bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Bace 1 selective inhibitor does not affect dendritic spine plasticity
Authors: Herms Jochen , Pratsch Katrin , Unemura Chie , Ito Mana , Horiguchi Naotaka 
Published: December 2023

AbstractBackgroundAll clinical BACE‐inhibitor trials for the treatment of Alzheimer´s Disease have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural and functional synaptic plasticity (Filser et al. Biol. Psych 2015, Blume et al. Front. Aging Neurosci. 2018), most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6, Zhu et al. Biol. Psych. 2018), which is exclusively processed by BACE1 and it is required for dendritic spine plasticity. The aim of the current study was to elucidate the effects of selective BACE1 inhibitors on dendritic spine plasticity at a dose that affects Sez6 cleavage to various degrees but not completely.MethodBy using longitudinal in vivo two‐photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with 2 novel highly selective BACE1 inhibitors developed at Shionogi in comparison to Elenbecestat which reduce soluble Sez6 to 27% (Elenbecastat), 17% (Shionogi Compound 1) and 39% (Shionogi Compound2) of baseline levels in untreated animals. For the detection of the soluble Sez6 ectodomain, the BACE cleavage product from full‐length Sez6, Western blot analysis was performed using a highly specific Sez6 antibody generated in the lab of Stefan Lichtenthaler (Pigoni et al. Mol. Neurodeg. 2016).ResultWe observed that BACE1 selective inhibitors do not alter dendritic spine density and plasticity in cortical neurons if at least 27% of soluble Sez6 remains. In detail, the density of gained and lost spines does not change under the treatment with Shionogi Compound 2 or Elenbecastat. Also, no differences in the stability of dendritic spines were found during treatment with these two compounds. With Compound 1 however, a significant spine loss occurs after 21 days of treatment.ConclusionSelective BACE1 inhibitors do not alter dendritic spine plasticity in mice if dosing reduces synaptic BACE1 cleavage of Sez6 not below 27% of baseline soluble Sez6 levels. BACE1 selective inhibitors may be potential novel candidates for clinical trials treating AD if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first weeks of treatment.
Replication of HLA‐DRB1*04:04 allele subtype protective effect against Alzheimer’s Disease in cognitively healthy centenarians using long‐read sequencing
Authors: Sirvent Daniel Alvarez , Salazar Alex N , Tesi Niccoló , Hulsman Marc , van der Lee Sven J , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Holstege Henne 
Published: December 2023

AbstractBackgroundGenomic‐Wide Association Studies (GWAS) of Alzheimer’s Disease (AD) have identified several single‐nucleotide‐polymorphisms (SNPs) in the Human Leukocyte Antigens (HLA) gene cluster. Fine mapping of the genetic signals, by means of model‐based HLA allele imputation from SNP‐array‐based genotyping data, was linked to a protective effect of three HLA‐DRB1*04 allele subtypes. These alleles would favor the binding of an aggregation‐prone Tau peptide by T‐cells, promoting early clearance of toxic Tau aggregate seeds, and reducing neurodegeneration. Here, we aim to replicate this association by means of HLA genotyping with long‐read sequencing.MethodWe used an HLA genotyping assay, [NGS‐go MX11‐3, GenDx], coupled with [PacBio] long‐read sequencing. This allows for genotyping of HLA genes at their full resolution of polymorphism. So far, we have genotyped HLA genes in 129 AD cases from the Amsterdam Dementia Cohort (ADC, mean age = 67.4 with SD = 7.56, N females = 85, N males = 44) and 138 cognitively healthy centenarians from the 100‐plus Study (mean age = 101.1 with SD = 3.33, N females = 92, N males = 46), thereby maximizing the analysis power. We then focused on the comparison of previously identified protective HLA‐DRB1*04 allele subtypes (DRB1*04:01, DRB1*04:04 and DRB1*04:07) between AD cases and centenarians.ResultFor all three HLA‐DRB1*04 allele subtypes, we observed no additional genetic variation concerning synonymous DNA substitutions in coding regions and changes in non‐coding regions. DRB1*04:04:01:02 had a frequency of 0.116 in centenarians, as compared to a 0.054 in AD cases (one‐sided Fisher’s exact test, p = 0.04). The frequency in centenarians was higher than the previously reported joint frequency of carriers in AD and controls, frequency = 0.073. DRB1*04:01:01:01 had similar frequencies in centenarians (0.174) and AD cases (0.178) (p>0.05). Similarly, DRB1*04:07:01:01 had a frequency of 0.014 in centenarians and 0.015 in AD (p>0.05).ConclusionWe confirmed a protective HLA‐DRB1*04:04 allele subtype, previously described by HLA imputation, with the use of long read sequencing. Genotyped at full resolution as DRB1*04:04:01:02, we observed an enrichment in cognitively healthy centenarians compared to the original AD vs controls setting. The HLA system could play a role in the enhanced immunity of centenarians, and how they are able to escape neurodegenerative diseases.
Movement with Dementia: A feasibility study of a resource to support the personalisation of therapeutic exercise programmes for people living with dementia
Authors: Booth Vicky , Harwood Rowan H , Foster Nadine , Graff Maud , Schneider Stefan , Wong Geoff , Pugh Pearl , Howe Louise , Logan Pip A 
Published: December 2023

AbstractBackgroundTherapeutic exercise is commonly used by healthcare professionals to support people recovering from injury or illness. There is little guidance on how to personalise these standardised programmes for people living with dementia (PLWD). The Movement with Dementia resource was co‐designed by PLWD, exercise instructors and healthcare professionals to address this knowledge gap. The aim of this study was to explore the feasibility and usability of implementing the Movement with Dementia shared decision‐making resource to assist prescribers and deliverers of therapeutic exercise interventions for PLWD.MethodA single site, non‐blinded feasibility study was conducted with an NHS community therapy team and their patients living with dementia. Eligibility criteria were people with a diagnosis of dementia, prescribed and undertaking an exercise programme as part of their care by the therapy team, able to provide consent and participate in the shared decision‐making process.Therapist participants undertook training (2‐hr session) on the Movement with Dementia resource and asked to use it during prescription and delivery of exercise with the patient participants, as part of their care episode. Questionnaires recorded demographic and usability information from all participants.ResultBetween January and March 2023 we recruited 9 therapist and 6 patient participants. Four physiotherapists (100% female; mean age = 39yrs) and six patient participants (50% female; mean age = 81yrs) completed the questionnaires. Patient participants had various dementia diagnoses (n = 1 AD, n = 3 VD, n = 1 LBD, n = 1 unsure), all were white‐British, and most lived with others (n = 4).None of the patient participants could recall using the resource, but 83% (n = 5) were still undergoing active care. All therapist participants were ‘likely’ or ‘very likely’ to recommend it but found the current material too ‘wordy’, both for themselves and PWLD. Whilst it reinforced knowledge and provided supportive ‘prompts’ for their approach, it was recommended for those with less experience treating PLWD.ConclusionThe co‐designed Movement with Dementia resource was successfully implemented into a clinical setting to support therapists prescribing and delivering exercise programmes for PLWD. Further refinement is required before wider evaluation and implementation. A focus on supporting therapists with less experience treating PLWD will direct future study.
Association of Polygenic Risk Score of Alzheimer’s disease with A/T/N Biomarkers and Cognitive Decline
Authors: Jung Joon Hyung , Byun Min Soo , Yi Dahyun , Jung Gijung , Ahn Hyejin , Liu Shiwei , Huang Yen‐Ning , Griswold Anthony J. , Pericak‐Vance Margaret A. A , Kim Yu Kyeong , Lee Yun‐Sang , Sohn Chul‐Ho , Kang Koung Mi , Lee Jun‐Young , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young 
Published: December 2023

AbstractBackgroundPolygenic risk scores (PRS) quantify the combined effects of genetic variants to enable the prediction of an individual’s risk of developing the disease. Alzheimer’s disease (AD) is a complex disorder in which the relationship among PRS, neuropathological substrates, and related cognitive decline remain especially understudied in Asian populations. We investigated the associations of PRS with AD neuroimaging biomarkers and cognitive phenotypes in a Korean Cohort.MethodThe study included 501 older adults (264 cognitively normal [CN], 146 mild cognitive impairment [MCI], and 91 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). Comprehensive clinical and neuropsychological evaluations, as well as multi‐modal neuroimaging including 3T MRI and 11C‐PiB‐PET were administered. A subset of participants underwent 18F‐AV‐1451 PET (n = 167). Imaging phenotypes including beta‐amyloid (Aβ) positivity, global tau deposition, and adjusted hippocampal volume (HVa) were used for amyloid (A), tau (T), and neurodegeneration (N) biomarkers, respectively., which was imputed using the TOPMed reference panel. PRS was calculated using the summary statistics of a recent large‐scale GWAS study for AD by PRS‐CS. The Apolipoprotein E (APOE) region was excluded in the calculation. The associations between standardized PRS and imaging/cognitive phenotypes were examined using either multiple linear or logistic regression analysis with covariates (age and sex for neuroimaging biomarker phenotypes; age, sex and education for cognitive phenotypes).ResultPRS was significantly higher in the AD dementia group compared to the CN group. Higher PRS was associated with greater CDR‐sum‐of‐boxes (β[SE] = 0.233[0.083], t = 2.818, p = 0.005) and lower MMSE scores (β[SE] = ‐0.648[0.198], t = ‐3.271, p = 0.001). In terms of AD neuroimaging biomarkers (Figure 1), higher PRS was significantly associated with an increased likelihood of Aβ positivity (OR = 1.233, 95%CI = 1.024‐1.491), and lower HVa (β[SE] = ‐132.79[49.624], t = ‐2.676, p = 0.008), but not with global tau deposition (β[SE] = 0.075[0.048], t = 1.573, p = 0.118).ConclusionThese findings suggest that higher PRS predicts increased pathological Aβ deposition and accelerated neurodegeneration, as well as greater cognitive decline. Further investigation in larger and multiethnic samples are needed to determine generalizability to other ethnoracial populations.
A Volume‐Based Alternative for classifying ATN: Data from the Tau Propagation over Time (T‐POT) cohort
Authors: Doering Elena , Hönig Merle C. , Dzialas Verena , Lothmann Julia , Giehl Kathrin , Theis Hendrik , Jäger Elena , Andrassy Gregory , Bauer Andreas , Elmenhorst David , Kroll Tina , Matusch Andreas , Krapf Philip , Neumaier Bernd , Lerche Christoph , Tellmann Lutz , Frensch Silke , Zeyen Philip , Sand Frederik , Richter Nils , Jessen Frank , Onur Oezguer A. , Ramirez Alfredo , van Eimeren Thilo , Drzezga Alexander , Bischof Gerard N 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the cerebral accumulation of amyloid‐beta (A), tau (T), and progressive neurodegeneration (N). The widely used ATN system, with regard to positron emission tomography (PET) biomarkers, categorizes AD based on the mean signal in specific regions of interest (ROI). However, this procedure disregards the spatial extent of pathology and neurodegeneration. Here, we propose an alternative quantification of the volume, i.e., fill states, of A, T and N in (pre)‐clinical AD.MethodWe analyzed data from the Tau Propagation over Time (T‐POT) study, including cognitively unimpaired individuals (CU, n = 58), and patients with mild cognitive impairment (MCI, n = 20) or AD dementia (n = 4). C11‐PIB‐PET (A), 18F‐AV1451 (T) and perfusion‐phase 18F‐AV1451 scans (N) were spatially and intensity‐normalized (reference: cerebellum). To quantify the volume of A, T and N, we z‐standardized and subsequently binarized all scans within–modality using a z‐score threshold. Fill states were then computed as the sum of abnormal voxels relative to a whole‐brain mask. Finally, mean fill states were compared across groups of clinical status (CU, MCI, AD) and partial correlations of either fill states or mean PET signal in established, tracer‐specific ROIs with cognitive performance (MMSE) were computed, adjusting for age, sex and education.ResultMean fill states reflected clinical status, as they increased with disease progression (CU: A = 4%, T = 4%, N = 3%; MCI: A = 15%, T = 11%, N = 4%; AD dementia: A = 20%, T = 23%, N = 5%). Moreover, A and T fill states were negatively associated with MMSE (rhoA = ‐.299, p < .001; rhoT = ‐.318, p < .01; rhoN = ‐.147, p = .20), while associations of mean PET signal and MMSE tended to be weaker (rhoA(global) = ‐.255, p = .03; rhoT(temporalmetaROI) = ‐.275, p = .01; rhoN(metaROI) = .179, p = .12).ConclusionWe present a competitive quantification scheme for ATN that is associated with both, clinical status and cognitive performance. These results, while currently validated in a larger sample, suggest that the spatiotemporal dynamics of pathology and neurodegeneration in the AD continuum are well captured by our multi‐parametric approach, which is possibly superior compared to classification from mean PET signal intensity.
GRADUATE I and II: Subgroup analysis and correlations of biomarkers
Authors: Bittner Tobias , Belousov Anton , Lane Christopher , Schwab Dietmar , Klein Gregory , Tonietto Matteo , Lott Dominik , Illiano Vittorio P , Blennow Kaj , Barkhof Frederik , Smith Janice , Doody Rachelle S. ,   for the GRADUATE I and GRADUATE II Investigators and the gantenerumab study group
Published: December 2023

AbstractBackgroundGantenerumab is a subcutaneous fully human monoclonal antibody targeting aggregated forms of amyloid‐beta. Phase III GRADUATE I (NCT03444870) and II (NCT03443973) trials were designed based on previous key learnings to provide evidence on the benefit:risk profile of subcutaneous gantenerumab in early symptomatic AD. Although primary endpoints were not met, gantenerumab showed treatment effects on amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) and plasma biomarkers. Correlations of biomarkers with clinical outcomes in the GRADUATE studies were assessed to further evaluate their utility.MethodParticipants aged 50‐90 years with mild cognitive impairment due to AD or mild AD dementia were randomised 1:1 to subcutaneous gantenerumab or placebo. Gantenerumab was up‐titrated over 36 weeks to target dose of 510 mg every 2 weeks. Changes in amyloid centiloid levels were obtained from [18F]Florbetaben or [18F]Flutemetamol PET. Regional changes in tau standardised uptake value ratio were obtained with [18F]GTP1 PET. Whole brain and regional atrophy were assessed via volumetric MRI. Fluid pharmacodynamics biomarkers were measured using Elecsys® immunoassays from Roche Diagnostics.ResultSignificant (but not corrected for multiple testing) treatment effects of gantenerumab on change from baseline to Week 116 were observed for CSF biomarkers (pooled GRADUATE I and II population) including Aβ40 (–10.42%, p = 0.0188), Aβ42 (26.06%, p<0.0001), tTau (–16.49%, p<0.0001), pTau181 (–23.35%; p < 0.0001), NfL (10.76%; p = 0.0159), GFAP (–5.49%; p = 0.0003), and plasma biomarkers including Aβ42 (GRADUATE I: 65.1%, p<0.0001; GRADUATE II: 54.9%, p<0.0001) and pTau181 (GRADUATE I: –17.2%, p<0.0001; GRADUATE II: –15.3%, p<0.0001). Preliminary biomarker analyses showed changes in amyloid PET in gantenerumab‐treated participants had a numerically higher correlation with changes in plasma Aβ42 (R = –0.43), versus pTau181 (R = 0.34) and GFAP (R = 0.16). Biomarker changes in subgroups will also be presented.ConclusionPhase III GRADUATE I and II study results provide evidence of the effect of subcutaneous gantenerumab on biomarkers of AD pathology and neurodegeneration in subgroups.
Measuring “What Matters Most™” to individuals living with Alzheimer’s disease and care partners: A conceptual model of Alzheimer’s Disease
Authors: Romano Carla (DeMuro) , Slota Christina , Bratlee‐Whitaker Emily , Edwards Teresa , Herring William L , McLeod Lori , Callahan Leigh F , Bullok Kristin E , Raimundo Karina , Taylor James , Taylor Geri , Kremer Ian N. , Lappin Debra , Frangiosa Theresa , Goss Diana , Gnanasakthy Kajan , Comer Meryl , Monks Doreen , Paulsen Russ , Hartry Ann , DiBenedetti Dana B 
Published: December 2023

AbstractBackgroundThe Alzheimer’s Disease Patient and Caregiver Engagement™ Initiative‘s What Matters Most™ (WMM) Research Program includes seminal studies to identify and measure treatment‐related needs, preferences, and priorities of people living with Alzheimer’s disease (PLWAD) and their informal care partners (CPs). WMM research identified 42 concepts deemed to be of highest relevance and importance in treatment related needs across the AD spectrum (preclinical – severe AD). Now, the WMM Next Generation Studies (WMM NG) are generating data to contextualize findings through a conceptual model of disease, verify previously identified concepts, and learn of new emerging concepts from a more diverse and inclusive study sample. Results will be used to broaden the context of an online survey to inform additional studies, including health economic evaluations, across the Alzheimer’s research field.MethodA draft conceptual model of disease was developed building on an existing model (Hartry, 2018) after careful examination of previously collected WMM data (DiBenedetti, 2020; Hauber, 2023). A cross‐sectional, observational qualitative research study was conducted, comprised of a series of individual, in‐depth interviews of those with clinically confirmed PLWAD and their CPs. Analyses of these data include qualitative content analysis and thematic analysis methods (Hsiu‐Fang, 2005).ResultThe 42 WMM concepts were categorized across thought processing (14), communication (3), mood/emotions (6), daily activities (12), social life/activities, (3) and independence (4) domains to form a draft conceptual model of disease. A total of 64 PLWAD and CPs of diverse ethnic and cultural backgrounds participated in in‐depth, web‐based interviews. Results reaffirmed the 42 WMM concepts, informed the model structure, and added missing concepts. Further, cognitive debriefing approaches elucidated participant perception of the terms “bother” and “interference” describing emotional connotation of these words, compared to the assessment of “impact”, to inform development of AD burden survey items.ConclusionWMM concepts contextualized by domains offer a roadmap to support future clinical trials seeking to measure clinically meaningful outcomes and patient‐centric endpoints. WMM NG data collection will enhance robustness of the findings to evaluate the impact of disease symptoms and inform health economic evaluation. The conceptual model will be refined continuously over the WMM research.
Sovateltide prevents loss of spatial memory retention and reduces neuroinflammation in a transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Sadigale Vaishnavi , Gulati Anil 
Published: December 2023

AbstractBackgroundAmyloid‐β (Aβ) accumulation, fibrillary tangles, neuroinflammation, and memory loss are hallmarks of Alzheimer’s disease (AD). We still lack an effective treatment for AD. Our group has demonstrated that endothelin B receptors (ETBR) in the brain could be a potential drug target to treat AD. However, a direct link between ETBR stimulation and regulation of AD‐related pro‐inflammatory cytokines is still lacking. In this study, we aimed to investigate the effect of sovateltide, an ETBR agonist, on inflammation and cognitive function improvement in transgenic AD (APP/PS1) mice.MethodWe assessed Aβ load, neuroinflammation, and cognitive changes in 3, 6, and 12 months old APP/PS1 transgenic mice. Animals were treated with vehicle or sovateltide (5 µg/kg) intravenously, and memory deficit was assessed using the Morris water maze test. In addition, the levels of beta‐amyloid plaques and inflammatory cytokines in the mouse brain were evaluated by immunoblotting.ResultOur results showed a significant (p<0.001) increased expression of pro‐inflammatory cytokines IL‐2 and IL‐6 and decreased expression of anti‐inflammatory cytokines IL‐4 and IL‐10 in APP/PS1 transgenic mice at 6 and 12 months of age. The expression of IL‐2 and IL‐6 was significantly (p<0.001) decreased, and IL‐4 and IL‐10 increased following sovateltide treatment in these mice, indicating an association of ETBR in regulating inflammatory factors. Moreover, APP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated amounts of Aβ plaque. While treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 and 12 months aged transgenic mice. There were no changes in the expression of any of these markers at three months.ConclusionAltogether, our work suggests a novel strategy by improving memory deficits and reducing Aβ plaque load and neuroinflammation by targeting ETBR and suggests that sovateltide could be an effective therapeutic option to treat AD.