bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropathological autopsy findings in an individual with Alzheimer’s disease who received long‐term treatment with lecanemab (BAN2401)
Authors: Honig Lawrence S , Sun Yu , Irizarry Michael C , Swanson Chad J , Dhadda Shobha , Charil Arnaud , Hart David E , Noble James M , Huey Edward D , Teich Andrew F 
Published: December 2022

AbstractBackgroundAnti‐amyloid antibodies administered to patients with Alzheimer’s disease can result in marked reduction of brain amyloid as measured by neuroimaging with amyloid PET ligands. However, there is a lack of pathological data. Here we present neuropathological findings in a patient who received ∼173 weeks of (interrupted) treatment with lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated β‐amyloid species (protofibrils) and insoluble fibrils, in a Phase 2 study (NCT01767311, Alz Res Therapy 2021;13:80).MethodBrain autopsy was performed on an ∼85 year old whose lecanemab treatment history over 6 years was: 79 weeks 10mg/kg monthly in the double‐blind (DB) phase, then 98 weeks without treatment, then 94 weeks at 10mg/kg biweekly in the open‐label extension (OLE) phase, followed by ∼12 weeks of treatment discontinuation prior to death.ResultClinically, memory symptoms started age ∼77. Study entry was at age ∼80, with mild dementia, CDR 0.5, CDR‐SB 3, and MMSE 24. Florbetapir PET scan was positive at baseline, and negative after 53 weeks DB treatment and at start of OLE. These findings and clinical measures are shown in Table 1. ARIA was not observed during the study. Autopsy showed low brain weight (1052g) with diffuse atrophy, including hippocampi, consistent with atrophy seen on clinical MRI scans. Microscopic findings showed tau pathology including tangles and threads (by AT8 antibody and Bielschowsky staining) throughout neocortex (Braak NF stage VI; B3). Beta‐amyloid immunohistochemical stain (6E10) showed only modest amyloid load (Thal phase 2; A1), with near‐absence of diffuse amyloid deposits and only scattered clusters of neuritic plaques (CERAD stage B; C2).ConclusionIn this autopsy of an individual with Alzheimer’s disease treated with lecanemab, neuropathological changes showed tau and β‐amyloid deposits. However, the pattern of significant tau pathology, accompanied by only a mild degree of β‐amyloid deposits, (A1B3C2), is uncommon in typical (untreated) Alzheimer’s disease. For example, in the NACC neuropathology dataset, only 2% of brains with Braak B2 or B3 show Thal stage A0 or A1. This pattern suggests that lecanemab treatment resulted in a reduction in brain amyloid, consistent with the amyloid PET scanning results in this patient.
Comparison of the effect of computerized multidomain cognitive training and pen‐and‐paper educational program in older adults with mild cognitive impairment: a preliminary randomized controlled trial
Authors: Kang Jae Myeong , Yun Seonkyung , Seo Ha‐Eun , Kim Sangsoon , Cho Seong‐jin 
Published: December 2022

AbstractBackgroundCognitive intervention is accepted as a potential therapy to prevent the incident dementia. It was found that computerized cognitive training might be effective for older adults with mild cognitive impairment (MCI) in previous studies. We aimed to find the effect of multidomain cognitive training using tablet computer on the cognitive and psychological function in patients with MCI.MethodParticipants in training group (n = 15) conducted a multidomain cognitive training program using table computer and those in control group (n = 13) conducted an educational book reading twice a week for eight weeks. They were evaluated of their cognitive and psychiatric function before and after the program. The differences of the pre‐ and post‐ scores were compared between training and control groups.ResultParticipants in training group showed improvement in cognitive domains such as language (p = 0.012), memory (p = 0.050), and frontal executive function (p = 0.017), and psychiatric symptoms such as apathy (p = 0.001) and quality of life (p = 0.035) after the training. Control group participants showed improvements in frontal executive function (p = 0.013), positive affect (p = 0.019), apathy (p = 0.022) and mild behavioral impairment score (p = 0.049). Between group comparison of the pre‐ and post‐training difference showed significant improvement in training group compared to control group in memory (p = 0.020), frontal executive function (p = 0.024), positive affect (p = 0.037), apathy (p = 0.048), and quality of life (p = 0.047).ConclusionWe found the effect of multidomain cognitive training using tablet computer in cognitive domain including memory and executive function, positive affect, apathy, and quality of life in MCI patients. Tablet computer cognitive training may be effective in multidomain cognitive training with transfer effect in the prodromal stage of dementia. Future trials with larger sample size and various devices would find the effect of the computerized cognitive training.
An epigenome wide association study of sub‐phenotypes in Parkinson’s disease.
Authors: Harvey Joshua , Smith Adam R. , Weymouth Luke Stephen , Smith Rebecca G. , Hubbard Leon , Bresner Kate , Pishva Ehsan , Williams Nigel , Lunnon Katie , Creese Byron 
Published: December 2022

AbstractBackgroundParkinson’s disease (PD) is a highly heterogeneous disorder, encompassing a complex spectrum of clinical presentation including motor, sleep, cognitive and neuropsychiatric symptoms. Together the cumulative effects of these symptoms have huge impacts on individual quality of life. Here we aim to investigate genome wide DNA‐methylation in post‐mortem PD brain samples and test for region specific association with common secondary symptoms of sleep disorder, visual hallucinations and dementia.MethodDNA methylation data was generated on the Illumina 450K microarray for a cohort of 142 individual post mortem brain samples from the Frontal Cortex (FC), Caudate Putamen (CP) and Substantia Nigra (SN). Data was quality controlled following standardized, previously published pipelines. Clinical records for each case were assessed for binary status of sleep disorder, visual hallucinations and dementia. Linear models were used to identify differentially methylated positions (DMPs) for each of these outcomes, controlling for age, sex, post‐mortem interval and inferred cell‐type proportions as covariates.ResultThus far, results been only been generated for the dementia phenotype, with one genome wide significant loci passing multiple testing correction in the frontal cortex (p = 5.25e‐8). This DMP, found in the gene FAM175A / ABRAXAS‐1 (cg14699004), is hypomethylated in PD patients with preserved cognition, with comparable higher measures in PD‐Dementia and control samples. This effect appeared to be FC specific, with no DMPs passing genome wide significance in other brain regions tested.ConclusionPreliminary evidence indicates potential sub‐phenotype associated DMPs, with methylation at one site specifically associated with dementia within the FC. Current analysis is focussing on generating reference results across each of the phenotypes and brain regions assessed. Future work will look at Weighted Gene Correlation Network Analysis to identify networks associated with these individual phenotypes.
Ex vivo target engagement of the Abeta oligomer disassembling compound RD2 in patient derived brain homogenates
Authors: Willbold Dieter , Kass Bettina , Bujnicki Tuyen , Pils Marlene , Zafiu Christian , Schemmert Sarah , Bannach Oliver , Kutzsche Janine 
Published: December 2022

AbstractBackgroundSoluble Aβ oligomers are highly toxic and may be responsible for development and progression of Alzheimer’s disease (AD). Elimination of Aβ oligomers is therefore a promising therapeutic strategy. The compound RD2 was developed to stabilize Aβ monomers in their native conformation, which is very close to an intrinsically disordered protein (IDP). RD2 has demonstrated already to directly eliminate soluble Aβ oligomers in vitro and in vivo and to improve cognition or decelerate neurodegeneration in four different animal models in four different laboratories 1,2. Here, we wanted to test if RD2 is able to disassemble Aβ oligomers obtained from AD patient derived brain tissue.MethodAβ oligomers in AD patient derived brain tissue homogenates were incubated with different concentrations of RD2 and control compounds. Aβ oligomer concentrations were determined longitudinally by the sFIDA assay, a single‐particle sensitive method for quantitating protein oligomers and aggregates.ResultRD2 concentration and incubation time‐dependent reduction of Aβ oligomers in brain homogenates was observed. Control compounds did not reduce Aβ oligomer concentrations.ConclusionThe incubation time and RD2 concentration dependent disassembly of Aβ oligomers from human brain homogenate suggest a very efficient ability of RD2 to fulfill its mode of action, namely the direct disassembly of Aβ oligomers into their Aβ monomer building blocks. Kinetic analysis and the mode of action resemble very much that of catalytic chaperones.
Fast and accurate amyloid brain PET quantification without MRI using deep neural networks
Authors: Shin Seong A , Kang Seung Kwan , Kim Daewoon , Choi Youngeun , Choi Hongyoon , Lee Jae Sung 
Published: December 2022

AbstractBackgroundWe propose a novel method for automatic quantification of amyloid PET using a deep learning‐based spatial normalization (SN) of PET images, which does not require corresponding MRI or CT image of the same patient. In this study, the accuracy of the proposed method was evaluated for three different amyloid PET radiotracers by comparison with MRI parcellation‐based PET quantification using FreeSurfer, which is more accurate than SN‐based method but requires significantly longer computation time.MethodDeep neural network model used for SN of amyloid PET images was trained using 994 multicenter amyloid PET images, as well as corresponding 3D MRIs of the patients with Alzheimer’s disease and mild cognitive impairments and cognitive normal subjects. The accuracy of SN and SUVR quantification accuracy relative to FreeSurfer‐based estimation was evaluated using other 148 PET images. Additional external validation was also performed using independent data set (30 18F‐Flutemetamol, 67 18F‐Florbetaben, and 39 18F‐Florbetapir). For the comparison, PET SN was also conducted using SPM12 program. Then, the quantification results using SN methods were compared with SUVR values obtained using on FreeSurfer in individual brain space. Reference region was cerebellar grey matter and AAL3 atlas was used to extract the regional SUVR values.ResultsThe quantification results using the proposed method showed stronger correlations with FreeSurfer estimates than SPM SN using MRI did. For example, the slope, y‐intercept and R2 value between SPM and FreeSurfer for global cortex were 0.869, 0.113 and 0.946, respectively. On the other hand, those for proposed method were 1.019, ‐0.016 and 0.986. The external validation study also demonstrated the better performance of proposed method without MR images than SPM with MRI. In most brain regions, it outperformed the SPM SN in terms of the linear regression parameters and intraclass correlation coefficients.ConclusionIn this study, we evaluated a novel deep learning‐based SN method, which allows quantitative analysis of amyloid brain PET images without structural MRI. The proposed quantification results showed strong correlation with MRI‐parcellation‐based amyloid PET quantification using FreeSurfer in all clinical amyloid radiotracers. Therefore, the proposed method will be useful for investigating Alzheimer’s disease and related brain disorders using amyloid PET scans.
How does alzheimer’s disease, atherosclerosis and comorbid alzheimer’s disease and atherosclerosis impact neurovascular function?
Authors: Eyre Beth , Shabir Osman , Lee Llewelyn , Francis Sheila , Howarth Clare , Berwick Jason 
Published: December 2022

AbstractBackgroundThe brain is an energy hungry organ, consuming approximately 20% of the body’s energy supply (Clark & Sokoloff 1999). Due to its high energy demands the brain has developed a critical mechanism termed neurovascular coupling (NVC). NVC is the relationship between neuronal activity and a subsequent increase in blood flow to the same brain region. This mechanism is suggested to be impaired in many disorders, including Alzheimer’s disease (AD) (Kisler et al., 2017). Additionally, approximately 90% of individuals living with dementia have a comorbidity (Browne et al., 2017), with some of the most common comorbidities being cardiovascular disease (Tini et al., 2020) and type 2 diabetes (Santiago et al., 2021). Therefore, we wanted to investigate neurovascular function in AD and comorbid mixed models of AD and atherosclerosis.MethodFour separate groups of mice were used, aged 9‐12 months: AD (APP/PS1 (B6;C3 Tg(APPswe,PSEN1dE9)85Dbo/Mmjax)), WT (APP/PS1‐WT littermates) , atherosclerosis (WT + rAAV8‐mPCSK9‐D377Y + Western Diet) and Mixed AD and atherosclerosis (APP/PS1 + rAAV8‐mPCSK9‐D377Y + Western Diet). At 9m mice completed the novel object recognition test (NOR) to assess cognition. Following this, a thinned window surgery was completed. One‐week post‐surgery 2‐dimensional optical imaging spectroscopy (2D‐OIS) was utilised to investigate changes in cerebral haemodynamics, in response to a whisker stimulation in awake mice. A separate imaging session in anaesthetised mice was also completed, using 2D‐OIS concurrent with electrophysiology to assess neurovascular coupling. Immunohistochemistry was performed to assess amyloid plaque load within the brain.ResultIn the awake imaging session we found that neurovascular function was preserved in the AD group. However, mice in the atherosclerosis group showed a reduction in blood volume in response to a 2s‐whisker stimulation, compared to the WT group. We hypothesised that the mixed model would have the greatest impairment in the neurovascular response, however this was not observed and this group showed an evoked‐blood volume change in between levels of AD and atherosclerosis only groups.ConclusionPreliminary results suggest that neurovascular function is impaired in mouse models of atherosclerosis but not in the AD or mixed models. Analysis is ongoing to determine how neural activity and AD pathology are impacted by comorbidity.
Modulation of the spread of pathological tau in vitro and in vivo
Authors: Panzi Chiara , Restani Laura , Novelli Elena , Guarascio Rosellina , Cheetham Michael , Wray Selina , Caleo Matteo , Schiavo Giampietro 
Published: December 2022

AbstractBackgroundIn tauopathies such as Alzheimer’s disease, tau aggregates are known to propagate across functionally connected neuronal networks, but the mechanisms underlying this process are poorly understood. Several lines of evidence support the hypothesis that tau release is dependent on neuronal activity. Pathological tau can be found in the extracellular space, inside synaptic vesicles, and other synaptic compartments, or in a free form. We aim to test both in vitro and in vivo the effect of selected botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) on the release of tau from synaptic terminals. BoNTs and TeNT enter synapses and cleave different synaptic SNARE proteins, impairing synaptic vesicle fusion and release and they may affect tau spread.MethodPrimary neurons were cultured in MFCs and transduced with lentiviruses expressing human tau (hTau) isoforms. Cells were treated with BoNTs and stimulating agents. The content of hTau in the culture media was quantified with an enzyme‐linked immunosorbent assay (ELISA). Adeno‐associated viral vectors (AAVs) expressing hTau were injected in the vitreous, and the superior colliculus (SC) and lateral geniculate nucleus (LGN) areas were analysed through immunohistochemistry.ResultThe release of the 1N4R mutant hTau (P301S), but not the wild‐type form, is affected by botulinum neurotoxin type A (BoNT/A) and neuronal stimulation, which, respectively, significantly decreases and increases the release of P301S hTau. The AAV constructs are correctly expressed in both primary neurons and in retinal ganglion cells (RGCs), and brain sections of SC and LGN were analysed.ConclusionClostridial neurotoxins represent a powerful tool for the study of neurons and synapses. Using BoNT/A, we showed that hTau release is modulated by specific SNARE complex components and differs depending on the isoform. The use of other BoNT types in both in vitro and in vivo models will help us to identify the SNARE proteins involved in tau release. This approach will provide novel insights on the mechanisms controlling tau release from synaptic terminals and identify novel molecular targets for the development of therapeutic interventions to treat tauopathies.
Prevalence of Suspected Dementia in a Sample of Adults Living in Kinshasa‐Democratic Republic of the Congo
Authors: Ikanga Jean N 
Published: December 2022

AbstractBackgroundThe improved life expectancy in Sub‐Saharan Africa are leading to increased burden of dementia. This study investigates the prevalence and risk factors for suspected dementia in elderly adults in Kinshasa, Democratic Republic of the Congo (DRC).MethodParticipants included 356 individuals over 65 years old (mean = 73.6 years; SD = 6.7 years; range = 65‐98 years) recruited in Kinshasa. The sample was 51% male with an average 7.3 (SD = 4.7 years; range 0‐20 years) years of education. Participants were screened using Community Screening Instrument for Dementia, Alzheimer’s Questionnaire, Geriatric Depression Scale, Beck Anxiety Inventory and Individual Fragility Questionnaire followed by clinical interview and neurological screening. Suspected dementia diagnoses were made based on DSM‐5 criteria including significant cognitive and functional impairments. Prevalence and odd ratios with 95% confidence interval were calculated using logistic regression.ResultThe crude prevalence was 6.2% in Kinshasa. The prevalence of suspected dementia was 9.0% in women and 3.8% in men. Female sex was a significant predictor of suspected dementia [OR = 2.81, 95% CI (1.08‐7.41), p = 0.03]. The prevalence of dementia increased with age (14.0% after 75 years and 23.1% after 85 years), with age being a significant risk factor [OR = 5.42, 95% CI (2.86‐10.28), p <.0001. Greater education was associated with lower prevalence of suspected dementia [OR = 0.36, 95% CI (0.14‐0.94), p = 0.04, comparing those with ≥7.3 to <7.3 years of education]. Widow and being semi‐retired or retired were significant risk factors. Anxiety [OR = 2.56, 95% CI (1.05‐6.13), p = 0.04] and death of a spouse or a relative after age 65 [OR = 0.73, 95% CI (0.58‐0.92), p = 0.01] were significant risk factors for suspected dementia while depression [OR = 1.92, 95% CI (0.81‐4.57)], hypertension [OR = 1.16, 95% CI (0.79‐1.71)], BMI [OR = 1.06, 95% CI (0.40‐2.79)], and alcohol consumption [OR = 0.83, 95% CI (0.19‐3.58)] were not significant predictors of suspected dementia.ConclusionThis study found a prevalence of suspected dementia in Kinshasa/DRC similar to other developing countries and Central African countries. Being elderly, female, less educated, widow, retired, having anxiety and experiencing death after age 65 were significant risk factors for suspected dementia.
Hyperorality in Frontotemporal dementia: Cognitive, Behavioral, and Neuroanatomic Profiles in Early‐Stage Disease
Authors: Morrow Christopher , Kamath Vidyulata , Onyike Chiadi U. ,   ALLFTD Consortium
Published: December 2022

AbstractBackgroundHyperorality represents a key feature observed in the behavioral variant of frontotemporal dementia (bvFTD). While hyperorality is common in advanced cases of bvFTD, less is known about its frequency in early‐stage disease. The cognitive, behavioral, and neuroanatomic patterns of patients with early stage bvFTD and hyperorality have also not been well established. The primary aim of this study is to describe the frequency of hyperorality in a sample of patients with early stage bvFTD while also exploring patterns of cognitive, behavioral, and neuroanatomic change.MethodData are from subjects enrolled in the ALLFTD study, an established US consortium with an ongoing cohort study of FTD. Cognitive profiles were assessed using validated neuropsychological batteries, and social behavior was measured using validated scales. Psychiatric states were coded as binary variables. Differences in baseline characteristics and clinical outcomes were compared using t‐tests for continuous variables and Pearson χ2 tests for categorical variables. Statistical significance was based on p values <0.05.ResultWe enrolled 1,694 subjects, comprising 145 with a CDR® plus NACC FTLD global score less than or equal to 1 at the first visit who were used in our analysis. 50% of subjects exhibited hyperorality. There were no demographic differences between groups other than CDR global scores which were higher in the hyperorality group (0.8 versus 0.7, p = 0.003). Cognitive profiles encompassing domains of processing speed, language, executive functioning, memory, and attention did not differ between groups. Subjects with hyperorality had lower scores on scales of self‐monitoring, empathetic concern, and perspective taking. Subjects with hyperorality had higher rates of motor disturbance, and ritualistic/compulsive behaviors. There were no volumetric differences in neuroanatomic regions of interest.ConclusionOur findings indicate that hyperorality is common in early stage bvFTD, arising prior to cognitive and neuroanatomic changes. Hyperorality travels with motor disturbances and ritualistic/compulsive behaviors alongside eroding social behavioral functioning. Hyperorality may serve as an early signal of disease, providing an opportunity for intervention prior to significant neurodegeneration using novel therapeutics and non‐invasive brain stimulation.