bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundGRADUATE 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.MethodEligible 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.ResultAcross 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.ConclusionSubgroup 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

AbstractBackgroundFewer 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.MethodWe 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.ResultOf 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).ConclusionWe 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

AbstractBackgroundLipoproteins 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.Method64 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].ResultNone 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).Conclusionε4 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

AbstractBackgroundSedentary 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.MethodA 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.ResultCompared 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).ConclusionThere 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

AbstractBackgroundTrials 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.MethodBased 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.ResultSince 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.ConclusionBACE 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

AbstractBackgroundA 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.MethodPrototype 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.ResultSNAP‐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.ConclusionThis 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

AbstractBackgroundEmerging 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.MethodParticipants 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.ResultFigure 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).ConclusionOur 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

AbstractBackground7T 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).Methods33 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.ResultsThere 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.ConclusionThe 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

AbstractBackgroundLongitudinal 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.MethodT2‐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.ResultFor 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.ConclusionThis 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.