bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drosophila eye model to study the role of NAT9 in Alzheimer’s Disease related Dementia (ADRD)
Authors: Deshpande Prajakta , Snider Emily , Chimata Anuradha Venkatakrishnan , Kango‐Singh Madhuri , Singh Amit 
Published: June 2023

AbstractBackgroundOne of the hallmarks of Alzheimer’s disease (AD), an age‐related progressive form of dementia, is accumulation of the amyloid beta (Aβ42) plaque, which manifests in decline in cognitive function. The accumulation of these Aβ42 plaques trigger the hyperphosphorylation of tau, a microtubule associated protein, which results in the intracellular accumulation of neurofibrillary tangles (NFTs) due to destabilization of microtubules.MethodWe employed the Gal4/UAS system in Drosophila melanogaster to misexpress human Aβ42 within the developing fly retina, exhibiting AD‐like neuropathology. Accumulation of Aβ42 plaque(s) triggers the aberrant activation of signaling pathways like the JNK pathway resulting in neuronal cell death by unknown mechanism(s). Using candidate based forward genetic screening, we identified N‐acetyltransferase 9 (NAT9) as one of the genetic modifiers of GMR>Aβ42 reduced eye phenotype. Previously NAT9 has been shown to stabilize microtubules by acetylation of tubulins, thereby inhibiting JNK signaling. This study aims to understand the role of NAT9 in Aβ42‐mediated neurodegeneration.ResultThe gain‐of‐function of NAT9 rescues Aβ42‐mediated neurodegeneration whereas loss‐of‐function of NAT9 enhances Aβ42‐mediated neurodegeneration. We have also found that the gain‐of‐function of human NAT9 also suppresses Aβ42‐mediated neurodegeneration suggesting the functional conservation. Interestingly, mutated NAT9 in the acetyl‐ CoA binding site shows similar phenotype as gain‐of‐function of NAT9 suggesting its function is independent of acetylation activity. Moreover, the eye antennal imaginal discs of loss‐of‐function of NAT9 in GMR>Aβ42 background shows the activation of JNK pathway by increased pJNK levels.ConclusionOur data suggests that NAT9 downregulates JNK signaling pathway which can ameliorate Aβ42‐mediated neurodegeneration.
Radiomics deep learning application to differentiate mild cognitive impairment patients (MCI) from healthy control (HC)
Authors: Cheung Eva YW 
Published: June 2023

AbstractBackgroundThis study aimed to build a radiomics based model using structural MRI to differentiate patients with mild cognitive impairment (MCI) from healthy control (HC).Methods202 healthy controls and 136 MCI patients were downloaded from a publicly available database, the ADNI database. The MPRAGE T1W MRI were re‐oriented, segmented and normalized to the whole brain mask template using DPARSF software. 107 radiomics features were extracted within the whole brain using 3D slicer software with pyradiomics extension. Both the MCI and HC groups were divided into a training group and a validation group. To minimize the chance of overfitting, out‐of‐bag predictions were performed. A random forest model was built using training set, and validated by the validation set by R software.ResultsThe receiver operating characteristics (ROC) curve showed that the average class accuracy achieved 95.7% and overall accuracy was 96.2%. The area under the curve (AUC) was 0.868.ConclusionThe radiomics deep learning model can accurately differentiate MCI from HC. The application can be fully automatic and it is practical in applying for MCI screening.
Correlates of neuroimaging biomarkers in a middle‐age racially diverse cohort: Updates from the association between cardiovascular risk and preclinical Alzheimer’s Disease pathology (ASCEND) study
Authors: Misiura Maria , Munkombwe Chinkuli , Verble Danielle D , Likos Kelly D. S. , Igwe Kay C. , Zetterberg Henrik , Kumar Veena , Brickman Adam M. , Hu William T. , Dotson Vonetta M , Wharton Whitney 
Published: June 2023

AbstractBackgroundBlack individuals (BIs) are at an increased risk of Alzheimer’s disease (AD) than white individuals (WIs), which is partially explained by increased prevalence of vascular risk, in conjunction with structural inequities including healthcare. Studies suggest that neuroimaging and CSF AD biomarkers may differ across race. We previously identified disparate relationships between brain activity within the frontal and parietal lobes and CSF AD biomarkers. We include analysis of structural and functional neuroimaging in a racially diverse, middle‐aged cohort with an AD family history. We aimed to identify relevant neuroimaging correlates of vascular health and AD, and how relationships may vary according to race.MethodsWe analyzed data from 76 individuals (29 BIs, 47 WIs). Neuroimaging measures included functional connectivity from functional resting state magnetic resonance imaging (rs‐fMRI) between fronto‐striatal regions (putamen, middle frontal gyrus, superior frontal gyrus), regions of the default mode network (hippocampus, parrahippocampal gyrus (PHG), ventromedial prefrontal cortex, inferior parietal lobule, temporal pole), structural neuroimaging (hippocampal volumes), and regional white matter hyperintensity volumes (frontal, temporal, parietal, occipital, cerebellar volumes). AD biomarkers included CSF phospho‐tau, total tau, & AB42. We included a race X CSF biomarker interaction term in our linear models.ResultsWe identified a race X tau and race X AB42 interaction term for connectivity measures between the middle frontal and superior frontal gyri and the putamen such that as biomarker burden increased, connectivity between these regions decreased within BIs. PHG to temporal pole connectivity also exhibited these same relationships to CSF tau and AB42. Hippocampal volumes did not exhibit relationships to AD biomarkers. We identified a significant race X CSF Ab42 interaction term such that increased AD CSF biomarker burden was related to increased WMH volume in the temporal and parietal lobe.ConclusionWe extend previous work in rs‐fMRI of AD to a middle‐aged cohort, supporting neuroimaging and CSF biomarker relationships may differ by race. Front‐striatal connectivity may be a clinically relevant biomarker in mid‐life studies of AD, sensitive to CSF AD biomarker levels. Results support previous consensus that functional and WM measures are more sensitive to early AD pathology and extends this knowledge to BIs.
Association between default‐mode network and medial temporal lobe functional connectivity and episodic memory in late middle‐aged and older patients with obstructive sleep apnea
Authors: Martinez Guillermo E. , Daneault Véronique , Martineau‐Dussault Marie‐Ève , André Claire , Baril Andree‐Ann , Gagnon Katia , Montplaisir Jacques , Carrier Julie , Gosselin Nadia 
Published: June 2023

AbstractBackgroundObstructive sleep apnea (OSA) is associated with risk of cognitive decline in older adults. Our group previously observed that more severe OSA was associated with lower functional connectivity between the hippocampus and multiple regions of the default‐mode network (DMN) and the limbic system. However, whether these lower functional connectivity is associated with memory impairment is unknown. Here, we tested the hypothesis that lower functional connectivity previously associated with OSA severity could be related to worse episodic memory performance in late middle‐aged and older adults.MethodWe included 37 participants with moderate‐to‐severe OSA (apnea‐hypopnea index [AHI] : 33±18 events/h, 7 females, 67.2±7 years old, 15.2±3.4 years of education, 15 with mild cognitive impairment [MCI]) and 59 control participants (AHI: 5.8±3.7 events/h, 18 females, 65±6.9 years old, 15.5±3.3 years of education, 25 MCI) matched for age, sex, education and cognitive diagnosis. They underwent a neuropsychological assessment, a full‐night of polysomnography and a resting‐state functional magnetic resonance imaging. A composite score for episodic memory performance was calculated with the Rey Auditory Verbal Learning Test (trials 1 to 5, immediate and delayed recalls) and the Brief Visuospatial Memory Test‐revised (total and delayed recalls). CONN toolbox was used to perform multiple regression analyses between resting‐state functional connectivity and memory performance for each group separately. All analyses were controlled for age, sex and education, and corrected for false‐discovery rate.ResultIn OSA participants, lower functional connectivity between the medial prefrontal cortex and the hippocampus was associated with better episodic memory performance (ps<0.05), while a trend was observed in the control group (p = 0.05). Lower functional connectivity between the lateral parietal cortex and the parahippocampus was also associated with better episodic memory performance in the OSA participants (p = 0.03).ConclusionContrary to our hypothesis, the lower resting‐state functional connectivity observed in OSA participants was associated with better episodic memory performance. This pattern of functional connectivity between the DMN and the limbic system negatively associated with episodic memory performance was previously reported in healthy older adults and patients with preclinical Alzheimer’s disease. Whether these functional connectivity patterns predict further cognitive decline in untreated OSA patients needs to be investigated.
Plasma metabolomics indexes time to clinical dementia in autosomal dominant Alzheimer’s disease mutation carriers
Authors: Gross Thomas J , Cheema Amrita K , Fiandaca Massimo S , Federoff Howard J , Ringman John M , Mapstone Mark 
Published: June 2023

AbstractBackgroundMetabolic dysregulation has been implicated in the pathobiology of Alzheimer’s disease (AD), including familial autosomal dominant AD (ADAD). Recent metabolic neuroimaging of preclinical ADAD mutation carriers has suggested that levels of the reactive glial marker myo‐inositol increase with proximity to expected age at dementia onset. It remains unclear, however, if similar metabolic change related to anticipated phenoconversion can be observed at network‐scale in the peripheral plasma metabolome of ADAD mutation carriers.MethodWe collected peripheral blood plasma from ADAD mutation carriers with and without objective cognitive decline (ncarrier = 55) who participated in a longitudinal kindred study. We used untargeted liquid chromatography‐ mass spectrometry (LC‐MS) metabolomics to infer putative metabolic pathway and protein disruptions associated with impending dementia diagnosis at whole‐genome scale. Spearman 𝝆 correlation coefficients were determined for each identified mass feature in relation to clinical, family‐wise estimated years to diagnosis prior to the submission of these summary statistics to metabolomic modeling.ResultA total of 91 LC‐MS mass features were significantly correlated with estimated years to dementia onset, nominal p’s < .05. Pathway‐based, genome‐scale metabolomic modeling analysis revealed a de novo plasma metabolomic activity network composed of interconnected lipid and small, polar metabolite hubs. These same correlations were also submitted to gene‐inferring, whole‐genome metabolomic modeling using PIUmet. Intriguingly, mRNA expression of prioritized genes was not limited to the brain and involved multiple peripheral tissues. In the CNS itself, however, genes prioritized by PIUMet metabolomic modeling frequently demonstrated expression in glia.ConclusionConsistent with prior metabolic findings in ADAD mutation carriers, network alterations to the peripheral plasma metabolome correspond with increasing proximity to expected age of dementia onset. Because neuroinflammation has been previously described as an immunometabolic process in pathological aging, emerging metabolic network disintegrity in ADAD may index reactive glial pathobiology previously suggested by prior metabolic investigations of this population. These perturbed networks inferred from participant blood plasma suggest targetable CNS‐peripheral metabolic dyshomeostases which otherwise precipitate pathobiological “failures of compensation” and concomitant cognitive decline in carriers of Mendelian ADAD mutations.
Decreased/increased beta/alpha functional connectivity in pathological and healthy aging. A dual pattern of brain dynamics revealed by magnetoencephalography
Authors: Chino Brenda N , Cuesta Pablo , Pacios Javier , Torres Lucia , Doval Sandra , Dolado Alberto Marcos , Fernández Ricardo Bruña , Maestú Fernando 
Published: June 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive neurodegenerative disorder that develops unnoticed during several years prior to the onset of clinical symptomatology. The deterioration of delayed recall is one of the most significant predictive factors to define the progression of Mild Cognitive Impairment (MCI) to AD, and it has a strong relationship with medial temporal dysfunction. Identifying a reliable measurement of brain health and cognitive function is essential to mitigate the side effects of cognitive decline by promoting early intervention. The purpose of this study was to explore, in MCI patients and ‐healthy participants, how memory loss modifies the functional integrity of resting‐state brain activity, as measured with MEG.Method118 MCI (aged from 58 to 87) and 261 healthy (aged from 41 to 82) participants were recruited from the Hospital Universitario San Carlos (Madrid, Spain). They all underwent an extensive neuropsychological evaluation, MRI, and MEG recordings.Results
Delayed recall (DR). The correlation analysis between functional connectivity (FC) and DR score showed a negative correlation, (rho = ‐0.208, p <0.001), between beta‐band FC and LTM performance in the occipital region, so that participants with higher FC showed lower memory performance. Furthermore, the correlation between LTM and beta FC‐st remained significant when looking at the MCI (rho = ‐0.236, p < 0.01) and healthy groups separately (rho = ‐0.207, p< 0.001). Short Term Memory (STM). The STM was found to be associated, (rho = 0.175, p < 0.001), with increased occipital alpha‐band FC, indicating that those participants with the higher FC, the higher the memory performance. Interestingly, a separate analysis of both groups revealed that this correlation was present only in the healthy group (rho = 0.141, p <0.02).ConclusionA dual pattern of a respective decreased/increased beta/alpha FC in the occipital brain region appeared to be associated with memory performance in healthy and pathological aging.
Progressive electrophysiological changes in a mouse prion model of terminal neurodegenerative disease
Authors: Bowden Jessica Elisabeth Kathleen , Riddell John S , Phillips Keith G , Tobin Andrew B , Bradley Sophie J 
Published: June 2023

AbstractBackgroundIntracerebral injection of prion brain homogenate into mice recapitulates several features of Alzheimer’s disease, including memory deficits, progressive neuronal loss and terminal disease. Pharmacological interventions can preserve species‐specific behaviour and extend survival, but whether treatment can modulate cognition‐related brain activity is unclear. The purpose of this study is to define electrophysiological changes in the murine prion model, and inform future studies of the effects of interventions on neural activity.MethodMice inoculated with either Rocky Mountain Laboratories prion (n = 5) or control brain homogenate (n = 3) underwent surgery to implant seven skull screw recording electrodes (Figure 1). From 4 weeks post‐inoculation, weekly recordings were made by attaching a wireless transmitter to the implant. Prion mice were humanely killed 9‐12 weeks post‐inoculation once they exhibited clinical signs of disease. Brains were retained for histological analysis.Decibel power spectra were generated from recordings using a 2.5 s sliding window with 50% overlap. Theta peak frequency and area under the curve measures were extracted (Figure 2). Effects of prion and week post‐inoculation on these features were determined using mixed effects analyses.ResultPrion mice exhibited a progressive reduction in peak theta frequency, which differed from control mice at 8‐ and 9‐weeks post‐inoculation. The mean ± 95% confidence interval for control mice at 8 weeks post‐inoculation was 8.9±0.4 Hz, compared to 7.0±0.7 Hz for prion mice (Figure 2). The extent of slowing at 9 weeks post‐inoculation correlated with survival outcomes: clinical signs occurred 10‐25 days earlier in mice with a peak theta frequency <6.5 Hz. Delta power showed a week by inoculation interaction, declining in control mice up to 6 weeks post‐inoculation and increasing in the latter weeks of prion infection.ConclusionWe have shown that slowing of electrical activity, a common feature of progressive neurodegenerative diseases, occurs in the murine prion model and correlates with survival. This further validates using the prion model to investigate interventions aimed at treating Alzheimer’s disease and related dementias. Elevated delta power is associated with neurodegenerative disease and muscarinic receptor antagonism, further demonstrating the suitability of the prion model to test pro‐muscarinic interventions in neurodegenerative disease.
Lesion‐network mapping for post‐stroke cognitive impairment
Authors: Lim Jae‐Sung , Lee Jae‐Joong , Kim Geon Ha , Woo Choong‐Wan , Bae Hee‐Joon 
Published: June 2023

AbstractBackgroundTo overcome difficulty obtaining functional neuroimaging data directly from acute stroke patients, researchers have developed a new mapping approach called the “indirect lesion‐network mapping.” This mapping approach uses a priori network information obtained from normative samples to account for brain areas functionally connected to patients’ local lesions. This new method has successfully mapped some peculiar stroke symptoms, such as aphasia and post‐stroke pain. However, it remains unclear whether this method can produce sensible mapping results for the post‐stroke cognitive impairment of community samples.MethodA total of 1,431 patients were enrolled from two university hospitals. They underwent a comprehensive neuropsychological test within one year post‐stroke. We used the Verbal Learning Test to examine memory performance and the trail‐making test‐A and digit symbol coding task to assess the speed of processing. We classified the patients into two groups— cognitively‐impaired (CI) (< ‐2.0 standard deviation) and cognitively‐unimpaired (CU) (> ‐1.0 SD)—based on the task performance. We calculated the lesion‐affected networks based on patients’ stroke lesions combined with the normative functional network data from the Human Connectome Project‐Aging cohort, n = 687. Then, we obtained and compared the lesion network maps for patients with versus without cognitive impairment.ResultA total of 348 patients showed impairment in the memory task, while 247 patients demonstrated impairment in the speed‐of‐processing task. For both tasks, the conventional lesion‐network mapping approach produced highly similar results between the CI versus CU groups—both groups were localized to the major hubs of the large‐scale functional networks, such as mid‐cingulate and insular cortices. However, the mapping results became more sensible when we contrasted the lesion‐network maps between the CI versus CU groups. For example, the memory impairment was localized to the functional network including the left medial and anterior temporal, inferior and dorsolateral frontal cortices, whereas the speed‐of‐processing impairment was localized to the network including both occipital and anterior temporal cortices.ConclusionWe suggest that some additional analysis steps to the conventional lesion‐network mapping, including the contrast analysis, can help improve the specificity and sensitivity of the results when targeting the stroke‐induced cognitive impairment of community samples.
Four‐year cognitive decline in mild cognitive impairment patients with distinct baseline neuroanatomical atrophy profiles: A MEMENTO and QyScore® study
Authors: Gordon Elizabeth , Cavedo Enrica , Santos Clarisse Longo dos , Samper‐González Jorge , Schwarz Adam J. ,   the MEMENTO Study Group
Published: June 2023

AbstractBackgroundNeuroanatomical atrophy profile is increasingly recognised as a valuable characterisation in mild cognitive impairment (MCI) individuals and may provide prognostic information about cognitive decline.Method1153 MCI participants from the MEMENTO memory clinic study with 48‐month longitudinal follow‐up were included (mean (sd) Age = 70.6 (8.2), 60% female, CDR‐SB = 0.63 (0.72)). QyScore® volumetric quantification was applied to baseline 3DT1 images and four recognized neuroanatomical subtypes defined based on regional atrophy with respect to an internal normative database (z←1.64) [1,2]: no/minimal atrophy [N‐] (n = 1,012), limbic predominant: LP (n = 37), hippocampal sparing: HS (n = 84) and combined hippocampal and cortical atrophy [typical/diffuse: TD] (n = 20). 145 participants were amyloid positive (A+) via CSF or PET (Age = 73.7 (5.9): 47% female: N‐ = 114, LP = 8, HS = 21 and TD = 2). All participants underwent cognitive and functional assessments at baseline and 48 months, including mini‐mental state examination (MMSE), clinical dementia rating (CDR), Free and Cued Selective Reminding Test (FCRST) and Instrumental Activities of Daily Living (IADL) scale. Linear regression analysis (correcting for age, sex and baseline performance) investigated the relationship between baseline neuroanatomical subtype and subsequent 4‐year cognitive decline. Bonferroni correction was applied.ResultAt month 48, all subtypes demonstrated significant decline across memory, orientation, and executive function. Severity of decline varied across subscales and subtype and was particularly marked in A+ LP individuals (Figure 1). IADL remained stable for the N‐ and TD subgroups. 143 participants converted to dementia [102 = N‐, 18 = LP, 15 = HS, and 8 = TD subtypes, representing 10%, 49%, 18% and 40% of the total N‐, LP, HS and TD atrophy subtypes respectively]. HS and N‐ individuals also demonstrated the least decline across all domains and did not significantly differ on any tests. LP atrophy subtype demonstrated the greatest decline across all cognitive domains as well as global CDR and IADL (p<0.001 compared with N‐ and HS subtypes). Similarly, TD phenotypes showed significant decline across multiple cognitive subscales compared with N‐ and HS subtypes (p<0.001) particularly for orientation and global CDR.ConclusionEarly atrophy profiles in MCI populations can provide insights into the domains and severity of future patient progression over 4 years.[1] Planche et al., (2020)[2] Schwarz et al., (AAIC2022)