive review critically assesses existing studies investigating the impact of dietary interventions on the modulation of the microbiota in relation to neurodegenerative diseases and neuroinflammation.

RECENT FINDINGS: There are limited studies on the effects of specific diets, such as the ketogenic diet, Mediterranean diet, vegetarian diet, and Western diet, on the progression of neuroinflammation and Alzheimer's and Parkinson's diseases through the gut-brain axis. The ketogenic diet displays promising potential in ameliorating the clinical trajectory of mild cognitive impairment and Alzheimer's disease. However, conflicting outcomes were observed among various studies, highlighting the need to consider diverse types of ketogenic diets and their respective effects on clinical outcomes and gut microbiota composition. Vegetarian and Mediterranean diets, known for their anti-inflammatory properties, can be effective against Parkinson's disease, which is related to inflammation in the gut environment. On the other hand, the westernization of dietary patterns was associated with reduced gut microbial diversity and metabolites, which ultimately contributed to the development of neuroinflammation and cognitive impairment. Various studies examining the impact of dietary interventions on the gut-brain axis with regard to neuroinflammation and Alzheimer's and Parkinson's diseases are thoroughly reviewed in this article. A strong mechanistic explanation is required to fully understand the complex interactions between various dietary patterns, gut microbiota, and microbial metabolites and the effects these interactions have on cognitive function and the progression of these diseases.},
}

@article {pmid38652180,
year = {2024},
author = {Ansari, S and Etekochay, MO and Atanasov, AG and Prasad, VP and Kandimalla, R and Mofatteh, M and V, P and Emran, TB},
title = {Human olfactory neurosphere-derived cells: A unified tool for neurological disease modelling and neurotherapeutic applications.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000001460},
pmid = {38652180},
issn = {1743-9159},
abstract = {As one of the leading causes of global mortality and morbidity, various neurological diseases cause social and economic burdens. Despite significant advances in the treatment of neurological diseases, establishing a proper disease model, especially for degenerative and infectious diseases, remains a major challenging issue. For long, mice were the model of choice but suffered from serious drawbacks of differences in anatomical and functional aspects of the nervous system. Furthermore, the collection of post-mortem brain tissues limits their usage in cultured cell lines. Overcoming such limitations has prompted the usage of stem cells derived from the peripheral nervous system, such as the cells of the olfactory mucosa as a preferred choice. These cells can be easily cultured in vitro and retain the receptors of neuronal cells life-long. Such cells have various advantages over embryonic or induced stem cells, including homology, and ease of culture and can be conveniently obtained from diseased individuals through either biopsies or exfoliation. They have continuously helped in understanding the genetic and developmental mechanisms of degenerative diseases like Alzheimer's and Parkinson's disease. Moreover, the mode of infection of various viruses that can lead to post-viral olfactory dysfunction, such as the Zika virus can be monitored through these cells in vitro and their therapeutic development can be fastened.},
}

@article {pmid38652179,
year = {2024},
author = {Yamada, K and Iwatsubo, T},
title = {Involvement of the glymphatic/meningeal lymphatic system in Alzheimer's disease: insights into proteostasis and future directions.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {81},
number = {1},
pages = {192},
pmid = {38652179},
issn = {1420-9071},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Glymphatic System/metabolism/pathology ; *Meninges/metabolism/pathology ; *Proteostasis ; *Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Animals ; Lymphatic System/metabolism/pathology ; Brain/metabolism/pathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aβ and tau proteins. There has long been a keen interest among researchers in understanding how Aβ and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD. This finding has sparked interest in exploring the potential contribution of the glymphatic/meningeal lymphatic system in AD. Furthermore, there is a growing emphasis and discussion regarding the possibility that activating the glymphatic/meningeal lymphatic system could serve as a novel therapeutic strategy against AD.

OBJECTIVES:  Given this current research trend, the primary focus of this comprehensive review is to highlight the role of the glymphatic/meningeal lymphatic system in the pathogenesis of AD. The discussion will encompass future research directions and prospects for treatment in relation to the glymphatic/meningeal lymphatic system.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Glymphatic System/metabolism/pathology
*Meninges/metabolism/pathology
*Proteostasis
*Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Animals
Lymphatic System/metabolism/pathology
Brain/metabolism/pathology

@article {pmid38652148,
year = {2024},
author = {Liyanage, NS and Awwad, F and Gonçalves Dos Santos, KC and Jayawardena, TU and Mérindol, N and Desgagné-Penix, I},
title = {Navigating Amaryllidaceae Alkaloids: Bridging Gaps and Charting Biosynthetic Territories - A Comprehensive Review.},
journal = {Journal of experimental botany},
volume = {},
number = {},
pages = {},
doi = {10.1093/jxb/erae187},
pmid = {38652148},
issn = {1460-2431},
abstract = {Amaryllidaceae alkaloid (AAs) biosynthesis has garnered significant attention in recent years, particularly with the commercialisation of galanthamine as a treatment for the symptoms of Alzheimer's disease. A significant amount of research work over the last 8 decades has focused on the understanding of AA biosynthesis, starting from early radiolabelling studies to recent multi-omics analysis with modern biotechnological advancements. Those studies enabled the identification of hundreds of metabolites, the characterisation of biochemical pathway, an understanding of the environmental stimuli, and of the molecular regulation of these pharmaceutically and agriculturally important metabolites. Despite the numerous works there remain significant gaps in understanding their biosynthesis in Amaryllidaceae plants. As such, further research is needed to fully elucidate the metabolic pathway and facilitate their production. This review aims to provide a comprehensive overall summary of the current state of knowledge on AAs biosynthesis, from elicitation of transcription factors expression in the cell nucleus to alkaloid transport in the apoplast, and to highlight the challenges that need to be overcome for further advancement.},
}

@article {pmid38652067,
year = {2024},
author = {Deike, K and Decker, A and Scheyhing, P and Harten, J and Zimmermann, N and Paech, D and Peters, O and Freiesleben, SD and Schneider, LS and Preis, L and Priller, J and Spruth, E and Altenstein, S and Lohse, A and Fliessbach, K and Kimmich, O and Wiltfang, J and Bartels, C and Hansen, N and Jessen, F and Rostamzadeh, A and Düzel, E and Glanz, W and Incesoy, EI and Butryn, M and Buerger, K and Janowitz, D and Ewers, M and Perneczky, R and Rauchmann, BS and Teipel, S and Kilimann, I and Goerss, D and Laske, C and Munk, MH and Spottke, A and Roy, N and Wagner, M and Roeske, S and Heneka, MT and Brosseron, F and Ramirez, A and Dobisch, L and Wolfsgruber, S and Kleineidam, L and Yakupov, R and Stark, M and Schmid, MC and Berger, M and Hetzer, S and Dechent, P and Scheffler, K and Petzold, GC and Schneider, A and Effland, A and Radbruch, A},
title = {Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.},
journal = {Investigative radiology},
volume = {},
number = {},
pages = {},
pmid = {38652067},
issn = {1536-0210},
abstract = {OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD.

MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale.

RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse.

CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.},
}

@article {pmid38651960,
year = {2024},
author = {Delaby, C and Lehmann, S},
title = {[On the road to biological blood diagnosis of Alzheimer's disease?].},
journal = {Medecine sciences : M/S},
volume = {40},
number = {4},
pages = {351-360},
doi = {10.1051/medsci/2024037},
pmid = {38651960},
issn = {1958-5381},
abstract = {The growing number of people suffering from Alzheimer's disease (AD) represents a major public health problem. The diagnosis of AD is multidisciplinary and involves the use of amyloid and tau biomarkers measured in cerebrospinal fluid. Recent advances in analytical techniques now allow us to measure these biomarkers in blood. Blood biomarkers offer particularly promising potential for early, minimally invasive detection of AD, as well as for differential diagnosis of dementia and patient follow-up. The aim of this review is to provide an overview of current and candidate blood biomarkers for AD, their informative value, and their potential to be integrated into clinical practice in the near future.},
}

@article {pmid38651955,
year = {2024},
author = {Kyalu Ngoie Zola, N and Balty, C and Vertommen, D and Hanseeuw, BJ},
title = {[Specific modifications of the soluble tau protein distinguish Alzheimer's disease from other tauopathies].},
journal = {Medecine sciences : M/S},
volume = {40},
number = {4},
pages = {328-331},
doi = {10.1051/medsci/2024032},
pmid = {38651955},
issn = {1958-5381},
support = {CCL40010417//The Belgian Fund for Scientific Research (FNRS)/ ; OL J.0099.20//Fonds de la Recherche Scientifique (FNRS) for the FRFS-WELBIO (Grant n° 40010035)/ ; T.0208.20//The Belgian Fund for Scientific Research (FNRS)/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism ; *tau Proteins/analysis/metabolism ; Humans ; *Tauopathies/diagnosis ; Diagnosis, Differential ; Solubility ; Animals ; Phosphorylation ; Protein Processing, Post-Translational ; },
}

*Alzheimer Disease/diagnosis/metabolism
*tau Proteins/analysis/metabolism
Humans
*Tauopathies/diagnosis
Diagnosis, Differential
Solubility
Animals
Phosphorylation
Protein Processing, Post-Translational

@article {pmid38651790,
year = {2024},
author = {Behrens, LL and Anderson, HL and Kowalchik, KH and Mogle, J and Roman Jones, J and Van Haitsma, K and Hodgson, N and Boltz, M},
title = {"I'm not a risk taker": Risk Perceptions of Nursing Home Residents With Dementia.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
pmid = {38651790},
issn = {1546-4156},
abstract = {BACKGROUND: Persons living with Alzheimer's disease and related dementia (ADRD) in nursing homes (NH) are often excluded from conversations about their health/safety. These omissions impinge on personhood and the rights to have care preferences heard and honored. While persons with ADRD maintain the ability to communicate their preferences long after their decision-making abilities are affected, little is known about how persons with ADRD understand the risks associated with their preferences.

METHODS: As part of a larger focused ethnography, in-depth interviews and an adapted risk propensity questionnaire explored the risk perceptions of NH residents with ADRD (N=7) associated with their preferences for care and activities of daily living.

RESULTS: Residents generally self-identified as risk avoiders (M=3.2±1.84) on the risk propensity scale and were able to rate risk associated with preferences described within 5 thematic categories: 1) participation in decision-making, 2) risk awareness, 3) paying attention to safety, 4) reliance on nursing home staff and family, and 5) impacts on quality of life and quality of care.

DISCUSSION: Results suggest NH residents with ADRD can express risk surrounding their preferences and should be encouraged to participate in discussions about their health and safety.},
}

@article {pmid38651489,
year = {2024},
author = {Marinova, P and Tamahkyarova, K},
title = {Synthesis and Biological Activities of Some Metal Complexes of Peptides: A Review.},
journal = {Biotech (Basel (Switzerland))},
volume = {13},
number = {2},
pages = {},
doi = {10.3390/biotech13020009},
pmid = {38651489},
issn = {2673-6284},
support = {project СП 23-ХФ-006//We acknowledge the financial support from the Fund for Scientific Research of the Plovdiv University/ ; },
abstract = {Peptides, both natural and synthetic, are well suited for a wide range of purposes and offer versatile applications in different fields such as biocatalysts, injectable hydrogels, tumor treatment, and drug delivery. The research of the better part of the cited papers was conducted using various database platforms such as MetalPDB. The rising prominence of therapeutic peptides encompasses anticancer, antiviral, antimicrobial, and anti-neurodegenerative properties. The metals Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, and Mo are ten of the twenty elements that are considered essential for life. Crucial for understanding the biological role of metals is the exploration of metal-bound proteins and peptides. Aside from essential metals, there are other non-essential metals that also interact biologically, exhibiting either therapeutic or toxic effects. Irregularities in metal binding contribute to diseases like Alzheimer's, neurodegenerative disorders, Wilson's, and Menkes disease. Certain metal complexes have potential applications as radiopharmaceuticals. The examination of these complexes was achieved by preforming UV-Vis, IR, EPR, NMR spectroscopy, and X-ray analysis. This summary, although unable to cover all of the studies in the field, offers a review of the ongoing experimentation and is a basis for new ideas, as well as strategies to explore and gain knowledge from the extensive realm of peptide-chelated metals and biotechnologies.},
}

@article {pmid38651483,
year = {2024},
author = {Rodríguez-Alcázar, FJ and Juárez-Vela, R and Sánchez-González, JL and Martín-Vallejo, J},
title = {Interventions Effective in Decreasing Burden in Caregivers of Persons with Dementia: A Meta-Analysis.},
journal = {Nursing reports (Pavia, Italy)},
volume = {14},
number = {2},
pages = {931-945},
doi = {10.3390/nursrep14020071},
pmid = {38651483},
issn = {2039-4403},
abstract = {Introduction: Chronic non-communicable diseases, including diseases of mental origin such as Alzheimer's, affect all age groups and countries. These diseases have a major impact on the patient and their family environment. It is interesting that different questionnaires are measured in the same direction, given that different health questionnaires are used to measure caregiver burden. Objectives: To identify which type of intervention is the most appropriate to improve the health of the primary caregiver in patients with dementia. To understand the role played by the nurse within multidisciplinary teams and to know whether the different questionnaires used in the studies measure caregiver health in the same direction. Methods: A systematic search of the published and gray literature was carried out without restriction of the language used in the studies. Caregiver burden of patients with dementia, receiving an intervention to improve caregiver burden, was assessed. Standardized mean difference was used as the effect size measure, and there were possible causes of heterogeneity in the effect size. Results: In total, 1512 records were found, and 39 articles with 4715 participants were included. We found individual information with an effect of 0.48 (CI95%: 0.18; 0.79; I2 = 0%); group therapy with an effect of 0.20 (CI95%: 0.08; 0.31; I2 = 6%); workshops with an effect of 0.21 (CI95%: 0.01; I2 = 48%) and 0.32 (CI95%: 0.01; 0.54; I2 = 0%) when a nurse intervenes; respite care with an effect of 0.22 (CI95%: 0.05; 0.40; I2 = 66%); individual therapy with an effect of 0.28 (CI95%: 0.15; 0.4; I2 = 68%); and support groups with an effect of 0.07 (CI95%: 0; 0.15; I2 = 78%). Conclusions: The magnitude of the effects of the interventions has been low-moderate. Different instruments are not associated with the magnitude of the effect. The presence of nurses improves the effect of the intervention on caregivers when it is carried out in the form of workshops.},
}

@article {pmid38651367,
year = {2024},
author = {Sanders, KL and Manuel, AM and Liu, A and Leng, B and Chen, X and Zhao, Z},
title = {Unveiling Gene Interactions in Alzheimer's Disease by Integrating Genetic and Epigenetic Data with a Network-Based Approach.},
journal = {Epigenomes},
volume = {8},
number = {2},
pages = {},
doi = {10.3390/epigenomes8020014},
pmid = {38651367},
issn = {2075-4655},
support = {U01AG079847//National Institute of Health/ ; R01LM012806//National Institute of Health/ ; RP180734//Cancer Prevention and Research Institute of Texas/ ; T15LM007093//United States National Library of Medicine/ ; T32ES027801//Gulf Coast Consortia on Training in Precision Environmental Health Sciences/ ; },
abstract = {Alzheimer's Disease (AD) is a complex disease and the leading cause of dementia in older people. We aimed to uncover aspects of AD's pathogenesis that may contribute to drug repurposing efforts by integrating DNA methylation and genetic data. Implementing the network-based tool, a dense module search of genome-wide association studies (dmGWAS), we integrated a large-scale GWAS dataset with DNA methylation data to identify gene network modules associated with AD. Our analysis yielded 286 significant gene network modules. Notably, the foremost module included the BIN1 gene, showing the largest GWAS signal, and the GNAS gene, the most significantly hypermethylated. We conducted Web-based Cell-type-Specific Enrichment Analysis (WebCSEA) on genes within the top 10% of dmGWAS modules, highlighting monocyte as the most significant cell type (p < 5 × 10[-12]). Functional enrichment analysis revealed Gene Ontology Biological Process terms relevant to AD pathology (adjusted p < 0.05). Additionally, drug target enrichment identified five FDA-approved targets (p-value = 0.03) for further research. In summary, dmGWAS integration of genetic and epigenetic signals unveiled new gene interactions related to AD, offering promising avenues for future studies.},
}

@article {pmid38651344,
year = {2024},
author = {Zheng, B and Chen, J and Cao, M and Zhang, Y and Chen, S and Yu, H and Liang, K},
title = {The effect of intermittent theta burst stimulation for cognitive dysfunction: a meta-analysis.},
journal = {Brain injury},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/02699052.2024.2344087},
pmid = {38651344},
issn = {1362-301X},
abstract = {BACKGROUND: Growing evidence suggests that cognitive dysfunction significantly impacts patients' quality of life. Intermittent theta burst stimulation (iTBS) has emerged as a potential intervention for cognitive dysfunction. However, consensus on the iTBS protocol for cognitive impairment is lacking.

METHODS: We conducted searches in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, Chinese National Knowledge Infrastructure, Wanfang Database and the Chongqing VIP Chinese Science and Technology Periodical Database from their inception to January 2024. Random-effects meta-analyzes were used to calculate standardized mean differences and 95% confidence intervals. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach.

RESULTS: Twelve studies involving 506 participants were included in the meta-analysis. The analysis showed a trend toward improvement of total cognitive function, activities of daily living and P300 latency compared to sham stimulation in patients with cognitive dysfunction. Subgroup analysis demonstrated that these effects were restricted to patients with post-stroke cognitive impairment but not Alzheimer's disease or Parkinson's disease. Furthermore, subthreshold stimulation also exhibited a significant improvement.

CONCLUSIONS: The results suggest that iTBS may improve cognitive function in patients with cognitive dysfunction, although the quality of evidence remains low. Further studies with better methodological quality should explore the effects of iTBS on cognitive function.},
}

@article {pmid38651272,
year = {2024},
author = {Jing, XJ and Zan, ZY and Zhou, X and Xiong, YL and Ren, SJ and Zhang, H and , },
title = {The associations of serum isoleucine with Alzheimer`s disease on assisting diagnosis, predicting conversion and assessing cognition.},
journal = {Annals of geriatric medicine and research},
volume = {},
number = {},
pages = {},
doi = {10.4235/agmr.23.0216},
pmid = {38651272},
issn = {2508-4909},
abstract = {BACKGROUND: Advances in blood biomarker discovery have enabled the improved diagnosis and prognosis of Alzheimer's disease (AD). Most branched-chain amino acids, except isoleucine (Ile), are correlated with both mild cognitive impairment (MCI) and AD. Therefore, this study investigated the association between serum Ile levels and MCI/AD.

METHODS: This study stratified 700 participants from the Alzheimer's Disease Neuroimaging Initiative database into four diagnostic groups: cognitively normal, stable MCI, progressive MCI, and AD. Analysis of covariance and chi-square analyses were used to test the demographic data. Receiver operating curve analyses were used to calculate the diagnostic accuracy of different biomarkers and were compared using MedCalc 20. Additionally, Cox proportional hazards models were used to measure the ability of serum Ile levels to predict disease conversion. Finally, a linear mixed-effects model was used to evaluate the associations between serum Ile levels and cognition, brain structure, and metabolism.

RESULTS: Serum Ile concentration was decreased in AD and demonstrated significant diagnostic efficacy. The combination of serum Ile and cerebrospinal fluid (CSF) phosphorylated tau (P-tau) levels improved the diagnostic accuracy in AD compared to T-tau alone. Serum Ile levels significantly predicted the conversion from MCI to AD (cutoff value = 78.3 μM). Finally, the results of this study also revealed a correlation between serum Ile levels and the Alzheimer's Disease Assessment Scale cognitive subscale Q4.

CONCLUSIONS: Serum Ile level may be a potential biomarker of AD. Ile had independent diagnostic efficacy and significantly improved the diagnostic accuracy of CSF P-tau in AD. Patients with MCI with a lower serum Ile level had a higher risk of progression to AD and a worse cognition assessment.},
}

@article {pmid38651179,
year = {2024},
author = {Li, J and Wu, Z and Wu, Y and Hu, XY and Yang, J and Zhu, D and Wu, M and Li, X and Bentum-Ennin, L and Hu, W},
title = {IL-22, a vital cytokine in autoimmune diseases.},
journal = {Clinical and experimental immunology},
volume = {},
number = {},
pages = {},
doi = {10.1093/cei/uxae035},
pmid = {38651179},
issn = {1365-2249},
abstract = {Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.},
}

@article {pmid38651161,
year = {2024},
author = {Hong, H and Chen, Y and Liu, W and Luo, X and Zhang, M and , },
title = {Distinct patterns of voxel- and connection-based white matter hyperintensity distribution and associated factors in early-onset and late-onset Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12585},
pmid = {38651161},
issn = {2352-8729},
abstract = {INTRODUCTION: The distribution of voxel- and connection-based white matter hyperintensity (WMH) patterns in early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), as well as factors associated with these patterns, remain unclear.

METHOD: We analyzed the WMH distribution patterns in EOAD and LOAD at the voxel and connection levels, each compared with their age-matched cognitively unimpaired participants. Linear regression assessed the independent effects of amyloid and vascular risk factors on WMH distribution patterns in both groups.

RESULTS: Patients with EOAD showed increased WMH burden in the posterior region at the voxel level, and in occipital region tracts and visual network at the connection level, compared to controls. LOAD exhibited extensive involvement across various brain areas in both levels. Amyloid accumulation was associated WMH distribution in the early-onset group, whereas the late-onset group demonstrated associations with both amyloid and vascular risk factors.

DISCUSSION: EOAD showed posterior-focused WMH distribution pattern, whereas LOAD was with a wider distribution. Amyloid accumulation was associated with connection-based WMH patterns in both early-onset and late-onset groups, with additional independent effects of vascular risk factors in late-onset group.

HIGHLIGHTS: Both early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) showed increased white matter hyperintensity (WMH) volume compared with their age-matched cognitively unimpaired participants.EOAD and LOAD exhibited distinct patterns of WMH distribution, with EOAD showing a posterior-focused pattern and LOAD displaying a wider distribution across both voxel- and connection-based levels.In both EOAD and LOAD, amyloid accumulation was associated with connection-based WMH patterns, with additional independent effects of vascular risk factors observed in LOAD.},
}

@article {pmid38651160,
year = {2024},
author = {Pivac, LN and Brown, BM and Sewell, KR and Doecke, JD and Villemagne, VL and Doré, V and Weinborn, M and Sohrabi, HR and Gardener, SL and Bucks, RS and Laws, SM and Taddei, K and Maruff, P and Masters, CL and Rowe, C and Martins, RN and Rainey-Smith, SR},
title = {Suboptimal self-reported sleep efficiency and duration are associated with faster accumulation of brain amyloid beta in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {2},
pages = {e12579},
pmid = {38651160},
issn = {2352-8729},
abstract = {INTRODUCTION: This study investigated whether self-reported sleep quality is associated with brain amyloid beta (Aβ) accumulation.

METHODS: Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean ± standard deviation 74.0 ± 6.2; 53.2% female), with baseline self-reported sleep data, and positron emission tomography-determined brain Aβ measured over a minimum of three time points (range 33.3-72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age.

RESULTS: Sleep duration <6 hours, in APOE ε4 carriers, and sleep efficiency <65%, in the whole sample and APOE ε4 non-carriers, is associated with faster accumulation of brain Aβ.

DISCUSSION: These findings suggest a role for self-reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease (AD) neuropathology in CU individuals. Additionally, poor sleep efficiency represents a potential route via which individuals at lower genetic risk may progress to preclinical AD.

HIGHLIGHTS: In cognitively unimpaired older adults self-report sleep is associated with brain amyloid beta (Aβ) accumulation.Across sleep characteristics, this relationship differs by apolipoprotein E (APOE) genotype.Sleep duration <6 hours is associated with faster brain Aβ accumulation in APOE ε4 carriers.Sleep efficiency < 65% is associated with faster brain Aβ accumulation in APOE ε4 non-carriers.Personalized sleep interventions should be studied for potential to slow Aβ accumulation.},
}

@article {pmid38651012,
year = {2024},
author = {Prasuhn, J and Xu, J and Hua, J and van Zijl, P and Knutsson, L},
title = {Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system.},
journal = {Frontiers in psychiatry},
volume = {15},
number = {},
pages = {1368489},
pmid = {38651012},
issn = {1664-0640},
abstract = {The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo. These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders.},
}

@article {pmid38650867,
year = {2024},
author = {Liang, K and Zhang, X},
title = {Association between Life's Essential 8 and cognitive function: insights from NHANES 2011-2014.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1386498},
pmid = {38650867},
issn = {1663-4365},
abstract = {INTRODUCTION: Life's Essential 8 (LE8) is prompted by the American Heart Association (AHA) to assess cardiovascular health. The association between LE8 and cognitive function in America is unknown. Our study was to investigate the association of LE8 with cognitive function in general adults.

MATERIALS AND METHODS: A total of 2,301 participants were enrolled in the National Health and Nutrition Examination Surveys (NHANES). LE8 scores (range 0-100) were obtained from measurements based on American Heart Association definitions, divided into health behavior and health factor scores. Cognitive function was assessed by three tests including the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal fluency test (AFT), and Digit Symbol Substitution test (DSST). The multivariable linear regression analysis explored the associations between LE8 and cognitive function. Smooth curve fitting was explored using restricted cubic splines. The inflection point was determined by the two-piecewise linear regression.

RESULTS: In the multivariable linear regression model with full adjustment for confounding variables, AFT scores were 1.2 points higher in participants with LE8 scores >80 than in those with LE8 scores <50 (high LE8 score group: β = 1.20, 95% CI 0.37, 2.03), and 3.32 points higher in DSST (high LE8 score group: β = 3.32, 95% CI 1.24, 5.39). Although high LE8 scores show a Negative association with high CERAD, we found a significant association between higher LE8 scores and higher CERAD when LE8 scores were higher than 82.5 (β = 0.21 95%CI 0.04, 0.39, p-value = 0.0179).

CONCLUSION: Our study highlighted a positive association between Life's Essential 8 and cognitive function in older adults.},
}

@article {pmid38650866,
year = {2024},
author = {Jiao, L and Kang, H and Geng, Y and Liu, X and Wang, M and Shu, K},
title = {The role of the nucleus basalis of Meynert in neuromodulation therapy: a systematic review from the perspective of neural network oscillations.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1376764},
pmid = {38650866},
issn = {1663-4365},
abstract = {As a crucial component of the cerebral cholinergic system and the Papez circuit in the basal forebrain, dysfunction of the nucleus basalis of Meynert (NBM) is associated with various neurodegenerative disorders. However, no drugs, including existing cholinesterase inhibitors, have been shown to reverse this dysfunction. Due to advancements in neuromodulation technology, researchers are exploring the use of deep brain stimulation (DBS) therapy targeting the NBM (NBM-DBS) to treat mental and neurological disorders as well as the related mechanisms. Herein, we provided an update on the research progress on cognition-related neural network oscillations and complex anatomical and projective relationships between the NBM and other cognitive structures and circuits. Furthermore, we reviewed previous animal studies of NBM lesions, NBM-DBS models, and clinical case studies to summarize the important functions of the NBM in neuromodulation. In addition to elucidating the mechanism of the NBM neural network, future research should focus on to other types of neurons in the NBM, despite the fact that cholinergic neurons are still the key target for cell type-specific activation by DBS.},
}

@article {pmid38650831,
year = {2024},
author = {Bøgh, N and Sørensen, CB and Alstrup, AKO and Hansen, ESS and Andersen, OM and Laustsen, C},
title = {Mice and minipigs with compromised expression of the Alzheimer's disease gene SORL1 show cerebral metabolic disturbances on hyperpolarized [1-[13]C]pyruvate and sodium MRI.},
journal = {Brain communications},
volume = {6},
number = {2},
pages = {fcae114},
pmid = {38650831},
issn = {2632-1297},
abstract = {The sortilin-related receptor 1 (SORL1) gene, encoding the cellular endosomal sorting-related receptor with A-type repeats (SORLA), is now established as a causal gene for Alzheimer's disease. As the latest addition to the list of causal genes, the pathophysiological effects and biomarker potential of SORL1 variants remain relatively undiscovered. Metabolic dysfunction is, however, well described in patients with Alzheimer's disease and is used as an imaging biomarker in clinical diagnosis settings. To understand the metabolic consequences of loss-of-function SORL1 mutations, we applied two metabolic MRI technologies, sodium ([23]Na) MRI and MRI with hyperpolarized [1-[13]C]pyruvate, in minipigs and mice with compromised expression of SORL1. At the age analysed here, both animal models display no conventional imaging evidence of neurodegeneration but show biochemical signs of elevated amyloid production, thus representing the early preclinical disease. With hyperpolarized MRI, the exchange from [1-[13]C]pyruvate to [1-[13]C]lactate and [13]C-bicarbonate was decreased by 32 and 23%, respectively, in the cerebrum of SORL1-haploinsufficient minipigs. A robust 11% decrease in the sodium content was observed with [23]Na-MRI in the same minipigs. Comparably, the brain sodium concentration gradually decreased from control to SORL1 haploinsufficient (-11%) to SORL1 knockout mice (-23%), suggesting a gene dose dependence in the metabolic dysfunction. The present study highlights that metabolic MRI technologies are sensitive to the functional, metabolic consequences of Alzheimer's disease and Alzheimer's disease-linked genotypes. Further, the study suggests a potential avenue of research into the mechanisms of metabolic alterations by SORL1 mutations and their potential role in neurodegeneration.},
}

@article {pmid38650747,
year = {2024},
author = {Cary, GA and Wiley, JC and Gockley, J and Keegan, S and Amirtha Ganesh, SS and Heath, L and Butler, RR and Mangravite, LM and Logsdon, BA and Longo, FM and Levey, A and Greenwood, AK and Carter, GW},
title = {Genetic and multi-omic risk assessment of Alzheimer's disease implicates core associated biological domains.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {10},
number = {2},
pages = {e12461},
pmid = {38650747},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome.

METHODS: Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi-omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system-level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome-wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank-and-organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains.

RESULTS: The top AD-risk-associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains.

DISCUSSION: This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.},
}

@article {pmid38650695,
year = {2024},
author = {Hassouneh, A and Bazuin, B and Danna-Dos-Santos, A and Acar, I and Abdel-Qader, I and , },
title = {Feature Importance Analysis and Machine Learning for Alzheimer's Disease Early Detection: Feature Fusion of the Hippocampus, Entorhinal Cortex, and Standardized Uptake Value Ratio.},
journal = {Digital biomarkers},
volume = {8},
number = {1},
pages = {59-74},
pmid = {38650695},
issn = {2504-110X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurological disorder characterized by mild memory loss and ranks as a leading cause of mortality in the USA, accounting for approximately 120,000 deaths per year. It is also the primary form of dementia. Early detection is critical for timely intervention as the neurodegenerative process often starts 15-20 years before cognitive symptoms manifest. This study focuses on determining feature importance in AD classification using fused texture features from 3D magnetic resonance imaging hippocampal and entorhinal cortex and standardized uptake value ratio (SUVR) derived from positron emission tomography (PET) images.

METHODS: To achieve this objective, we employed four distinct classifiers (Linear Support Vector Classification, Linear Discriminant Analysis, Logistic Regression, and Logistic Regression Classifier with Stochastic Gradient Descent Learning). These classifiers were used to derive both average and top-ranked importance scores for each feature based on their outputs. Our framework is designed to distinguish between two classes, AD-negative (or mild cognitive impairment stable [MCIs]) and AD-positive (or MCI conversion [MCIc]), using a probabilistic neural network classifier and the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

RESULTS: The findings from the feature importance highlight the crucial role of the GLCM texture features extracted from the hippocampus and entorhinal cortex, demonstrating their superior performance compared to the volume and SUVR. GLCM texture AD classification achieved approximately 90% sensitivity in identifying MCIc cases while maintaining low false positives (below 30%) when fused with other features. Moreover, the receiver operating characteristic curves validate the GLCMs' superior performance in distinguishing between MCIs and MCIc. Additionally, fusing different types of features improved classification performance compared to relying solely on any single feature category.

CONCLUSION: Our study emphasizes the pivotal role of GLCM texture features in early Alzheimer's detection.},
}

@article {pmid38650656,
year = {2024},
author = {Spanos, F and Gerenu, G and Goikolea, J and Latorre-Leal, M and Balleza-Tapia, H and Gomez, K and Álvarez-Jiménez, L and Piras, A and Gómez-Galán, M and Fisahn, A and Cedazo-Minguez, A and Maioli, S and Loera-Valencia, R},
title = {Impaired astrocytic synaptic function by peripheral cholesterol metabolite 27-hydroxycholesterol.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1347535},
pmid = {38650656},
issn = {1662-5102},
abstract = {Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer's disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.},
}

@article {pmid38650384,
year = {2024},
author = {Tam, S and Wear, D and Morrone, CD and Yu, WH},
title = {The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.16108},
pmid = {38650384},
issn = {1471-4159},
support = {AG069130/NH/NIH HHS/United States ; AG079774/NH/NIH HHS/United States ; },
abstract = {Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease.},
}

@article {pmid38649866,
year = {2024},
author = {Jiang, S and Cai, G and Yang, Z and Shi, H and Zeng, H and Ye, Q and Hu, Z and Wang, Z},
title = {Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer's Disease.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.3c13150},
pmid = {38649866},
issn = {1936-086X},
abstract = {The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aβ and its nerve repair function. In addition, siRNA reduces the production of Aβ plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aβ, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD.},
}

@article {pmid38649596,
year = {2024},
author = {Kamble, SA and Barale, SS and Mohammed, AA and Paymal, SB and Naik, NM and Sonawane, KD},
title = {Structural insights into the potential binding sites of Cathepsin D using molecular modelling techniques.},
journal = {Amino acids},
volume = {56},
number = {1},
pages = {33},
pmid = {38649596},
issn = {1438-2199},
abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia caused by the accumulation of amyloid beta (Aβ) peptides. The extracellular deposition of Aβ peptides in human AD brain causes neuronal death. Therefore, it has been found that Aβ peptide degradation is a possible therapeutic target for AD. CathD has been known to breakdown amyloid beta peptides. However, the structural role of CathD is not yet clear. Hence, for the purpose of gaining a deeper comprehension of the structure of CathD, the present computational investigation was performed using virtual screening technique to predict CathD's active site residues and substrate binding mode. Ligand-based virtual screening was implemented on small molecules from ZINC database against crystal structure of CathD. Further, molecular docking was utilised to investigate the binding mechanism of CathD with substrates and virtually screened inhibitors. Localised compounds obtained through screening performed by PyRx and AutoDock 4.2 with CathD receptor and the compounds having highest binding affinities were picked as; ZINC00601317, ZINC04214975 and ZINCC12500925 as our top choices. The hydrophobic residues Viz. Gly35, Val31, Thr34, Gly128, Ile124 and Ala13 help stabilising the CathD-ligand complexes, which in turn emphasises substrate and inhibitor selectivity. Further, MM-GBSA approach has been used to calculate binding free energy between CathD and selected compounds. Therefore, it would be beneficial to understand the active site pocket of CathD with the assistance of these discoveries. Thus, the present study would be helpful to identify active site pocket of CathD, which could be beneficial to develop novel therapeutic strategies for the AD.},
}

@article {pmid38649330,
year = {2024},
author = {Comptdaer, T and Tardivel, M and Schirmer, C and Buée, L and Galas, MC},
title = {Cell redistribution of G quadruplex-structured DNA is associated with morphological changes of nuclei and nucleoli in neurons during tau pathology progression.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e13262},
doi = {10.1111/bpa.13262},
pmid = {38649330},
issn = {1750-3639},
support = {/MRC_/Medical Research Council/United Kingdom ; },
abstract = {While the double helical structure has long been its iconic representation, DNA is structurally dynamic and can adopt alternative secondary configurations. Specifically, guanine-rich DNA sequences can fold in guanine quadruplexes (G4) structures. These G4 play pivotal roles as regulators of gene expression and genomic stability, and influence protein homeostasis. Despite their significance, the association of G4 with neurodegenerative diseases such as Alzheimer's disease (AD) has been underappreciated. Recent findings have identified DNA sequences predicted to form G4 in sarkosyl-insoluble aggregates from AD brains, questioning the involvement of G4-structured DNA (G4 DNA) in the pathology. Using immunofluorescence coupled to confocal microscopy analysis we investigated the impact of tau pathology, a hallmark of tauopathies including AD, on the distribution of G4 DNA in murine neurons and its relevance to AD brains. In healthy neurons, G4 DNA is detected in nuclei with a notable presence in nucleoli. However, in a transgenic mouse model of tau pathology (THY-Tau22), early stages of the disease exhibit an impairment in the nuclear distribution of G4 DNA. In addition, G4 DNA accumulates in the cytoplasm of neurons exhibiting oligomerized tau and oxidative DNA damage. This altered distribution persists in the later stage of the pathology when larger tau aggregates are present. Still cytoplasmic deposition of G4 DNA does not appear to be a critical factor in the tau aggregation process. Similar patterns are observed in neurons from the AD cortex. Furthermore, the disturbance in G4 DNA distribution is associated with various changes in the size of neuronal nuclei and nucleoli, indicative of responses to stress and the activation of pro-survival mechanisms. Our results shed light on a significant impact of tau pathology on the dynamics of G4 DNA and on nuclear and nucleolar mechanobiology in neurons. These findings reveal new dimensions in the etiopathogenesis of tauopathies.},
}

@article {pmid38649307,
year = {2024},
author = {Pang, C and Wang, R and Liu, K and Yuan, X and Ni, J and Cao, Q and Chen, Y and Dong, PL and Han, H},
title = {Serum and urine metabolomics based on UPLC-QTOF/MS reveal the effect and potential mechanism of "schisandra-evodia" herb pair in the treatment of Alzheimer's disease.},
journal = {Biomedical chromatography : BMC},
volume = {},
number = {},
pages = {e5882},
doi = {10.1002/bmc.5882},
pmid = {38649307},
issn = {1099-0801},
support = {LH2019H053//Natural Science Foundation of Heilongjiang Province/ ; 2017XY01//Heilongjiang University of Traditional Chinese Medicine Scientific Research Fund Project/ ; },
abstract = {The "schisandra-evodia" herb pair (S-E) is a herbal preparation to treat Alzheimer's disease (AD). This study aims to investigate the therapeutic efficacy and potential mechanism of S-E in AD rats, utilizing pharmacodynamic assessments and serum- and urine-based metabolomic analyses. Pharmacodynamic assessments included Morris water maze test, hematoxylin-eosin staining and immunohistochemistry experiments. The results of the study showed that the AD model was successful; the S-E significantly enhanced long-term memory and spatial learning in AD rats. Meanwhile, S-E notably ameliorated Aβ25-35-induced cognitive impairment, improved hippocampal neuron morphology, decreased Aβ deposition in the hippocampus and mitigated inflammatory damage. We then analyzed serum and urine samples using UPLC-MS/MS to identify potential biomarkers and metabolic pathways. Metabolomic analysis revealed alterations in 40 serum metabolites and 38 urine metabolites following S-E treatment, predominantly affecting pathways related to taurine and hypotaurine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism and arachidonic acid metabolism. This study elucidates the biochemical mechanism underlying AD and the metabolic pathway influenced by S-E, laying the groundwork for future clinical applications.},
}

@article {pmid38649269,
year = {2024},
author = {Murakami, R and Watanabe, H and Hashimoto, H and Kashiwagi-Hakozaki, M and Hashimoto, T and Karch, CM and , and Iwatsubo, T and Okano, H},
title = {Inhibitory roles of Apolipoprotein E Christchurch astrocytes in curbing tau propagation using human pluripotent stem cell-derived models.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1709-23.2024},
pmid = {38649269},
issn = {1529-2401},
abstract = {Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.Significance Statement Alzheimer's disease (AD) is a degenerative disease that causes cognitive decline. Familial AD is a severe form caused by mutations in the PSEN1, PSEN2, or APP genes. One carrier of the PSEN1 mutation did not develop dementia. This carrier also had a rare variant of the APOE gene, the Christchurch variant. The APOE Christchurch variant may protect against familial AD. The mechanism of this protection is not fully understood. In the present study, we have successfully demonstrated that the APOE Christchurch variant suppresses the propagation of tau and exhibits a diminished capacity to convert native astrocytes into reactive astrocytes. These significant findings contribute novel insights to the field of the APOE gene and AD research.},
}

@article {pmid38648960,
year = {2024},
author = {Liu, YL and Cao, YG and Hao, FX and Zeng, MN and Niu, Y and Chen, L and Chen, X and Zheng, XK and Feng, WS},
title = {Chemical constituents from stipes of Lentinus edodes and their protective effects against Aβ25-35-induced N9 microglia cells injury.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114098},
doi = {10.1016/j.phytochem.2024.114098},
pmid = {38648960},
issn = {1873-3700},
abstract = {Nine undescribed compounds, along with eight known compounds, were isolated from the stipes of Lentinus edodes. Their structures were established by extensive spectroscopic and circular dichroism analyses. The protective effects against Aβ25-35-induced N9 microglia cells injury of these compounds were tested by MTT method, and the levels of apoptosis and ROS were detected by flow cytometry. In addition, the binding sites and interactions of compound with amyloid precursor protein were revealed using molecular docking simulations. These findings further establish the structural diversity and bioactivity of stipes of L. edodes, and provide an experimental basis for targeting Alzheimer's disease as a potential strategy.},
}

@article {pmid38648940,
year = {2024},
author = {Shippy, DC and Oliai, SF and Ulland, TK},
title = {Zinc utilization by microglia in Alzheimer's disease.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {107306},
doi = {10.1016/j.jbc.2024.107306},
pmid = {38648940},
issn = {1083-351X},
abstract = {Alzheimer's disease (AD) is the most common form of dementia defined by two key pathological characteristics in the brain, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Microglia, the primary innate immune cells of the central nervous system (CNS), provide neuroprotection through Aβ and tau clearance, but may also be neurotoxic by promoting neuroinflammation to exacerbate Aβ and tau pathogenesis in AD. Recent studies have demonstrated the importance of microglial utilization of nutrients and trace metals in controlling their activation and effector functions. Trace metals, such as zinc, have essential roles in brain health and immunity, and zinc dyshomeostasis has been implicated in AD pathogenesis. As a result of these advances, the mechanisms by which zinc homeostasis influences microglial-mediated neuroinflammation in AD is a topic of continuing interest since new strategies to treat AD are needed. Here, we review the roles of zinc in AD, including zinc activation of microglia, the associated neuroinflammatory response, and the application of these findings in new therapeutic strategies.},
}

@article {pmid38648920,
year = {2024},
author = {Reid, GA and Darvesh, S},
title = {Interaction of Exogenous Acetylcholinesterase and Butyrylcholinesterase with Amyloid-β Plaques in Human Brain Tissue.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111012},
doi = {10.1016/j.cbi.2024.111012},
pmid = {38648920},
issn = {1872-7786},
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are associated with amyloid-β (Aβ) plaques and exhibit altered biochemical properties in human Alzheimer's disease (AD), as well as in the transgenic 5XFAD mouse model of AD amyloidosis. In the brains of the 5XFAD mouse model devoid of BChE enzyme (5XFAD/BChE-KO), incubation of tissue sections with exogenous BChE purified from human plasma (pl-BChE) leads to its association with Aβ plaques and its biochemical properties are comparable to those reported for endogenous BChE associated with plaques in both human AD and in 5XFAD mouse brain tissue. We sought to determine whether these observations in 5XFAD/BChE-KO mice also apply to human brain tissues. To do so, endogenous ChE activity in human AD brain tissue sections was quenched with 50% aqueous acetonitrile (MeCNaq) leaving the tissue intact for further studies. Quenched sections were then incubated with recombinant AChE (r-AChE) or pl-BChE and stained for each enzymes' activity. Exogenous r-AChE or pl-BChE became associated with Aβ plaques, and when bound, had properties that were comparable to the endogenous ChE enzymes associated with plaques in AD brain tissues without acetonitrile treatment. These findings in human AD brain tissue extend previous observations in the 5XFAD/BChE-KO mouse model and demonstrate that exogenously applied r-AChE and pl-BChE have high affinity for Aβ plaques in human brain tissues. This association alters the biochemical properties of these enzymes, most likely due a conformational change. If incorporation of AChE and BChE in Aβ plaques facilitates AD pathogenesis, blocking this association could lead to disease-modifying approaches to AD. This work provides a method to study the mechanism of AChE and BChE interaction with Aβ plaque pathology in post-mortem human brain tissue.},
}

@article {pmid38648886,
year = {2024},
author = {D'Amelio, M and Costa, C},
title = {Clarifying the role of D1 receptor signalling in Alzheimer's-related epilepsy commentary on Szabo et al. (2024).},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.16359},
pmid = {38648886},
issn = {1460-9568},
support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; },
}

@article {pmid38648843,
year = {2024},
author = {Barry, HC},
title = {Brexpiprazole Improves Agitation Scores in Adults With Alzheimer Disease and Agitated Behaviors.},
journal = {American family physician},
volume = {109},
number = {4},
pages = {373},
pmid = {38648843},
issn = {1532-0650},
}

@article {pmid38648467,
year = {2024},
author = {Harding, E and Sullivan, MP and Camic, PM and Yong, KXX and Stott, J and Crutch, SJ},
title = {"I Want to Do Something" - Exploring What Makes Activities Meaningful for Community-Dwelling People Living With Dementia: A Focused Ethnographic Study.},
journal = {Qualitative health research},
volume = {},
number = {},
pages = {10497323241239487},
doi = {10.1177/10497323241239487},
pmid = {38648467},
issn = {1049-7323},
abstract = {Supporting ageing in place, quality of life, and activity engagement are public health priorities for people with dementia. The importance of maintaining opportunities for meaningful activities has been widely acknowledged for those with dementia in long-term care, but little is known about what makes activities meaningful for, and how they are experienced by, people with different types of dementia in their own homes. This study used focussed ethnographic methods to explore the motivations and meanings of everyday activity engagement within the homes of 10 people with memory-led Alzheimer's disease and 10 people with posterior cortical atrophy. While participants' interactions with their everyday environments were challenged by their diagnoses, they were all finding ways to continue meaning-making via various activities. The main findings are encapsulated in three themes: (1) The fun and the function of activities; (2) Reciprocities of care, and (3) The constitution and continuity of (a changing) self. Ongoing engagement with both fun and functional activities offered participants living with different dementias opportunities to connect with others, to offer care and support (as well as receive it), and to maintain a sense of self and identity. Implications are discussed regarding the development and delivery of tailored interventions and support to enable continued engagement in meaningful activities for people with different types of dementia living in the community.},
}

@article {pmid38648449,
year = {2024},
author = {Macoir, J and Tremblay, P and Beaudoin, S and Parent, M and Hudon, C},
title = {Impaired lexical access for unique entities in individuals with subjective cognitive decline.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/23279095.2024.2344636},
pmid = {38648449},
issn = {2327-9109},
abstract = {Subjective cognitive decline (SCD) may serve as an early indicator of Alzheimer's disease (AD). However, accurately quantifying cognitive impairment in SCD is challenging, mainly because existing assessment tools lack sensitivity. This study examined how tasks specifically designed to assess knowledge of famous people, could potentially aid in identifying cognitive impairment in SCD. A total of 60 adults with SCD and 60 healthy controls (HCs) aged 50 to 82 years performed a famous people verbal fluency task and a famous people naming task. In the famous people fluency task, the results showed that the individuals with SCD produced significantly fewer famous names in the total time allowed than the HCs, and this difference was also found in the first and the second time interval. In the famous people naming task, the performance of the SCD group was significantly lower than that of the HC group only in the more recent period of fame. Overall, these results suggest that retrieving the names of famous people was more difficult for people with SCD than for people without cognitive complaints. They also suggest that famous people verbal fluency and naming tasks could be useful in detecting cognitive decline at the preclinical stage of AD.},
}

@article {pmid38648448,
year = {2024},
author = {Tahan, K and Cayrier, A and Baratgin, J and N'kaoua, B},
title = {ZORA robot to assist a caregiver in prospective memory tasks: A preliminary study.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/23279095.2024.2343766},
pmid = {38648448},
issn = {2327-9109},
abstract = {The objective of the present study was to evaluate the interest of an assistance robot to help caregivers manage the activities of daily living of institutionalized elderly people with Alzheimer's disease. Twenty-three institutionalized persons (60% women; average age 89; average MMSE score of 20.8) with Alzheimer Disease (AD) were recruited and invited to participate in prospective memory exercise sessions, conducted either by a caregiver or by a robot (assisted by a caregiver). They were divided into two groups equivalent in age, level of education and MMSE score. In addition, the sessions were recorded in order to compare the interaction behaviors of the 2 groups, using a validated observation grid. The results showed that: 1) prospective memory tasks are better performed when offered by the caregiver; 2) when strong help linked to the recovery index is provided to perform the tasks, the robot or caregiver no longer show significant differences; 3) participants interact more with the caregiver than with the robot. Our results confirm that the use of companion robots is a promising way to help caregivers manage the daily activities of people with Alzheimer's. However, to optimize this assistance, further investigations should be conducted to improve the fluidity of interactions between the patient and the robot.},
}

@article {pmid38648391,
year = {2024},
author = {Hu, C and Li, H and Huang, L and Wang, R and Wang, Z and Ma, R and Chang, B and Li, S and Li, H and Li, G},
title = {Periodontal disease and risk of Alzheimer's disease: A two-sample Mendelian randomization.},
journal = {Brain and behavior},
volume = {14},
number = {4},
pages = {e3486},
doi = {10.1002/brb3.3486},
pmid = {38648391},
issn = {2162-3279},
support = {2022LJ02//Innovative leading talents program of The Affiliated Stomatological Hospital of Southwest Medical University/ ; 2022Z01//Project of Affiliated Stomatological Hospital of Southwest Medical University/ ; 2022ZD015//Program of Southwest Medical University/ ; 2022BS02//Talent Introduction Program of The Affiliated Stomatological Hospital of Southwest Medical University/ ; S21063//Foundation Project of Sichuan Medical Association/ ; 2022-GYF-12//Key Research and Development Program of Luzhou/ ; 2022-SYF-33//Key Research and Development Program of Luzhou/ ; 2022YFS0634//Sichuan Science and Technology Program/ ; 2022YFS0634-C2//Sichuan Science and Technology Program/ ; },
abstract = {BACKGROUND: Evidence from observational studies and clinical trials suggests an association between periodontal disease and Alzheimer's disease (AD). However, the causal relationship between periodontal disease and AD remains to be determined.

METHODS: We obtained periodontal disease data from the FinnGen database and two sets of AD data from the IEU consortium and PGC databases. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between periodontal disease and AD.

RESULTS: The results of the random-effects IVW analysis revealed no evidence of a genetic causal relationship between periodontal disease and AD, regardless of whether the AD data from the IEU consortium or the AD data from the PGC database were utilized. No heterogeneity, multiple effects of levels, or outliers were observed in this study.

CONCLUSIONS: Our findings indicate that there is no causal relationship between periodontal disease and AD at the genetic level.},
}

@article {pmid38648354,
year = {2024},
author = {Zhang, J and Chen, H and Wang, J and Huang, Q and Xu, X and Wang, W and Xu, W and Guan, Y and Liu, J and Wardlaw, JM and Deng, Y and Xie, F and Li, B},
title = {Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13845},
pmid = {38648354},
issn = {1552-5279},
support = {82271441//National Natural Science Foundation of China/ ; 82071962//National Natural Science Foundation of China/ ; 82171473//National Natural Science Foundation of China/ ; 81871388//National Natural Science Foundation of China/ ; 21QA1405800//Shanghai Rising-Star Program/ ; 2022ZD0213800//National Key Research and Development Program of China, Scientific and technological innovation 2030 - "Brain science"/ ; UKDRI - Edin002//UK Dementia Research Institute, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK/ ; DRIEdi17/18//UK Dementia Research Institute, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK/ ; MRC MC_PC_17113//UK Dementia Research Institute, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK/ ; AD.ROW4.35. BRO-D.FID3668413//The Row Fogo Centre for Research into Ageing and the Brain/ ; 16 CVD 05//Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease/ ; },
abstract = {INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images.

METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aβ) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography.

RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aβ and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using [18]F-SynVesT-1 PET. In addition, higher ratios of Aβ in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months.

DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms.

HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.},
}

@article {pmid38648267,
year = {2024},
author = {Salvador, AFM and Abduljawad, N and Kipnis, J},
title = {Meningeal Lymphatics in Central Nervous System Diseases.},
journal = {Annual review of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-neuro-113023-103045},
pmid = {38648267},
issn = {1545-4126},
abstract = {Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.},
}

@article {pmid38648167,
year = {2024},
author = {Warren, HT and Saeger, HN and Tombari, RJ and Chytil, M and Rasmussen, K and Olson, DE},
title = {Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.3c01696},
pmid = {38648167},
issn = {1520-4804},
abstract = {Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.},
}

@article {pmid38648143,
year = {2024},
author = {Bringas, S and Duque, R and Lage, C and Montana, JL},
title = {CLADSI: Deep Continual Learning for Alzheimer's Disease Stage Identification using accelerometer data.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2024.3392354},
pmid = {38648143},
issn = {2168-2208},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that can cause a significant impairment in physical and cognitive functions. Gait disturbances are also reported as a symptom of AD. Previous works have used Convolutional Neural Networks (CNNs) to analyze data provided by motion sensors that monitor Alzheimer's patients. However, these works have not explored continual learning algorithms that allow the CNN to configure itself as it receives new data from these sensors. This work proposes a method aimed at enabling CNNs to learn from a continuous stream of data from motion sensors without having full access to previous data. The CNN identifies the stage of AD from the analysis of data provided by motion sensors. The work includes an experimentation with data captured by accelerometers that monitored the activity of 35 Alzheimer's patients for a week in a daycare center. The CNN achieves an accuracy of 86,94%, 86,48% and 84,37% for 2, 3 and 4 experiences respectively. The proposal provides advantages to working with a continuous stream of data so that the CNN are constantly self-configuring without the intervention of a human. The work can be considered as promising and helpful in finding deep learning solutions in medical cases in which patients are constantly monitored.},
}

@article {pmid38647111,
year = {2024},
author = {Chemparathy, DT and Ray, S and Ochs, C and Ferguson, N and Gawande, DY and Dravid, SM and Callen, S and Sil, S and Buch, S},
title = {Neuropathogenic role of astrocyte-derived extracellular vesicles in HIV-associated neurocognitive disorders.},
journal = {Journal of extracellular vesicles},
volume = {13},
number = {4},
pages = {e12439},
pmid = {38647111},
issn = {2001-3078},
support = {/RG/CSR NIH HHS/United States ; R21AG069541/GF/NIH HHS/United States ; RO1DA050545/GF/NIH HHS/United States ; },
abstract = {Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.},
}

@article {pmid38647048,
year = {2024},
author = {Niess, F and Strasser, B and Hingerl, L and Bader, V and Frese, S and Clarke, WT and Duguid, A and Niess, E and Motyka, S and Krššák, M and Trattnig, S and Scherer, T and Lanzenberger, R and Bogner, W},
title = {Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.},
journal = {Human brain mapping},
volume = {45},
number = {6},
pages = {e26686},
pmid = {38647048},
issn = {1097-0193},
support = {R01EB031787/NH/NIH HHS/United States ; 225924/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non-invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium-labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase-encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non-Cartesian spatial-spectral sampling schemes for whole-brain [2]H FID-MR Spectroscopic Imaging to assess time-resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower-resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6']-[2]H glucose. Time-resolved whole brain [2]H FID-DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density-weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal-to-noise ratios associated with smaller voxels, low-rank denoising of the spatiotemporal data was performed during reconstruction. Sixty-three minutes after oral tracer uptake three-dimensional (3D) CRT-DMI maps featured 19% higher (p = .006) deuterium-labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p = .01) [2]H-Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low-resolution PE-DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM- and WM-dominated areas for [2]H-Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p = .045), while no regional differences were observed for [2]H-Glx concentrations. In this study, we successfully implemented 3D FID-MRSI with fast CRT encoding for dynamic whole-brain DMI at 7 T with 2.5-fold increased spatial resolution compared with conventional whole-brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM- compared with WM-dominated regions, which could not be reproduced using whole-brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non-invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications.},
}

@article {pmid38648023,
year = {2024},
author = {Desai, P and Ng, TKS and Krueger, KR and Wilson, RS and Evans, DA and Rajan, KB},
title = {Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.},
journal = {Psychosomatic medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001317},
pmid = {38648023},
issn = {1534-7796},
abstract = {INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline.

METHODS: This study consists of 1,118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time.

RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition (β = -0.064 (SE = 0.028), p-value = 0.023) and on episodic memory (β = -0.097 (SE = 0.036), p-value = 0.007).

CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce rate of cognitive decline in individuals with high concentrations of NfL.},
}

@article {pmid38647924,
year = {2024},
author = {Wagatsuma, K and Sakata, M and Miwa, K and Hamano, Y and Kawakami, H and Kamitaka, Y and Yamao, T and Miyaji, N and Ishibashi, K and Tago, T and Toyohara, J and Ishii, K},
title = {Phantom and clinical evaluation of the Bayesian penalised likelihood reconstruction algorithm Q.Clear without PSF correction in amyloid PET images.},
journal = {EJNMMI physics},
volume = {11},
number = {1},
pages = {37},
pmid = {38647924},
issn = {2197-7364},
support = {JP20K16747//Japan Society for the Promotion of Science/ ; },
abstract = {PURPOSE: Bayesian penalised likelihood (BPL) reconstruction, which incorporates point-spread-function (PSF) correction, provides higher signal-to-noise ratios and more accurate quantitation than conventional ordered subset expectation maximization (OSEM) reconstruction. However, applying PSF correction to brain PET imaging is controversial due to Gibbs artefacts that manifest as unpredicted cortical uptake enhancement. The present study aimed to validate whether BPL without PSF would be useful for amyloid PET imaging.

METHODS: Images were acquired from Hoffman 3D brain and cylindrical phantoms for phantom study and 71 patients administered with [[18]F]flutemetamol in clinical study using a Discovery MI. All images were reconstructed using OSEM, BPL with PSF correction, and BPL without PSF correction. Count profile, %contrast, recovery coefficients (RCs), and image noise were calculated from the images acquired from the phantoms. Amyloid β deposition in patients was visually assessed by two physicians and quantified based on the standardised uptake value ratio (SUVR).

RESULTS: The overestimated radioactivity in profile curves was eliminated using BPL without PSF correction. The %contrast and image noise decreased with increasing β values in phantom images. Image quality and RCs were better using BPL with, than without PSF correction or OSEM. An optimal β value of 600 was determined for BPL without PSF correction. Visual evaluation almost agreed perfectly (κ = 0.91-0.97), without depending on reconstruction methods. Composite SUVRs did not significantly differ between reconstruction methods.

CONCLUSION: Gibbs artefacts disappeared from phantom images using the BPL without PSF correction. Visual and quantitative evaluation of [[18]F]flutemetamol imaging was independent of the reconstruction method. The BPL without PSF correction could be the standard reconstruction method for amyloid PET imaging, despite being qualitatively inferior to BPL with PSF correction for [[18]F]flutemetamol amyloid PET imaging.},
}

@article {pmid38647433,
year = {2024},
author = {Mousavi, H and Rimaz, M and Zeynizadeh, B},
title = {Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00055},
pmid = {38647433},
issn = {1948-7193},
abstract = {Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2[(G2019S)], hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.},
}

@article {pmid38647399,
year = {2024},
author = {Lin, RR and Jin, LL and Xue, YY and Zhang, ZS and Huang, HF and Chen, DF and Liu, Q and Mao, ZW and Wu, ZY and Tao, QQ},
title = {Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2306675},
doi = {10.1002/advs.202306675},
pmid = {38647399},
issn = {2198-3844},
support = {2021ZD0201103//Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects/ ; 2021ZD0201803//Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects/ ; 2024SSYS0018//Key R&D Program of Zhejiang Province/ ; LBY21H090003//Natural Science Foundation of Zhejiang Province/ ; 2022ZDYF22//Key Science & Technologies R&D Program of Lishui City/ ; },
abstract = {The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.},
}

@article {pmid38647314,
year = {2024},
author = {Moorthy, H and Ramesh, M and Padhi, D and Baruah, P and Govindaraju, T},
title = {Polycatechols inhibit ferroptosis and modulate tau liquid-liquid phase separation to mitigate Alzheimer's disease.},
journal = {Materials horizons},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4mh00023d},
pmid = {38647314},
issn = {2051-6355},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects learning, memory, and cognition. Current treatments targeting amyloid-β (Aβ) and tau have shown limited effectiveness, necessitating further research on the aggregation and toxicity mechanisms. One of these mechanisms involves the liquid-liquid phase separation (LLPS) of tau, contributing to the formation of pathogenic tau aggregates, although their conformational details remain elusive. Another mechanism is ferroptosis, a type of iron-dependent lipid peroxidation-mediated cell death, which has been implicated in AD. There is a lack of therapeutic strategies that simultaneously target amyloid toxicity and ferroptosis. This study aims to explore the potential of polycatechols, PDP and PLDP, consisting of dopamine and L-Dopa, respectively, as multifunctional agents to modulate the pathological nexus between ferroptosis and AD. Polycatechols were found to sequester the labile iron pool (LIP), inhibit Aβ and tau aggregation, scavenge free radicals, protect mitochondria, and prevent ferroptosis, thereby rescuing neuronal cell death. Interestingly, PLDP promotes tau LLPS, and modulates their intermolecular interactions to inhibit the formation of toxic tau aggregates, offering a conceptually innovative approach to tackle tauopathies. This is a first-of-its-kind polymer-based integrative approach that inhibits ferroptosis, counteracts amyloid toxicity, and modulates tau LLPS to mitigate the multifaceted toxicity of AD.},
}

@article {pmid38647197,
year = {2024},
author = {Saadmaan, G and Dalmasso, MC and Ramirez, A and Hiltunen, M and Kemppainen, N and Lehtisalo, J and Mangialasche, F and Ngandu, T and Rinne, J and Soininen, H and Stephen, R and Kivipelto, M and Solomon, A},
title = {Alzheimer's disease genetic risk score and neuroimaging in the FINGER lifestyle trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13843},
pmid = {38647197},
issn = {1552-5279},
support = {804371/ERC_/European Research Council/International ; },
abstract = {INTRODUCTION: We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial.

METHODS: 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N = 126 participants underwent magnetic resonance imaging (MRI), and N = 47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N = 107 and N = 38 had repeated 2-year scans.

RESULTS: The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (β = -0.27, p = 0.001), greater amyloid deposition (β = 0.48, p = 0.001), 2-year decline in hippocampus (β = -0.27, p = 0.01), total gray matter volume (β = -0.25, p = 0.01), and cortical thickness (β = -0.28, p = 0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (β = -0.60, p = 0.03).

DISCUSSION: AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE).

HIGHLIGHTS: First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.},
}

@article {pmid38646816,
year = {2024},
author = {Longo, S and Messi, ML and Wang, ZM and Meeker, W and Delbono, O},
title = {Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {},
number = {},
pages = {},
doi = {10.1002/jcsm.13482},
pmid = {38646816},
issn = {2190-6009},
support = {R01AG071545/NH/NIH HHS/United States ; R01AG80586/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.

METHODS: We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1-12 months).

RESULTS: Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7-8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (P < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (P < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, P < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, P < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5-6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3-4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 μm[2] versus PS19's 1208 ± 94 μm[2], and WT males at 1731 ± 185 μm[2] versus PS19's 1227 ± 116 μm[2]. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 μm[2] versus PS19's 858 ± 62 μm[2], and WT males at 1257 ± 43 μm[2] versus PS19's 1030 ± 55 μm[2]. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline.

CONCLUSIONS: Progressive and accelerated neurogenic sarcopenia may precede and potentially predict cognitive deficits observed in AD.},
}

@article {pmid38646795,
year = {2024},
author = {Maru, K and Singh, A and Jangir, R and Jangir, KK},
title = {Amyloid detection in neurodegenerative diseases using MOFs.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4tb00373j},
pmid = {38646795},
issn = {2050-7518},
abstract = {Neurodegenerative diseases (amyloid diseases such as Alzheimer's and Parkinson's), stemming from protein misfolding and aggregation, encompass a spectrum of disorders with severe systemic implications. Timely detection is pivotal in managing these diseases owing to their significant impact on organ function and high mortality rates. The diverse array of amyloid disorders, spanning localized and systemic manifestations, underscores the complexity of these conditions and highlights the need for advanced detection methods. Traditional approaches have focused on identifying biomarkers using imaging techniques (PET and MRI) or invasive procedures. However, recent efforts have focused on the use of metal-organic frameworks (MOFs), a versatile class of materials known for their unique properties, in revolutionizing amyloid disease detection. The high porosity, customizable structures, and biocompatibility of MOFs enable their integration with biomolecules, laying the groundwork for highly sensitive and specific biosensors. These sensors have been employed using electrochemical and photophysical techniques that target amyloid species under neurodegenerative conditions. The adaptability of MOFs allows for the precise detection and quantification of amyloid proteins, offering potential advancements in early diagnosis and disease management. This review article delves into how MOFs contribute to detecting amyloid diseases by categorizing their uses based on different sensing methods, such as electrochemical (EC), electrochemiluminescence (ECL), fluorescence, Förster resonance energy transfer (FRET), up-conversion luminescence resonance energy transfer (ULRET), and photoelectrochemical (PEC) sensing. The drawbacks of MOF biosensors and the challenges encountered in the field are also briefly explored from our perspective.},
}

@article {pmid38646682,
year = {2024},
author = {Singh, A and Maheshwari, S and Yadav, JP and Varshney, AP and Singh, S and Prajapati, BG},
title = {A Review on Tau Targeting Biomimetics Nano Formulations: Novel Approach for Targeting Alzheimer's Diseases.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249289120240321065936},
pmid = {38646682},
issn = {1875-6166},
abstract = {Central nervous system disorders are prevalent, profoundly debilitating, and poorly managed. Developing innovative treatments for these conditions, including Alzheimer's disease, could significantly improve patients' quality of life and reduce the future economic burden on healthcare systems. However, groundbreaking drugs for central nervous system disorders have been scarce in recent years, highlighting the pressing need for advancements in this field. One significant challenge in the realm of nanotherapeutics is ensuring the precise delivery of drugs to their intended targets due to the complex nature of Alzheimer's disease. Although numerous therapeutic approaches for Alzheimer's have been explored, most drug candidates targeting amyloid-β have failed in clinical trials. Recent research has revealed that tau pathology can occur independently of amyloid-β and is closely correlated with the clinical progression of Alzheimer's symptoms. This discovery suggests that tau could be a promising therapeutic target. One viable approach to managing central nervous system disorders is the administration of nanoparticles to neurons, intending to inhibit tau aggregation by directly targeting p-tau. In Alzheimer's disease, beta-amyloid plaques and neurofibrillary tau tangles hinder neuron transmission and function. The disease also triggers persistent inflammation, compromises the blood-brain barrier, leads to brain shrinkage, and causes neuronal loss. While current medications primarily manage symptoms and slow cognitive decline, there is no cure for Alzheimer's.},
}

@article {pmid38646677,
year = {2024},
author = {Yu, FF and Rathnakar, J and Ryder, B and Hitt, B and Kashmer, OM and Sherry, AD and Vinogradov, E},
title = {Differentiation and characterization of healthy versus pathological tau using chemical exchange saturation transfer.},
journal = {NMR in biomedicine},
volume = {},
number = {},
pages = {e5160},
doi = {10.1002/nbm.5160},
pmid = {38646677},
issn = {1099-1492},
support = {//Texas Alzheimer's Research and Care Consortium/ ; },
abstract = {Neurofibrillary tangles of tau constitute one of the key biological hallmarks of Alzheimer's disease. Currently, the assessment of regional tau accumulation requires intravenous administration of radioactive tracers for PET imaging. A noninvasive MRI-based solution would have significant clinical implications. Herein, we utilized an MRI technique known as chemical exchange saturation transfer (CEST) to determine the imaging signature of tau in both its monomeric and pathologic fibrillated conformations. Three sets of purified recombinant full-length (4R) tau protein were prepared for collection of CEST spectra using a 9.4 T NMR spectrometer at varying temperatures (25, 37, and 42 °C) and RF intensities (0.7, 1.0, 1.5, and 2.2 μT). Monomeric and fibrillated tau were readily distinguished based on their Z-spectrum profiles. Fibrillated tau demonstrated a less prominent peak at 3.5 ppm with additional peaks near 0.5 and 1.5 ppm. No significant differences were identified between fibrillated tau prepared using heparin versus seed-competent tau. In conclusion, monomeric and fibrillated tau can be readily detected and distinguished based on their CEST-derived Z-spectra, pointing to the potential utility of CEST-MRI as a noninvasive biomarker of regional pathologic tau accumulation in the brain. Further testing and validation in vitro and in vivo will be necessary before this can be applied clinically.},
}

@article {pmid38646608,
year = {2024},
author = {Yamada, Y and Shinkawa, K and Kobayashi, M and Nemoto, M and Ota, M and Nemoto, K and Arai, T},
title = {Distinct eye movement patterns to complex scenes in Alzheimer's disease and Lewy body disease.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1333894},
pmid = {38646608},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD), the two most common causes of neurodegenerative dementia with similar clinical manifestations, both show impaired visual attention and altered eye movements. However, prior studies have used structured tasks or restricted stimuli, limiting the insights into how eye movements alter and differ between AD and LBD in daily life.

OBJECTIVE: We aimed to comprehensively characterize eye movements of AD and LBD patients on naturalistic complex scenes with broad categories of objects, which would provide a context closer to real-world free viewing, and to identify disease-specific patterns of altered eye movements.

METHODS: We collected spontaneous viewing behaviors to 200 naturalistic complex scenes from patients with AD or LBD at the prodromal or dementia stage, as well as matched control participants. We then investigated eye movement patterns using a computational visual attention model with high-level image features of object properties and semantic information.

RESULTS: Compared with matched controls, we identified two disease-specific altered patterns of eye movements: diminished visual exploration, which differentially correlates with cognitive impairment in AD and with motor impairment in LBD; and reduced gaze allocation to objects, attributed to a weaker attention bias toward high-level image features in AD and attributed to a greater image-center bias in LBD.

CONCLUSION: Our findings may help differentiate AD and LBD patients and comprehend their real-world visual behaviors to mitigate the widespread impact of impaired visual attention on daily activities.},
}

@article {pmid38646507,
year = {2024},
author = {Zhang, X and Zhu, Z and Huang, Y and Shang, X and O'Brien, TJ and Kwan, P and Ha, J and Wang, W and Liu, S and Zhang, X and Kiburg, K and Bao, Y and Wang, J and Yu, H and He, M and Zhang, L},
title = {Shared genetic aetiology of Alzheimer's disease and age-related macular degeneration by APOC1 and APOE genes.},
journal = {BMJ neurology open},
volume = {6},
number = {1},
pages = {e000570},
pmid = {38646507},
issn = {2632-6140},
abstract = {BACKGROUND: Alzheimer's disease (AD) and age-related macular degeneration (AMD) share similar pathological features, suggesting common genetic aetiologies between the two. Investigating gene associations between AD and AMD may provide useful insights into the underlying pathogenesis and inform integrated prevention and treatment for both diseases.

METHODS: A stratified quantile-quantile (QQ) plot was constructed to detect the pleiotropy among AD and AMD based on genome-wide association studies data from 17 008 patients with AD and 30 178 patients with AMD. A Bayesian conditional false discovery rate-based (cFDR) method was used to identify pleiotropic genes. UK Biobank was used to verify the pleiotropy analysis. Biological network and enrichment analysis were conducted to explain the biological reason for pleiotropy phenomena. A diagnostic test based on gene expression data was used to predict biomarkers for AD and AMD based on pleiotropic genes and their regulators.

RESULTS: Significant pleiotropy was found between AD and AMD (significant leftward shift on QQ plots). APOC1 and APOE were identified as pleiotropic genes for AD-AMD (cFDR <0.01). Network analysis revealed that APOC1 and APOE occupied borderline positions on the gene co-expression networks. Both APOC1 and APOE genes were enriched on the herpes simplex virus 1 infection pathway. Further, machine learning-based diagnostic tests identified that APOC1, APOE (areas under the curve (AUCs) >0.65) and their upstream regulators, especially ZNF131, ADNP2 and HINFP, could be potential biomarkers for both AD and AMD (AUCs >0.8).

CONCLUSION: In this study, we confirmed the genetic pleiotropy between AD and AMD and identified APOC1 and APOE as pleiotropic genes. Further, the integration of multiomics data identified ZNF131, ADNP2 and HINFP as novel diagnostic biomarkers for AD and AMD.},
}

@article {pmid38646460,
year = {2024},
author = {Shaheen, H and Melnik, R and Singh, S and , },
title = {Data-driven Stochastic Model for Quantifying the Interplay Between Amyloid-beta and Calcium Levels in Alzheimer's Disease.},
journal = {Statistical analysis and data mining},
volume = {17},
number = {2},
pages = {},
pmid = {38646460},
issn = {1932-1864},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {The abnormal aggregation of extracellular amyloid-β(Aβ) in senile plaques resulting in calcium Ca+2 dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving Aβ deposition and Ca+2 dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal Aβ accumulation. Moreover, increasing evidence show a feed-forward loop between Aβ and Ca+2 levels, i.e. Aβ disrupts neuronal Ca+2 levels, which in turn affects the formation of Aβ. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between Aβ and Ca+2 using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2-year visits for AD patients, we employ this method to investigate the interplay between Aβ and Ca+2 levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either Aβ metabolism or intracellular Ca+2 homeostasis causes the relative growth rate in both Ca+2 and Aβ, which corresponds to the development of AD. The imbalance of Ca+2 ions causes Aβ disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of Ca+2 ion transportation and deposition. This suggests that altering the Ca+2 balance or the balance between Aβ and Ca+2 by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.},
}

@article {pmid38646161,
year = {2024},
author = {De Waegenaere, S and van den Berg, M and Keliris, GA and Adhikari, MH and Verhoye, M},
title = {Early altered directionality of resting brain network state transitions in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {18},
number = {},
pages = {1379923},
pmid = {38646161},
issn = {1662-5161},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in memory loss and cognitive decline. Synaptic dysfunction is an early hallmark of the disease whose effects on whole-brain functional architecture can be identified using resting-state functional MRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of AD's pathophysiology.

METHODS: Here, we obtained rsfMRI data in the TgF344-AD rat model at the pre- and early-plaque stages. This model recapitulates the major pathological and behavioral hallmarks of AD. We used co-activation pattern (CAP) analysis to investigate if and how the dynamic organization of intrinsic brain functional networks states, undetectable by earlier methods, is altered at these early stages.

RESULTS: We identified and characterized six intrinsic brain states as CAPs, their spatial and temporal features, and the transitions between the different states. At the pre-plaque stage, the TgF344-AD rats showed reduced co-activation of hub regions in the CAPs corresponding to the default mode-like and lateral cortical network. Default mode-like network activity segregated into two distinct brain states, with one state characterized by high co-activation of the basal forebrain. This basal forebrain co-activation was reduced in TgF344-AD animals mainly at the pre-plaque stage. Brain state transition probabilities were altered at the pre-plaque stage between states involving the default mode-like network, lateral cortical network, and basal forebrain regions. Additionally, while the directionality preference in the network-state transitions observed in the wild-type animals at the pre-plaque stage had diminished at the early-plaque stage, TgF344-AD animals continued to show directionality preference at both stages.

DISCUSSION: Our study enhances the understanding of intrinsic brain state dynamics and how they are impacted at the early stages of AD, providing a nuanced characterization of the early, functional impact of the disease's neurodegenerative process.},
}

@article {pmid38645989,
year = {2024},
author = {Peng, Y and Zhou, C},
title = {Network Pharmacology and Molecular Docking Identify the Potential Mechanism and Therapeutic Role of Scutellaria baicalensis in Alzheimer's Disease.},
journal = {Drug design, development and therapy},
volume = {18},
number = {},
pages = {1199-1219},
pmid = {38645989},
issn = {1177-8881},
abstract = {AIM: Scutellaria baicalensis, a traditional Chinese medicinal herb renowned for its anti-inflammatory, antioxidant, and anti-tumor properties, has shown promise in alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Scutellaria baicalensis against Alzheimer's disease remains unclear. In this study, network pharmacology was employed to explore the possible mechanisms by which Scutellaria baicalensis protects against Alzheimer's disease.

METHODS: The active compounds of Scutellaria baicalensis were retrieved from the TCMSP database, and their corresponding targets were identified. Alzheimer's disease-related targets were obtained through searches in the GeneCards and OMIM databases. Cytoscape 3.6.0 software was utilized to construct a regulatory network illustrating the "active ingredient-target" relationships. Subsequently, the target genes affected by Scutellaria baicalensis in the context of Alzheimer's disease were input into the String database to establish a PPI network. GO analysis and KEGG analysis were conducted using the DAVID database to predict the potential pathways associated with these key targets. Following this, the capacity of these active ingredients to bind to core targets was confirmed through molecular docking. In vitro experiments were then carried out for further validation.

RESULTS: A total of 36 active ingredients from Scutellaria baicalensis were screened out, which corresponded to 365 targets. Molecular docking results demonstrated the robust binding abilities of Baicalein, Wogonin, and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to key target proteins (SRC, PIK3R1, and STAT3). In vitro experiments showed that the active components of Scutellaria baicalensis can inhibit STAT3 expression by downregulating the PIK3R1/SRC pathway in Neuro 2A cells.

CONCLUSION: In summary, these findings collectively suggest that Scutellaria baicalensis holds promise as a viable treatment option for Alzheimer's disease.},
}

@article {pmid38645778,
year = {2024},
author = {Varinthra, P and Anwar, SNMN and Shih, SC and Liu, IY},
title = {The role of the GABAergic system on insomnia.},
journal = {Tzu chi medical journal},
volume = {36},
number = {2},
pages = {103-109},
pmid = {38645778},
issn = {2223-8956},
abstract = {Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABAA and GABAB receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines.},
}

@article {pmid38645748,
year = {2024},
author = {Yap, LE and Hunt, JE and Turner, RS},
title = {Aging as a target for the prevention and treatment of Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1376104},
pmid = {38645748},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD.},
}

@article {pmid38645691,
year = {2024},
author = {Eugenín, J and Richerson, GB},
title = {Editorial: Alternative and expanding views on central respiratory chemoreception in health and disease.},
journal = {Frontiers in physiology},
volume = {15},
number = {},
pages = {1403768},
pmid = {38645691},
issn = {1664-042X},
}

@article {pmid38645663,
year = {2024},
author = {Sun, J and Xie, Z and Sun, Y and Shen, A and Li, R and Yuan, X and Lu, B and Li, Y},
title = {Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.},
journal = {MedComm},
volume = {5},
number = {5},
pages = {e532},
pmid = {38645663},
issn = {2688-2663},
abstract = {Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid β-protein (Aβ) indicators. The findings of this research reveal that individuals displaying reduced Aβ1-42/Aβ-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aβ1-42/Aβ-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.},
}

@article {pmid38645585,
year = {2024},
author = {Lee, K and Park, TY and Lee, W and Kim, H},
title = {A review of functional neuromodulation in humans using low-intensity transcranial focused ultrasound.},
journal = {Biomedical engineering letters},
volume = {14},
number = {3},
pages = {407-438},
pmid = {38645585},
issn = {2093-985X},
abstract = {Transcranial ultrasonic neuromodulation is a rapidly burgeoning field where low-intensity transcranial focused ultrasound (tFUS), with exquisite spatial resolution and deep tissue penetration, is used to non-invasively activate or suppress neural activity in specific brain regions. Over the past decade, there has been a rapid increase of tFUS neuromodulation studies in healthy humans and subjects with central nervous system (CNS) disease conditions, including a recent surge of clinical investigations in patients. This narrative review summarized the findings of human neuromodulation studies using either tFUS or unfocused transcranial ultrasound (TUS) reported from 2013 to 2023. The studies were categorized into two separate sections: healthy human research and clinical studies. A total of 42 healthy human investigations were reviewed as grouped by targeted brain regions, including various cortical, subcortical, and deep brain areas including the thalamus. For clinical research, a total of 22 articles were reviewed for each studied CNS disease condition, including chronic pain, disorder of consciousness, Alzheimer's disease, Parkinson's disease, depression, schizophrenia, anxiety disorders, substance use disorder, drug-resistant epilepsy, and stroke. Detailed information on subjects/cohorts, target brain regions, sonication parameters, outcome readouts, and stimulatory efficacies were tabulated for each study. In later sections, considerations for planning tFUS neuromodulation in humans were also concisely discussed. With an excellent safety profile to date, the rapid growth of human tFUS research underscores the increasing interest and recognition of its significant potential in the field of non-invasive brain stimulation (NIBS), offering theranostic potential for neurological and psychiatric disease conditions and neuroscientific tools for functional brain mapping.},
}

@article {pmid38645567,
year = {2024},
author = {Ji, X and Walczak, P and Boltze, J},
title = {Mitigating the impact of mechanisms causing neuronal degeneration.},
journal = {Neuroprotection},
volume = {2},
number = {1},
pages = {1-3},
pmid = {38645567},
issn = {2770-730X},
}

@article {pmid38645276,
year = {2024},
author = {Okafor, M and Champomier, O and Raibaut, L and Ozkan, S and El Kholti, N and Ory, S and Chasserot-Golaz, S and Gasman, S and Hureau, C and Faller, P and Vitale, N},
title = {Restoring cellular copper homeostasis in Alzheimer disease: a novel peptide shuttle is internalized by an ATP-dependent endocytosis pathway involving Rab5- and Rab14-endosomes.},
journal = {Frontiers in molecular biosciences},
volume = {11},
number = {},
pages = {1355963},
pmid = {38645276},
issn = {2296-889X},
abstract = {CPPs, or Cell-Penetrating Peptides, offer invaluable utility in disease treatment due to their ability to transport various therapeutic molecules across cellular membranes. Their unique characteristics, such as biocompatibility and low immunogenicity, make them ideal candidates for delivering drugs, genes, or imaging agents directly into cells. This targeted delivery enhances treatment efficacy while minimizing systemic side effects. CPPs exhibit versatility, crossing biological barriers and reaching intracellular targets that conventional drugs struggle to access. This capability holds promise in treating a wide array of diseases, including cancer, neurodegenerative disorders, and infectious diseases, offering a potent avenue for innovative and targeted therapies, yet their precise mechanism of cell entry is far from being fully understood. In order to correct Cu dysregulation found in various pathologies such as Alzheimer disease, we have recently conceived a peptide Cu(II) shuttle, based on the αR5W4 CPP, which, when bound to Cu(II), is able to readily enter a neurosecretory cell model, and release bioavailable Cu in cells. Furthermore, this shuttle has the capacity to protect cells in culture against oxidative stress-induced damage which occurs when Cu binds to the Aβ peptide. The aim of this study was therefore to characterize the cell entry route used by this shuttle and determine in which compartment Cu is released. Pharmacological treatments, siRNA silencing and colocalization experiments with GFP-Rab fusion proteins, indicate that the shuttle is internalized by an ATP-dependent endocytosis pathway involving both Rab5 and Rab14 endosomes route and suggest an early release of Cu from the shuttle.},
}

@article {pmid38645255,
year = {2024},
author = {Sanati, M and Bayat, S and Panahi, MM and Khodadadi, A and Rezaee, S and Ghasimi, M and Besharat, S and Fooladi, ZM and Dooghaee, MA and Taheri, MS and Dickerson, BC and Goldberg, A and Rezaii, N},
title = {Impaired language in Alzheimer's disease: A comparison between English and Persian implicates content-word frequency rather than the noun-verb distinction.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.09.24305534},
pmid = {38645255},
abstract = {This study challenges the conventional psycholinguistic view that the distinction between nouns and verbs is pivotal in understanding language impairments in neurological disorders. Traditional views link frontal brain region damage with verb processing deficits and posterior temporoparietal damage with noun difficulties. However, this perspective is contested by findings from patients with Alzheimer's disease (pwAD), who show impairments in both word classes despite their typical temporoparietal atrophy. Notably, pwAD tend to use semantically lighter verbs in their speech than healthy individuals. By examining English-speaking pwAD and comparing them with Persian-speaking pwAD, this research aims to demonstrate that language impairments in Alzheimer's disease (AD) stem from the distributional properties of words within a language rather than distinct neural processing networks for nouns and verbs. We propose that the primary deficit in AD language production is an overreliance on high-frequency words. English has a set of particularly high-frequency verbs that surpass most nouns in usage frequency. Since pwAD tend to use high-frequency words, the byproduct of this word distribution in the English language would be an over-usage of high-frequency verbs. In contrast, Persian features complex verbs with an overall distribution lacking extremely high-frequency verbs like those found in English. As a result, we hypothesize that Persian-speaking pwAD would not have a bias toward the overuse of high-frequency verbs. We analyzed language samples from 95 English-speaking pwAD and 91 healthy controls, along with 27 Persian-speaking pwAD and 27 healthy controls. Employing uniform automated natural language processing methods, we measured the usage rates of nouns, verbs, and word frequencies across both cohorts. Our findings showed that English-speaking pwAD use higher-frequency verbs than healthy individuals, a pattern not mirrored by Persian-speaking pwAD. Crucially, we found a significant interaction between the frequencies of verbs used by English and Persian speakers with and without AD. Moreover, regression models that treated noun and verb frequencies as separate predictors did not outperform models that considered overall word frequency alone in classifying AD. In conclusion, this study suggests that language abnormalities among English-speaking pwAD reflect the unique distributional properties of words in English rather than a universal noun-verb class distinction. Beyond offering a new understanding of language abnormalities in AD, the study highlights the critical need for further investigation across diverse languages to deepen our insight into the mechanisms of language impairments in neurological disorders.},
}

@article {pmid38645244,
year = {2024},
author = {Alcantara-Gonzalez, D and Kennedy, M and Criscuolo, C and Botterill, J and Scharfman, HE},
title = {Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.02.09.579729},
pmid = {38645244},
abstract = {INTRODUCTION: Hyperexcitability in Alzheimer's disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We hypothesized that mossy cells (MCs), regulators of DG excitability, contribute to early hyperexcitability in AD. Indeed, MCs generate hyperexcitability in epilepsy.

METHODS: Using the Tg2576 model and WT mice (∼1month-old), we compared MCs electrophysiologically, assessed c-Fos activity marker, Aβ expression and mice performance in a hippocampal-dependent memory task.

RESULTS: Tg2576 MCs exhibit increased spontaneous excitatory events and decreased inhibitory currents, increasing the charge transfer excitation/inhibition ratio. Tg2576 MC intrinsic excitability was enhanced, and showed higher c-Fos, intracellular Aβ expression, and axon sprouting. Granule cells only showed changes in synaptic properties, without intrinsic changes. The effects occurred before a memory task is affected.

DISCUSSION: Early electrophysiological and morphological alterations in Tg2576 MCs are consistent with enhanced excitability, suggesting an early role in DG hyperexcitability and AD pathophysiology.

HIGHLIGHTS: ∘ MCs from 1 month-old Tg2576 mice had increased spontaneous excitatory synaptic input. ∘ Tg2576 MCs had reduced spontaneous inhibitory synaptic input. ∘ Several intrinsic properties were abnormal in Tg2576 MCs. ∘ Tg2576 GCs had enhanced synaptic excitation but no changes in intrinsic properties. ∘ Tg2576 MCs exhibited high c-Fos expression, soluble Aβ and axonal sprouting.},
}

@article {pmid38645234,
year = {2024},
author = {Heavener, K and Kabra, K and Yidenk, M and Bradshaw, E},
title = {IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.08.588607},
pmid = {38645234},
abstract = {The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer's disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-driven IL1β and IL18 production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.},
}

@article {pmid38645146,
year = {2024},
author = {Dando, O and McGeachan, R and McQueen, J and Baxter, P and Rockley, N and McAlister, H and Prasad, A and He, X and King, D and Rose, J and Jones, PB and Tulloch, J and Chandran, S and Smith, C and Hardingham, G and Spires-Jones, TL},
title = {Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10+16 mutation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.09.24305501},
pmid = {38645146},
abstract = {Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau cortex as well as a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau caused by the MAPT 10+16 mutation.},
}