bluuebunny/crossref_metadata_2025 huggingface dataset:
Dementia risk‐stratification in a large, decentralized cohort of aging individuals with subjective cognitive complaints from the INTUITION brain health study
Authors: Gabelle Audrey , Butler P. Monroe , Saha‐Chaudhuri Paramita , Brown Roland , Hobbs Matt , Becker Andrew , Bianchi Matt , Lenyoun Hanson , Hughes Richard , Belachew Shibeshih ,   Intuition Scientific Committee
Published: December 2023

Background

Subjective cognitive complaints (SCC) signal risk of objective cognitive decline. To better understand the bio‐behavioral factors that signal cognitive trajectories at‐risk for the earliest stages of Alzheimer’ disease, there is a need for well‐phenotyped large‐scale population‐based cohorts with longitudinal assessments.

Method

From the INTUITION decentralized observational brain health study (NCT0505895), using app‐collected self‐report data, we compared the demographic, clinical, and neuropsychological profiles of 2045 SCC versus 4090 age‐ and education‐matched cognitively normal (CN) participants. The SCC cohort was defined by age (> = 50 years) and presence of significant cognitive concerns based on total scores> = 4 on the 14‐item Cognitive Function Instrument (CFI‐14). Using customized assessments from Cambridge Cognition, Pattern Recognition Memory (PRM), Paired Associates Learning (PAL), Spatial Working Memory (SWM), and Match‐to‐Sample (MTS) tests were performed. SCC participants were stratified and compared by presence or absence of dementia risk factors (first‐degree family history of dementia (FH+/FH‐) or 2+ cardiovascular risk factors (CVRF2+/CVRF2‐)).

Result

Cognitive and neuropsychiatric symptom‐burden were greater among the SCC cohort compared to CN participants (e.g., E‐Cog‐12: 1.8(0.5) vs 1.2(0.3), pathological PHQ2 (Total> = 3): 14% vs 2.7%, pathological GAD‐2(Total> = 3): 11.8% vs 1.9%, respectively p<0.001). Lifestyle factors differed, with SCC participants reporting lower level of physical activity, higher substance use and impaired sleep, relative to CN. Among SCC participants the prevalence of CVRF2+ and FH+ were 53.2% and 37.8%, respectively; and 43% (CVRF2+) and 33.5% (FH+) among CN. Among SCC, individuals with CVRF2+ were more likely to be older, male, and with higher rates of anxiety/depression symptoms. Mean total CFI‐14 scores were similar between FH+/FH‐ or CVRF2+/CVRF2‐, but item‐level CFI profiles differed (e.g., word‐finding complaints in FH+/CVRF2+). SCC scored lower on key CANTAB outcomes (e.g., PAL/PRM) evaluated compared to CN. Both CVRF2+ and FH+ participants with SCC performed worse on cognitive measures of learning (SWM) and attention (MTS) compared to CVRF2‐ and FH‐ respectively.

Conclusion

In a large, decentralized cohort, SCC was associated with higher burden of modifiable and non‐modifiable risk factors. First‐degree family history of dementia and cardiovascular disease, when coupled with SCC, revealed more severe measurable objective cognitive deficits. Future work will assess individual longitudinal cognitive trajectories.
GRADUATE I AND II: Factors that may influence participant response to subcutaneous gantenerumab
Authors: Thanasopoulou Angeliki , Lane Christopher , Delmar Paul , Voyle Nicola , Huang Zhiyue , Schwab Dietmar , Fox Nick C , Smith Janice , Doody Rachelle S. ,   for the GRADUATE I and GRADUATE II Investigators and the gantenerumab study group
Published: December 2023

Background

GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two Phase III trials that investigated the efficacy and safety of gantenerumab, a subcutaneous fully human monoclonal antibody that binds aggregated forms of amyloid‐beta, in participants with early Alzheimer’s disease (AD). Although the studies did not meet their primary endpoints, participant characteristics that might influence response to gantenerumab were evaluated.

Method

Eligible participants with early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) were randomized 1:1 to receive gantenerumab or placebo. Gantenerumab‐treated participants were up‐titrated to 510 mg subcutaneous gantenerumab every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Secondary endpoints of cognition (ADAS‐Cog13) and function (ADCS‐ADL, FAQ) were assessed. Pre‐specified and exploratory post‐hoc subgroup analyses on these endpoints were performed.

Result

Across endpoints, there were consistent trends towards larger point estimates of gantenerumab treatment effect compared with placebo at Week 116 in males (using CDR‐SB as representative example: GRADUATE I: 16% relative reduction (RR); GRADUATE II: 17% RR) vs females (GRADUATE I: 3% RR; GRADUATE II: –2% RR) and participants with MCI (GRADUATE I:15% RR; GRADUATE II:10% RR) vs mild AD (GRADUATE I: 4% RR; GRADUATE II: 2% RR). This pattern was not consistently seen when using CDR‐Global Score (0.5 vs >0.5) to define disease stage. Compliers, defined as participants who received ≥90% of the intended cumulative dose, had an increased point estimate of treatment effect (CDR‐SB: GRADUATE I: 17% RR; GRADUATE II: 18% RR) vs non‐compliers (CDR‐SB: GRADUATE I: –1% RR; GRADUATE II: –3% RR). In a pooled analysis, a larger point estimate of treatment effect vs placebo was observed in East‐Asian vs Non‐East‐Asian countries (CDR‐SB: RR 38% vs 5%). The East‐Asian population had lower baseline weight, greater treatment compliance, and accordingly higher plasma exposure, than the Non‐East‐Asian population, suggesting this observation is not driven by racial differences in treatment response.

Conclusion

Subgroup analyses in the GRADUATE studies provide insights into participant characteristics that may influence the degree of clinical response to gantenerumab treatment. Higher gantenerumab exposure may result in greater clinical efficacy.
Cognitive Screening Beliefs and Behaviors Among Older US Adults: Results from the National Poll on Healthy Aging
Authors: Cox Chelsea G. , Hoffman Geoffrey J. , Kullgren Jeffrey T. , Singer Dianne C. , Solway Erica , Kirch Matthias , Malani Preeti N. , Roberts J. Scott
Published: December 2023

Background

Fewer than half of people with dementia have been formally diagnosed by a clinician. Consequently, the US National Plan to Address Alzheimer’s Disease (AD) has prioritized early disease detection. A critical first step to early detection is primary care‐based screening for cognitive decline. Greater understanding of public perceptions and use of cognitive screening is needed to optimize early detection of AD among older adults.

Method

We analyzed data from the March 2023 fielding of the University of Michigan National Poll on Healthy Aging, a nationally representative web and telephone survey of community‐dwelling US adults aged 50‐80 using the NORC AmeriSpeak panel. Respondents for this analysis were aged 65‐80 without AD or dementia. Our primary outcome was self‐reported history of cognitive screening (never versus ever had screening). Logistic regression was used to estimate associations between respondent characteristics (i.e., sociodemographic factors, health factors, beliefs about cognitive screening) and self‐report of cognitive screening, and to examine whether primary care provider status moderates the association between screening beliefs and self‐report of screening.

Result

Of 1,242 respondents, 42% reported having ever undergone cognitive screening (21% within the past year). In adjusted analyses, sociodemographic factors (i.e., older age, higher level of education), insurance status (Medicare Advantage vs. traditional Medicare) and poorer physical health were associated with greater likelihood of cognitive screening (all p<0.05). Respondents with positive versus negative beliefs about cognitive screening were 45% more likely to report screening (adjusted risk ratio: 1.45, p<0.001). The probability of cognitive screening did not vary overall by provider status; however, among respondents with negative beliefs about screening, having a provider was associated with greater probability of having undergone screening (35% versus 11%, p<0.05).

Conclusion

We identified a range of factors associated with older adults’ self‐report of cognitive screening including age, health, and beliefs about the pros and cons of screening. Primary care providers may play an important role in cognitive screening decisions, particularly among patients with negative beliefs about screening. Providers can play an active role in initiating conversations about cognition with older adult patients on the advantages and disadvantages of screening to help patients make informed decisions.
APOE ε4 genotype modulates the relationship between fatty acids consumption and brain connectivity
Authors: de Frutos Jaisalmer , Rojo Inmaculada Concepción Rodríguez , Cuesta Pablo , Vizuete Aranzazu Aparicio , Cuadrado‐Soto Esther , Salas‐González María Dolores , Maestú Fernando , Sobaler Ana Maria Lopez ,   Center for Cognitive and Computational Neuroscience
Published: December 2023

Background

Lipoproteins play a crucial role in the brain, where they assist in lipid transport, as lipids constitute a majority of the brain’s dry mass. The apolipoprotein E (APOE) ε4 gene allele carriage promotes lipid dysfunction, endothelial injury and cerebrovascular disease, contributing to increased risk of dementia. Furthermore, it also results in insufficient lipid availability for neuronal remodelling and repair processes, leading to altered synaptogenesis and neurogenesis. In this scenario, we explored the relationship between the consumption of various kinds of fatty acids and functional brain connectivity in carriers and non‐carriers of this genetic risk factor.

Method

64 individuals (24 APOE ε4+; 40 APOE ε4‐) at high cardiovascular risk (waist/height index ≥0.5), aged 50 and above and without cognitive impairment underwent four minutes of eyes‐closed resting state magnetoencephalography recording. We estimated functional connectivity using phase‐locking value and applied data driven cluster‐based permutation test to detect the brain regions for which mean connectivity with every other region across the brain was modulated by each of four fatty acids consumption variables: consumption of monounsaturated fatty acids, consumption of saturated fatty acids, ω‐3/ω‐6 fatty acids consumption and overall quality of fatty acids consumption [(monounsaturated+polyunsaturated)/saturated].

Result

None of the studied variables yielded significant results across the whole sample. However, an interesting result emerged after stratification by genotype:

‐ higher consumption of monounsaturated fatty acids was associated with lower functional connectivity in the theta (temporal cluster) and delta bands (frontal cluster).

‐ higher ω‐3/ω‐6 consumption ratios were associated with lower functional connectivity in the alpha band (occipital cluster).

Conclusion

ε4 carriers seem to benefit from greater ω‐3/ω‐6 consumption, which was found to be associated to lower connectivity in the alpha band. Relevantly, several studies point towards alpha hyperconnectivity as a early sign of dysfunction in healthy individuals at high risk for Alzheimer’s disease. On the other hand, for ε4 non‐carriers, where lipid transportation within the brain is expected to be optimal, monounsaturated fatty acids appear to be more beneficial.
The Effects of Breaking Up Prolonged Sitting on Cognitive Performance in Middle‐Aged and Older Adults: Dose Response Analysis of a Randomized Crossover Trial
Authors: Murdock Margaret E , Duran Andrea T , Friel Ciaran P , Serafini Maria A , Ensari Ipek , Cheung Ying Keun , Diaz Keith M
Published: December 2023

Background

Sedentary behavior (SED) is highly prevalent and associated with poor health outcomes and cognitive decline, independent of physical activity (PA). Studies have established the harmful effects on cognition and information processing, and while PA guidelines endorse reducing SED, they fail to address how often SED should be broken up, and for how long. The purpose of this study is to assess how frequently and for how long SED should be disrupted with light‐intensity physical activity (PA) to offset the effects on cognitive performance.

Method

A randomized crossover study of n = 11 middle and older aged adults (>45 years) completed five 8‐hour visits: a sedentary (control) condition and four experimental conditions with varied walking (1.9 mph, 0% grade) frequency and durations: every 30 minutes for 1 minute, every 30 minutes for 5 minutes, every 60 minutes for 1 minute, and every 60 minutes for 5 minutes. Cognition was assessed at baseline, 4 hours, and 6 hours via the Single Digit Modalities Test (SDMT), a validated cognitive performance measure that assesses information processing speed and accuracy.

Result

Compared with control, there was significant improvement in SDMT score for the every 30 minutes for 5 minutes dose (net difference compared to control: 3.1 [SE: 1.4], p‐value = 0.034), every 60 minutes for 1 minute dose (net difference compared to control: 3.4 [SE: 1.4], p‐value = 0.016), and every 60 minutes for 5 minutes dose (net difference compared to control: 3.3 [SE: 1.4], p‐value = 0.017). The effect on SDMT was not statistically significant for the every 30 minutes for 1 minute dose, but a positive trend was observed (net difference compared to control: 2.6 [SE: 1.4], p‐value = 0.069).

Conclusion

There was a significant effect of breaking up SED on SDMT scores with light intensity walking for both low frequency breaks (1 minute every 60 minutes and for 5 minutes every 60 minutes) and high frequency breaks (5 minutes every 60 minutes). This suggests that even brief breaks in SED may offset harmful effects on cognitive performance. This result provides a specific and achievable mechanism for offsetting the harm caused by SED on cognitive performance.
How will BACE inhibitors be studied in clinical trials?
Authors: Aisen Paul S. S
Published: December 2023

Background

Trials of multiple amyloid‐reducing antibodies have demonstrated slowing of Alzheimer’s disease (AD) progression by 25‐30% with optimal treatment, confirming the validity of the amyloid therapeutic hypothesis. These antibodies target fibrillar and, in some cases, pre‐fibrillar forms of aggregated amyloid. BACE (β‐site amyloid precursor protein cleaving enzyme) inhibitors block generation of the amyloid peptide, reducing smaller diffusible species that may contribute to amyloid toxicity. BACE inhibition may therefore complement immunotherapy.

Method

Based on the results of trials with amyloid‐removing antibodies and various BACE inhibitors, trials can be envisioned to explore the therapeutic values of inhibiting amyloid peptide generation.

Result

Since multiple forms of amyloid are neurotoxic, the beneficial effects of BACE inhibition alone, in sequence or in combination with amyloid‐reducing antibodies should be tested in trials. BACE inhibitors are ideal candidates for primary prevention trials, with high‐risk amyloid‐PET negative individuals identified using plasma biomarkers (amyloid β peptide and ptau ratios); the impact of therapy may be assessed with effect on plasma ptau species as the primary biomarker endpoint. In individuals with positive amyloid PET scans, whether asymptomatic or with early AD, BACE inhibition should be tested in combination with or following effective amyloid removal with immunotherapy; cognitive and clinical outcome measures are appropriate in these populations. Dosing should target 25‐50% inhibition of BACE, with monitoring of cognition to facilitate dose adjustment when necessary. Clinical trial designs will be presented.

Conclusion

BACE inhibitor therapy to reduce the generation of amyloid peptides offers an opportunity to build on the success of amyloid‐removing antibodies in the treatment and prevention of Alzheimer’s disease.
Blood‐based SNAP‐25 and VAMP‐2 in Alzheimer’s disease; relation to cognition, atrophy and synaptic density.
Authors: Sauer Mathias , De Rocker Charlotte , Grötschel Lana , Goossens Julie , Benedet Andrea L. , Schöll Michael , Nilsson Johanna , Brinkmalm Ann , Janelidze Shorena , Stomrud Erik , O'Brien John T , Chouliaras Leonidas , Malpetti Maura , Rosa‐Neto Pedro , Rowe James B. , Zetterberg Henrik , Blennow Kaj , Hansson Oskar , Vanmechelen Eugeen , Ashton Nicholas J.
Published: December 2023

Background

A hallmark of neurodegenerative disorders is synaptic dysfunction and degeneration. This makes the presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25) and the Vesicle‐associated membrane protein 2 (VAMP‐2) targets of interest and importance. Previously, these proteins have only been measurable in cerebrospinal fluid (CSF) and are increased in Alzheimer’s disease (AD) patients. Considering the advancement of blood‐based detection of phosphorylated tau (p‐tau), neurofilament light (NfL) and amyloid‐β (Aβ42/40), a measure of synaptic degeneration in blood would be important for disease prognosis and clinical trial outcome. In this study, we describe results from novel single molecular arrays (Simoa) for blood SNAP‐25 and VAMP‐2.

Method

Prototype Simoa assays for N‐terminal SNAP‐25 and VAMP‐2 were developed as more sensitive versions of previously validated in‐house CSF assays with diluent suited for both plasma and CSF. We examined 110 participants (54 AD and 56 healthy controls) from the Swedish BioFINDER pilot study. The mean age of patients was 75.9 years (7.1 SD) and there was an even distribution of sex. We examined group differences by the Wilcoxon rank sum test and associations between these two blood biomarkers and Aβ‐PET, tau‐PET, MRI and MMSE were determined by linear regression, adjusting for age and sex.

Result

SNAP‐25 was significantly increased in patients with AD (mean [SD], 0.81 pg/mL [0.27]; p < 0.001) as compared to controls (0.60 pg/mL [0.22]). SNAP‐25 distinguished AD patients from controls with an area under the curve of 0.74 (95% CI = 0.65‐0.83). SNAP‐25 showed association with Aβ PET (β = 0.10, p = 0.007) but not tau PET. SNAP‐25 associated with cortical thickness (β = ‐0.05, p = 0.009) and MMSE (β = ‐6.69, p = 0.001). No significant associations were found when analysing the AD group alone. VAMP‐2 showed no significant association with any of the mentioned parameters above.

Conclusion

This novel ultra‐sensitive immunoassay demonstrates an increase of plasma SNAP‐25 in AD patients, and a significant relationship with cognition and cortical atrophy. Further studies will verify these changes in independent cohorts and explore the relationship between plasma SNAP‐25 and VAMP‐2 with synaptic vesicle glycoprotein 2A (SV2A) PET in a broad range of neurodegenerative disorders.
Investigating white matter hyperintensities in a multicenter COVID‐19 study using 7T MRI
Authors: Li Jinghang , Liou Jr‐Jiun , Santini Tales , Alkateeb Salem , Adeyemi Oluwatobi F , de Erausquin Gabriel A. , Garbarino Valentina R. , Goss Monica , Habes Mohamad , Himali Jayandra Jung , Karmonik Christof , Li Karl , Masdeu Joseph C. , Nair Rejani R , Patel Vibhuti N , Snitz Beth E. , Aizenstein Howard J , Wu Minjie , Bowtell Richard , Penny Gowland , Roman Gustavo C , Ganguli Mary , Vahidy Farhaan S , Girard Timothy D. , Jacobs Heidi I.L. , Hosseini Akram A. , Seshadri Sudha , Ibrahim Tamer
Published: December 2023

Background

Emerging evidence indicates that COVID‐19 can negatively impact patient’s brain health (Douaud et al., 2022) (Cecchetti et al., 2022). Common clinical symptoms include brain fog, headaches, difficulty concentrating, and loss of sense of smell or taste. Some studies suggest that SARS‐CoV‐2 infection can damage the blood brain barrier either directly or through immune‐inflammatory mechanisms (Zhang, et al. 2021). White matter hyperintensities (WMH) are imaging biomarkers of brain vascular or inflammatory injury. We investigated the association between severity of COVID‐19 infection and burden of white matter hyperintensity volumes within a diverse multi‐nation, multi‐racial cohort using 7 Tesla (7T) MRI that can detect more subtle injury than conventional 1.5 or 3T MRI.

Method

Participants were recruited at 4 sites: Pittsburgh, San Antonio and Houston, USA, and Nottingham, UK. To date, we have scanned and included the following participants in our analysis (Table 1). Detailed cognitive, neurological, mood and functional assessments and high‐resolution MRI scans were collected. Subsequent WMH segmentation was performed using our in‐house built deep learning based model (Figure 1). All segmentations were visually inspected and manually corrected before statistical analysis. Normalized WMH is calculated as a ratio of the WMH volume and the intracranial volume (WMH/ICV). Imaging data for an additional 36 age‐matched controls were retrieved from the 7 Tesla Bioengineering Research Program (7TBRP) imaging bank at Pittsburgh.

Result

Figure 1 shows the WMH segmentation outputs from our deep learning based model on images acquired at the 3 sites. Our Linear regression models along with our non‐parametric Kruskal‐Wallis test result suggests that compared to mild COVID cases and healthy control, COVID infected individuals that were ICU admitted show elevated WMH burden (Figure 2).

Conclusion

Our results demonstrate that white matter hyperintensity volumes were higher among patients who had severe acute COVID infection that required ICU admission, compared to healthy age‐matched controls. In contrast, no difference in white matter burden was observed in patients with mild COVID infection compared to healthy controls. Additional data (both cross‐sectional and longitudinal), including more sensitive MRI measures is being collected to define the full spectrum of brain injury associated with sequelae of COVID infection.
Using 7T MRI to study hippocampal structures in Alzheimer’s disease and post‐SARS‐CoV2 infection
Authors: Hosseini Akram A. , Adeyemi Oluwatobi F , Bowtell Richard , Penny Gowland , Ibrahim Tamer , Liou Jr‐Jiun , Santini Tales , Li Jinghang , Alkateeb Salem , Habes Mohamad , Goss Monica , Vahidy Farhaan S , Jacobs Heidi I.L. , Girard Timothy D. , de Erausquin Gabriel A. , Snyder Heather M , Seshadri Sudha
Published: December 2023

Background

7T MRI allows implementation of high‐resolution quantitative susceptibility mapping (QSM) which can be used to assess the cerebral microvascular/hypoperfusion pathogenic hypothesis in Alzheimer’s disease (AD) and in the post‐SARS‐CoV2 setting to explore if there may be similarities in brain changes in these two conditions. The magnetic susceptibility (reflective of tissue iron) of hippocampal subfields was assessed in patients with 1) CSF‐Amyloidß‐status AD; 2) mild COVID‐19 over 6 months previously (Cv); 3) severe COVID‐19 with ICU admission >6 months previously (ICU‐Cv); and 4) age‐matched healthy controls (HC).

Methods

33 participants (10 HC, 14 Cv, 9 ICU‐Cv) for the COVID study and 24 participants (14 AD, 11HC) from AD patients with confirmed CSF‐Amyloidß levels, aged 42‐79, were scanned on a 7T scanner with the following protocol T2* GRE for the AD groups (0.7×0.7×0.7mm3,TE/TR = 20/31ms) and T2* multi‐echo GRE for the Cv groups (0.38×0.38×0.75mm3,TE1/TE2/TR = 8.2/18.4/24ms). Data were processed using QSMbox1 to produce susceptibility maps. PSIR (0.55×0.55×0.55mm3,TE/TR = 3.1/6.9ms) and T2‐weighted FSE (0.38×0.39×1.5mm3, TE/TR = 117/5900ms) images were used to segment the hippocampal subfields (Figure 1)2. One‐way analyses were used in SPSS for comparison between the HC group and each of the Cv, ICU‐Cv, and AD groups.

Results

There was no change in susceptibility for the whole hippocampus between AD and HC, but there was a significant difference for the DG subfield (p = 0.045), Figure 2. For COVID patients, there was a significant difference between the susceptibility of the whole hippocampus in the ICU‐Cv group (p = 0.035), but not in the Cv group (p = 0.788), Figure 3, compared to HC. In subfield analyses there was a trend towards decreased susceptibility in the subiculum, an area known to be affected by Alzheimer pathology, in the ICU‐Cv group (p = 0.032) compared to HC.

Conclusion

The lower susceptibility within the hippocampal structures observed in AD and ICU‐Cv patients may reflect less iron either from cerebral hypoperfusion or vascular injuries in AD or additionally result from sequelae of hypoxaemia in ICU‐Cv. The study provides preliminary evidence of detectable in vivo microstructural changes in hippocampal subfields in both AD and post‐COVID settings.

Funding: Medical Research Council, UK (MR/T005580/1); National Institute of Health, USA (1R56AG074467‐01)

References:

1. https://doi.org/10.1016/j.neuroimage.2018.07.065

2. https://doi.org/10.1002/hbm.22627
Comparison of Focal Hippocampal T2‐Weighted MRI and Whole‐Brain T1‐Weighted MRI for Detection of Longitudinal Atrophy Using Deep Learning‐Based and Conventional Approaches
Authors: Dong Mengjin , Xie Long , Wisse Laura , de Flores Robin , Wang Jiancong , Das Sandhitsu R. , Wolk David A. , Yushkevich Paul A.
Published: December 2023

Background

Longitudinal measurement of medial temporal lobe (MTL) atrophy is shown to be effective in measuring Alzheimer’s disease (AD) progression and has been extensively studied on T1‐weighted MRI. However, there has been little work analyzing atrophy on high‐resolution T2‐weighted MRI of the hippocampal region, and it is unknown which MRI modality would yield a more effective biomarker of disease progression. We compare atrophy measurements derived from T1 and T2‐weighted MRI using a deep learning framework DeepAtrophy and a deformation‐based morphometry method ALOHA.

Method

T2‐weighted MRI of 481 participants from ADNI2/3 are included in the study. DeepAtrophy was trained on 74 participants and evaluated on 407. During training, DeepAtrophy explicitly infers temporal information, such as the scan temporal order for a single scan pair and which image pair has a longer scan time interval for multiple scan pairs. During inference, DeepAtrophy predicts a “total progression score” for each scan pair. This score is expected to be higher (more progression) in individuals with more advanced AD. A similar experiment was conducted using T1‐weighted MRI from 481 ADNI2/GO participants (partially overlapping with T2‐weighted experiment). ALOHA pipelines tailored for T1‐weighted and hippocampal T2‐weighted MRI were evaluated on the same subjects and scan pairs as DeepAtrophy.

Result

For both T1 and T2‐weighted MRI, DeepAtrophy is more accurate, compared with ALOHA, in inferring the temporal order of a pair of longitudinal scans. In hypothetical one‐year and two‐years clinical trials scenarios simulated using ADNI data, DeepAtrophy has an improvement over ALOHA in detecting differences in progression between disease groups in both imaging modalities. The strongest effect for differentiating between Amyloid‐positive and Amyloid‐negative cognitively unimpaired group was obtained using DeepAtrophy progression measures on T2‐weighted MRI.

Conclusion

This study supports the potential of high‐resolution focal T2‐weighted MRI of the hippocampus as a longitudinal biomarker of early AD progression suitable for future clinical trials.
DNA Quadruplex Structure with a Unique Cation Dependency
Authors: Gajarsky Martin , Stadlbauer Petr , Sponer Jiri , Cucchiarini Anne , Dobrovolna Michaela , Brazda Vaclav , Mergny Jean‐Louis , Trantirek Lukas , Lenarcic Zivkovic Martina
Published: December 2023

DNA quadruplex structures provide an additional layer of regulatory control in genome maintenance and gene expression and are widely used in nanotechnology. We report the discovery of an unprecedented tetrastranded structure formed from a native G‐rich DNA sequence originating from the telomeric region of Caenorhabditis elegans. The structure is defined by multiple properties that distinguish it from all other known DNA quadruplexes. Most notably, the formation of a stable so‐called KNa‐quadruplex (KNaQ) requires concurrent coordination of K+ and Na+ ions at two distinct binding sites. This structure provides novel insight into G‐rich DNA folding under ionic conditions relevant to eukaryotic cell physiology and the structural evolution of telomeric DNA. It highlights the differences between the structural organization of human and nematode telomeric DNA, which should be considered when using C. elegans as a model in telomere biology, particularly in drug screening applications. Additionally, the absence/presence of KNaQ motifs in the host/parasite introduces an intriguing possibility of exploiting the KNaQ fold as a plausible antiparasitic drug target. The structure's unique shape and ion dependency and the possibility of controlling its folding by using low‐molecular‐weight ligands can be used for the design or discovery of novel recognition DNA elements and sensors.
Cobalt‐Catalyzed Enantio‐ and Regioselective C(sp3)−H Alkenylation of Thioamides
Authors: Staronova Lucia , Yamazaki Ken , Xu Xing , Shi Heyao , Bickelhaupt F. Matthias , Hamlin Trevor A. , Dixon Darren J.
Published: December 2023

An enantioselective cobalt‐catalyzed C(sp3)−H alkenylation of thioamides with but‐2‐ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.
Latency measurement in functional analysis and treatment of behaviors targeted for reduction
Authors: Mattson Stephanie L. , Spinks Hailey M. , Joslyn P. Raymond , Spinks Elissa M. , Moore Taylor F.
Published: December 2023

Research has demonstrated that latency is a reasonable index of response strength in the functional analysis and treatment of behaviors targeted for reduction. The literature contains numerous examples of functional analyses emphasizing latency informing effective treatment for problem behavior in various scenarios. Latency measurement can improve the versatility of functional analyses by allowing researchers and practitioners to examine behaviors that are not amenable to a traditional functional analysis arrangement and conduct assessments in challenging environments. Although there have been several reviews of the functional analysis literature, to date none have specifically addressed functional analyses emphasizing latency measurement. Given the unique advantages of latency‐based functional analyses, a systematic review could be beneficial to researchers and practitioners in behavior analysis. Therefore, we conducted a systematic literature review of research on functional analyses using latency to measure target behaviors. Our review included 79 cases across 27 empirical research articles. We present a summary of the extant literature, highlight strengths and limitations of the empirical foundations, provide clinical implications, and discuss future directions for research.
Discovery of new triterpenoids from Leptopus clarkei and their antiproliferative activity on cancer cells
Authors: Chu Dong‐Hai , Qi Shi‐Zhou , Gao Hui‐Yuan , Wang Miao
Published: December 2023

Two new triterpenoids (1–2), along with six known analogues (3–8) were obtained from the dried whole plant of Leptopus clarkei. Compound 1 is a 3,4‐seco‐lupane‐type triterpenoid, and compound 2 is a phenylpropanoid‐conjugated pentacyclic triterpenoid possessing trans‐p‐coumaroyl unit attached to oleanane‐type skeleton. This is the first report on chemical investigation of the L. clarkei, and the triterpenoid derivatives were found in this plant for the first time. The structures of the new compounds were unequivocally elucidated by HRESIMS and 1D/2D NMR data. Additionally, the isolated compounds were evaluated for theircytotoxicities against four cancer cell lines including HepG2, MCF‐7, A549 and HeLa. Notably, compound 2 exhibited the most significant antiproliferative activity with IC50 less than 20 μM for four cancer lines.
Annulated Heterocyclic[g]Coumarin Composites: Synthetic Approaches and Bioactive Profiling
Authors: Mazin Zeki Nameer , Fakri Mustafa Yasser
Published: December 2023

Coumarins, widely abundant natural heterocyclic compounds, are extensively employed in creating various biologically and pharmacologically potent substances. The hybridization of heterocycles presents a key opportunity to craft innovative multicyclic compounds with enhanced biological activity. Fusing different heterocyclic rings with the coumarin structure presents an intriguing method for crafting fresh hybrid compounds possessing remarkable biological effects. In the pursuit of creating heterocyclic‐fused coumarins, a wide range of annulated heterocyclic[g]coumarin composites has been introduced, displaying impressive biological potency. The influence of the linear attachment of heterocyclic rings to the coumarin structure on the biological performance of the resulting compounds has been investigated. This review centers on the synthetic methodologies, structural activity relationship investigation, and biological potentials of annulated heterocyclic[g]coumarin composites. We conducted searches across several databases, including Web of Science, Google Scholar, PubMed, and Scopus. After sieving, we ultimately identified and included 71 pertinent studies published between 2000 and the middle of 2023. This will provide valuable perspectives for medicinal chemists in the prospective design and synthesis of lead compounds with significant therapeutic effects, centered around heterocycle‐fused coumarin frameworks.
In vitro Production of Hemin‐Based Artificial Metalloenzymes
Authors: López‐Domene Rocío , Manteca Aitor , Rodriguez‐Abetxuko Andoni , Beloqui Ana , Cortajarena Aitziber L.
Published: December 2023

Developing enzyme alternatives is pivotal to improving and enabling new processes in biotechnology and industry. Artificial metalloenzymes (ArMs) are combinations of protein scaffolds with metal elements, such as metal nanoclusters or metal‐containing molecules with specific catalytic properties, which can be customized. Here, we engineered an ArM based on the consensus tetratricopeptide repeat (CTPR) scaffold by introducing a unique histidine residue to coordinate the hemin cofactor. Our results show that this engineered system exhibits robust peroxidase‐like catalytic activity driven by the hemin. The expression of the scaffold and subsequent coordination of hemin was achieved by recombinant expression in bulk and through in vitro transcription and translation systems in water‐in‐oil drops. The ability to synthesize this system in emulsio paves the way to improve its properties by means of droplet microfluidic screenings, facilitating the exploration of the protein combinatorial space to discover improved or novel catalytic activities.
Recent research progresses of Sn/Bi/In‐based electrocatalysts for electroreduction CO2 to formate
Authors: Liu Ms. Fei , Zhang Chen , Wang Jiajun , Han Xiaopeng , Hu Wenbin , Deng Yida
Published: December 2023

Carbon dioxide electroreduction reaction (CO2RR) can take full advantage of sustainable power to reduce the continuously increasing carbon emissions. Recycling CO2 to produce formic acid or formate is a technologically and economically viable route to accomplish CO2 cyclic utilization. Developing efficient and cost‐effective electrocatalysts with high selectivity towards formate is prioritized for the industrialized applications of CO2RR electrolysis. From the previous explored CO2RR catalysts, Sn, Bi and In based materials have drawn increasing attentions due to the high selectivity towards formate. However, there are still confronted with several challenges for the practical applications of these materials. Therefore, a rational design of the catalysts for formate is urgently needed for the target of industrialized applications. Herein, we comprehensively summarized the recent development in the advanced electrocatalysts for the CO2RR to formate. Firstly, the reaction mechanism of CO2RR is introduced. Then the preparation and design strategies of the highly active electrocatalysts are presented. Especially the innovative design mechanism in engineering materials for promoting catalytic performance, and the efforts on mechanistic exploration using in situ (ex situ) characterization techniques are reviewed. Subsequently, some perspectives and expectations are proposed about current challenges and future potentials in CO2RR research.
Binary Mg‐1 at%Gd alloy anode for high‐performance rechargeable magnesium batteries
Authors: Liu Han , Tan Shuangshuang , Wang Zhongting , Chen Yifan , Yue Jili , Wang Dong , Huang Guangsheng , Wang Jingfeng , Pan Fusheng
Published: December 2023

Rechargeable magnesium batteries (RMBs) become a highly promising candidate for the large‐scale energy storage system by right of the high volumetric capacity, intrinsic safety and abundant resources of Mg anode. However, the uneven Mg stripping and large overpotential will cause a severe pitting perforation and the followed failure of Mg anode. Herein, we proposed a high‐performance binary Mg‐1 at% Gd alloy anode prepared by the melting and hot extrusion. The introduction of 1 at% Gd element can effectively reduce the Mg2+ diffusion energy barrier (0.34 eV) on alloy surface and induces the formation of a robust and low‐resistance electrolyte/anode interphase, thus enabling a uniform and fast Mg plating/stripping. As a result, the Mg‐1 at.% Gd anode displays a largely enhanced life of 220 h and a low overpotential of 213 mV at a high current density of 5.0 mA cm−2 with 2.5 mAh cm−2. Moreover, the assembled Mg‐1 at.% Gd//Mo6S8 full cell delivers a high rate performance (73.5 mAh g−1 at 5 C) and ultralong cycling stability of 8000 cycles at 5 C. This work brings new insights to design the new‐type and practical Mg alloy anodes for commercial RMBs.
Interictal magnetic signals in new‐onset Rolandic epilepsy may help with timing of treatment selection
Authors: Xu Fengyuan , Li Yihan , Wang Yingfan , Wang Siyi , Sun Fangling , Wang Xiaoshan
Published: December 2023

Objective

With research progress on Rolandic epilepsy (RE), its “benign” nature has been phased out. Clinicians are exhibiting an increasing tendency toward a more assertive treatment approach for RE. Nonetheless, in clinical practice, delayed treatment remains common because of the “self‐limiting” nature of RE. Therefore, this study aimed to identify an imaging marker to aid treatment decisions and select a more appropriate time for initiating therapy for RE.

Methods

We followed up with children newly diagnosed with RE, classified them into medicated and non‐medicated groups according to the follow‐up results, and compared them with matched healthy controls. Before beginning follow‐up visits, interictal magnetic data were collected using magnetoencephalography in treatment‐naïve recently diagnosed patients. The spectral power of the whole brain during initial diagnosis was determined using minimum normative estimation combined with the Welch technique.

Results

A difference was observed in the magnetic source intensity within the left caudal anterior cingulate and precentral and postcentral gyri in the delta band between the medicated and non‐medicated groups. The results revealed good discriminatory ability within the receiver operator characteristic curve. In the medicated group, there was a specific change in the frontotemporal magnetic source intensity, which shifted from high to low frequencies, compared with the healthy control group.

Significance

The intensity of the precentral gyrus magnetic source within the delta band showed good specificity. Considering the rigor of initial treatment, the intensity of the precentral gyrus magnetic source can provide some help as an imaging marker for initial RE treatment, particularly for the timing of treatment initiation.
The structure and vasculature in pollen cones of Taxus (Taxaceae, Gymnospermae) and its evolutionary significance
Authors: Dörken Veit Martin
Published: December 2023

The pollen cone structure and vasculature of Taxus baccata and T. wallichiana were investigated in the context of comparative studies in other conifers. The results indicate that the simple, flower‐like pollen cone of Taxus could be derived from an ancestral compound inflorescence as in Cephalotaxus and Pseudotaxus. In Cephalotaxus, each lateral flower‐like structure represents an entire pollen cone, compared with a single perisporangiate microsporangiophore in Pseudotaxus. The microsporangiophores are exclusively perisporangiate in both Pseudotaxus and Taxus, but in Pseudotaxus they are inserted in the axil of a pherophyll. By a simple reduction of these pherophylls, the Taxus pollen cone is formed—a strongly reduced inflorescence with flowers reduced to perisporangiate microsporangiophores, which are inserted directly at the cone axis, without pherophylls. Thus, the perisporangiate Taxus microsporangiophores correspond to the axillary flowers in Cephalotaxus and Pseudotaxus. The Taxus flower results from a strong reduction of an ancestral Cephalotaxus‐like flower type (lateral pollen cones), where all remaining hyposporangiate microsporangiophores have fused to a radial structure during evolution. Thus, perisporangiate Taxus microsporangiophores represent radial synangia and not peltate microsporophylls, suggesting that hyposporangiate microsporangiophores are the ancestral condition in Taxaceae s.l.
Mitigating Global Challenges: Harnessing Green Synthesized Nanomaterials for Sustainable Crop Production Systems
Authors: Sundararajan Niranjana , Habeebsheriff Heena Shabnam , Dhanabalan Karthikkumar , Cong Vo Huu , Wong Ling Shing , Rajamani Ranjithkumar , Dhar Bablu Kumar
Published: December 2023

Green nanotechnology, an emerging field, offers economic and social benefits while minimizing environmental impact. Nanoparticles, pivotal in medicine, pharmaceuticals, and agriculture, are now sourced from green plants and microorganisms, overcoming limitations of chemically synthesized ones. In agriculture, these green‐made nanoparticles find use in fertilizers, insecticides, pesticides, and fungicides. Nanofertilizers curtail mineral losses, bolster yields, and foster agricultural progress. Their biological production, preferred for environmental friendliness and high purity, is cost‐effective and efficient. Biosensors aid early disease detection, ensuring food security and sustainable farming by reducing excessive pesticide use. This eco‐friendly approach harnesses natural phytochemicals to boost crop productivity. This review highlights recent strides in green nanotechnology, showcasing how green‐synthesized nanomaterials elevate crop quality, combat plant pathogens, and manage diseases and stress. These advancements pave the way for sustainable crop production systems in the future.
Overweight‐years and cancer risk: A prospective study of the association and comparison of predictive performance with body mass index (Atherosclerosis Risk in Communities Study)
Authors: Hawwash Nadin K. , Sperrin Matthew , Martin Glen P. , Joshu Corinne E. , Florido Roberta , Platz Elizabeth A. , Renehan Andrew G.
Published: December 2023

Excess body mass index (BMI) is associated with a higher risk of at least 13 cancers, but it is usually measured at a single time point. We tested whether the overweight‐years metric, which incorporates exposure time to BMI ≥25 kg/m2, is associated with cancer risk and compared this with a single BMI measure. We used adulthood BMI readings in the Atherosclerosis Risk in Communities (ARIC) study to derive the overweight‐years metric. We calculated associations between the metric and BMI and the risk of cancers using Cox proportional hazards models. Models that either included the metric or BMI were compared using Harrell's C‐statistic. We included 13,463 participants, with 3,876 first primary cancers over a mean of 19 years (SD 7) of cancer follow‐up. Hazard ratios for obesity‐related cancers per standard deviation overweight‐years were 1.15 (95% CI: 1.05–1.25) in men and 1.14 (95% CI: 1.08–1.20) in women. The difference in the C‐statistic between models that incorporated BMI, or the overweight‐years metric was non‐significant in men and women. Overweight‐years was associated with the risk of obesity‐related cancers but did not outperform a single BMI measure in association performance characteristics.
Cannabis Science and Therapeutics: An Overview for Clinicians
Authors: Sera Leah , Hempel‐Sanderoff Carrie
Published: December 2023

Cannabis‐based therapeutics have garnered increasing attention in recent years as patients seek alternative treatments for various medical conditions. This narrative review provides a comprehensive overview of the science behind the medical use of cannabis, focusing on the medical evidence for commonly treated conditions. In addition, the review addresses the practical considerations of using cannabis as a therapeutic agent, offering insights into dosing strategies, variations in cannabinoid formulation, and individual patient responses. Precautions, adverse consequences, and drug interactions are also discussed, with a focus on patient safety and the potential risks associated with cannabis use.
Systemic immune‐inflammation index is associated with ulcerative plaque in patients with acute ischemic stroke: A single center exploratory study
Authors: Zhang Lianlian , Xu Xinchun , Zhang Xinyuan , Jiang Shu , Hui Pinjing
Published: December 2023

Purpose

This study explored the correlation between inflammatory markers and ulcerative plaques based on carotid doppler ultrasound (CDU) in individuals with acute ischemic stroke (AIS).

Methods

A total of 202 cases diagnosed with AIS associated with atherosclerotic plaque (AP) in the carotid artery were enrolled in this research. Collecting clinical baseline data, laboratory data (such as the complete blood count) and imaging data (CDU and Brain magnetic resonance imaging [MRI]). Then the correlation between Systemic immune‐inflammation index (SII, SII = P N/L, where P, N, and L were the peripheral blood platelet, neutrophil and lymphocyte counts, respectively), the shape and position of AP, the degree of carotid artery stenosis, and the presence of ulcerative plaques. Cutoff values were determined accordingly.

Results

SII and high sensitivity CRP (hs‐CRP) were independent risk factors for the presence of vulnerable carotid plaques. SII, type A plaque, plaque above carotid bifurcation, and severe carotid stenosis were independent risk factors for the presence of ulcerative plaque. The AUC value, the sensitivity, specificity, the best cutoff value of SII in predicting the presence of ulcerative plaque was 0.895, 93.3%, 89.2%, and 537.4 (109/L), respectively.

Conclusion

SII at admission was found to be independently associated with the presence of AIS with vulnerable plaque, especially ulcerative plaques. Moreover, plaque ulceration was more likely to form when the area of higher plaque thickness was located in the upstream arterial wall of maximum plaque thickness (WTmax), plaque was above the carotid bifurcation and severe carotid stenosis.
Simultaneous chromatographic separation of the anomers of saccharides on a polymer sulfobetaine zwitterionic stationary phase
Authors: Yang Min , Mei Haokun , Jiang Yu , Zhang Feifang , Yu Ziteng , Yang Bingcheng
Published: December 2023

Simultaneous chromatographic separation of the anomers of saccharides was achieved by using a polymer zwitterionic stationary phase functionalized by acrylamide‐type sulfobetaine. By optimization of separation parameters including column temperature, pH, and flow rate, the column operated in hydrophilic interaction chromatography mode exhibited excellent separation selectivity toward five monosaccharides and their anomers (including ribose, xylose, galactose, glucose, and arabinose) and two disaccharides (lactose and maltose). Baseline separation could be achieved at mild operation conditions such as 20–30°C of column temperature or typical mobile phase composition (85% acetrontrile–15% 20 mM ammonium formate [NH4FA]) with wide pH tolerance range of 2–8. This offers a rapid way to determine the configuration of α or β anomer of the saccharides.