bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intra‐cellular accumulation of Aβ and pTau in Alzheimer’s disease is neuronal‐subtype specific
Authors: Caramello Alessia , Jackson Johanna , Hardy John A. , Matthews Paul M 
Published: December 2023

AbstractBackgroundNeuronal degeneration in Alzheimer’s disease (AD) is believed to selectively affect a subset of vulnerable neurons (VNs) first. Here we sought to define intrinsic cell characteristics and local pathology involving pTau and b‐amyloid (Aβ) associated with VNs with the long‐term objective of developing cell type‐specific neuroprotective therapies.MethodWe analysed 43 post‐mortem human middle temporal gyri (MTG) from controls and AD donors, bearing either the common variant (CV) or the AD high‐risk R47H/R62H TREM2 variants (TREM2var; Fancy et al., 2022). To identify VNs and characterize their morphology, local β‐amyloid and pTau and glial activation, we developed an antibody panel for imaging mass cytometry (IMC) that included 21 markers for synapses, excitatory and inhibitory neurons, 10 markers for astrocytes, oligodendrocytes, and microglia, and 3 for Aβ, pTau and APP. The SIMPLI pipeline (Bortolomeazzi et al., 2022) was used for image processing, analysis, and clustering. Data and statistical analysis were performed in R using T test corrected for multiple testing.ResultIndividual neuronal populations are not significantly reduced in AD samples compared to controls, both in total number and layer‐specific distribution. While extra‐cellular pTau and Aβ accumulation was increased in AD samples, intra‐cellular signal for Aβ was higher in controls (13.76±5.95% Aβ+ cells) than with AD, particularly in AD TREM2var cases (6.4±2.82%; p = 0.0035). Ab accumulated particularly in VIP+, PCP4+ and RORB+ neurons (6.58x, 4.82x and 4.38x more Aβ+ these neurons in the control vs. AD TREM2var), the former also showing highest proportion of APP expressing cells in controls. Compared to controls, pTau accumulation in AD TREM2var was increased 2‐3x in few neuronal subpopulations (ADARB1, CALB1, GAD1, NPY, VIP), with RORB+ cells having the most striking increase (51.95x).ConclusionIntra‐cellular accumulation of pTau and Aβ is cell‐type specific, selectively involving RORB+ and VIP+ neuronal subpopulations. Greater Aβ accumulation was found in samples from Braak stages <III, suggesting these pathological aggregates long anticipate neuronal death. Analysis of brain regions affected earlier in AD will be used to test this hypothesis.
Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson’s disease
Authors: Phillips Bridget , Western Daniel , Wang Lihua , Timsina Jigyasha , Sun Yichen , Gorijala Priyanka , Yang Chengran , Do Anh , Nykanen Niko‐Petteri , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Morris John C , Schindler Suzanne E. , Fagan Anne M. , Puerta Raquel , García‐González Pablo , de Rojas Itziar , Marquié Marta , Boada Mercè , Ruiz Agustin , Perlmutter Joel S. , Ibanez Laura , Perrin Richard J. , Sung Yun Ju , Cruchaga Carlos 
Published: December 2023

AbstractBackgroundLeucine‐rich repeat kinase 2 (LRRK2) common gene variants (tagged by rs76904798) are associated with Parkinson’s disease (PD) risk. In a previous study, we found that rs76904798 was associated with CSF GRN levels, but a comprehensive unbiased analysis of associated proteins remains incomplete due to prior focus on cis‐protein quantitative trait loci (pQTL). Using the largest aptamer‐based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals), we performed a trans‐pQTL study to identify proteins associated with the LRRK2 variants and used additional mediation and pathway analyses to better understand downstream effects (Figure 1).MethodSNP selection using Conditional and Joint Association Analysis (GTCA‐COJO) and PLINK LD r2 scores identified 11 other independently associated SNPs. Fine mapping was performed between each significant aptamer and PD GWAS via proteome‐wide association studies (PWAS) and Mendelian randomization (MR). These aptamers were further analyzed based on PD risk association, brain cell‐type specificity, and gene pathway annotations.ResultOverall, 26 proteins passed FDR correction and eleven were implicated in PD prior like GRN and GPNMB. PWAS analyses using TWAS/FUSION also indicate 12 proteins were significant and positively associated with PD risk, such as novel proteins C1QTNF1 and SDCBP2, and half were validated by the PPMI data. MR analyses indicate that GRN, GPNMB, HLA‐DQA2, CD68, and LCT are also causal for PD risk (Table 1). Cell‐type enrichment analyses indicate microglia‐specific protein enrichment (Fold change: 7.35, P = 4.91×10−5). Enrichment analyses indicate enrichment for leukocyte activation (GO:0045321, P = 0.002) and microglial cell activation (GO:0001774, P = 0.003) pathways.ConclusionTrans‐pQTL can identify novel protein interactions in an unbiased manner. This study linked LRRK2 variants with both PD implicated (GRN, GPNMB) and novel (ITGB2, C1QTNF1) proteins that have support in our PWAS, MR, and PPMI differential protein level analyses. Microglia and lysosome enrichment support the previous observations regarding the importance of microglia and immune system function in the underlying pathobiology of PD (Figure 2). Our results suggest that the CSF concentrations of these proteins (such as GRN, GPNMB, C1QTNF1, and ITGB2) have potential as biomarkers for target engagement and disease progression modification in clinical trials that target LRRK2.
AL002c‐mediated reduction in amyloid β pathology is reflected by changes in plasma Alzheimer’s disease biomarkers in 5XFAD mice
Authors: Burgess Brady , Ibrahim Adiljan , Stansley Branden , Schwabe Tina , Wang Shoutang , Colonna Marco , Tassi Ilaria 
Published: December 2023

AbstractBackgroundThe R47H variant of the triggering receptor expressed on myeloid cells‐2 (TREM2) gene increases the risk for late‐onset Alzheimer’s disease (LOAD) and reduces TREM2 ligand binding in vitro, suggesting that enhancing TREM2 signaling has therapeutic potential in AD. AL002 is a novel humanized monoclonal Immunoglobulin G1 (IgG1) antibody that targets TREM2 and is currently being tested in a phase 2 trial in patients with early AD. Previously, AL002c, a variant of AL002, reduced filamentous amyloid β (Aβ) plaques and neurite dystrophy and increased inert plaques in a 5XFAD mouse model, while other Aβ pathology measures did not show treatment effects. Total Aβ42/40 ratio in plasma is inversely associated with amyloid burden independent of AD clinical diagnosis2 and is being used as a biomarker in AD clinical trials.3 To further evaluate the impact of AL002c on Aβ pathology, the present study assessed plasma AD biomarkers, including Aβ42/40 ratio, in residual samples from these 5XFAD mice.MethodFive‐month‐old 5XFAD mice (N = 32, n = 6‐13 per group) expressing either common variant (CV) or R47H variant human TREM2 (hTREM2), but lacking endogenous mouse Trem2, were injected intraperitoneally with 30 mg/kg AL002c or control mouse IgG1 weekly for 12 weeks (Figure 1). Levels of plasma Aβ42, Aβ40, and total tau (t‐tau) were quantified using Simoa® assay (Quanterix).ResultAL002c‐treated CV‐5XFAD and R47‐5XFAD mice had a higher plasma Aβ42/40 ratio (CV‐5XFAD p <0.001; R47‐5XFAD p<0.05; pooled CV and R47‐5XFAD p < 0.01) and lower plasma t‐tau (CV‐5XFAD p <0.05; R47‐5XFAD p<0.001; pooled CV and R47‐5XFAD p < 0.01) compared with their IgG1‐treated genotype counterparts (Figure 2). No differences were observed between R47H and CV genotypes in plasma Aβ42/40 ratio or t‐tau.ConclusionAL002c‐associated changes in plasma Aβ42/40 and tau were consistent with a concomitant reduction in filamentous plaques and neurite dystrophy.1 These results lend further support to the clinical utility of plasma Aβ42/40 as a marker for the reduction of neurotoxic amyloid plaques in clinical trials with AL002.
CSF proteome profiling reveals a protein panel detecting amyloidosis and progression to dementia in cognitively unimpaired individuals
Authors: del Campo Marta , Quesada Carlos , Vermunt Lisa , Peeters Carel F.W. , Hok‐A‐Hin Yanaika S. , den Braber Anouk , Verberk Inge M.W. , Visser Pieter Jelle , Tijms Betty M. , van der Flier Wiesje M. , Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundUnderstanding the earliest biochemical changes related to Alzheimer´s disease (AD) pathology is essential for the development of biomarkers and disease‐modifying therapies. Here, we aimed to map the cerebrospinal fluid (CSF) proteomic changes associated with amyloid ß (Aß) pathology in cognitively unimpaired individuals and identify a panel of CSF biomarkers detecting amyloid positivity as well as clinical progression to dementia.MethodProximity extension‐based multiplex immunoassays were used to measure 614 proteins in 297 CSF samples from cognitively unimpaired controls with and without amyloid pathology (232 CON/Aβ‐ (age: 68±8; sex: 37% female) and 65 CON/Aβ+ (age: 65±7; sex: 49% female) from the Amsterdam Dementia cohort. A total of 39 cases (13%) progressed to mild cognitive impairment (MCI; n = 19) or dementia (n = 20). An additional cognitively unimpaired control cohort from the EMIF‐twin60+ study (103 CON/Aβ‐ and 19 CON/Aβ+) was used to validate the panel. Data was analysed using nested linear models adjusted for multiple testing and penalized generalized linear modelling.ResultWe identified 110 CSF proteins with different levels in CON/Aβ+ compared to Aβ‐ (q<0.05). Proteins were enriched in processes related to proteolysis, enzyme activation and immunity. Classification modelling revealed a panel of 12‐CSF markers that detect amyloid positivity with high accuracy in both the discovery (AUC: 0.93) and validation (AUC: 0.89) cohorts. This panel also predicted clinical progression to MCI and dementia with high accuracy (AUC: 0.83). Chow´s test analysis revealed a structural change in the relation between a subset of these proteins and CSF Aβ42 before the amyloid positivity threshold.ConclusionOverall, this study provides novel pathophysiological leads associated to distinct biological processes in individuals at risk of developing AD‐dementia and provides potential biomarker tools for clinical settings or trials.
A new non‐verbal was developed to differentiate dementia and non‐dementia people and the study was to evaluate its validation
Authors: Huang Guan‐Tsz , Li Kuan‐Ying , Huang Ling‐Chun , Yang Yuan‐Han 
Published: December 2023

AbstractBackgroundDementia, which presents as cognitive decline in one or more cognitive domains affecting function, is increasing globally. Early diagnosis of dementia for general population is important, which needs a screening tool capable of identifying dementia efficiently.Most cognitive tests for screening dementia are based on verbal administration, which will be influenced by cultural background and language differences, if any.Developing a screening tool less depended on verbal administration is crucial for these necessities.MethodParticipants aged from 50 to 89 years old were recruited from department of Neurology, Kaohsiung Municipal Ta‐Tung Hospital, Taiwan. Dementia was diagnosed based on clinical diagnosis with referring to cognitive test performance by psychologists by 2011 National Institute on Aging and Alzheimer’s Association (NIA‐AA) criteria for all‐cause dementia .Participants were assessed with Clinical dementia rating (CDR), Cognitive Abilities Screening Instrument (CASI), derived Mini‐Mental State Examination (MMSE) and the non‐verbal cognitive test consisted of visual memory test, digital connection test, clock puzzle, shape color matching and simple card sorting test. These tests were designed to capture cognitive function including visual memory, visuospatial ability, and executive function. Statistical analysis was performed using MedCalc, version 20.14.ResultIn total, 160 demented patients and 81 non‐demented participants were recruited. The performance of the dementia group was worse than that of the control group in all non‐verbal tests. Among these tests, visual memory had the greatest ability to examine dementia with its percentage of recalled visual memory with optimal cut‐off point 70% having a sensitivity 73.38%,specificity 85.19% and area under the curve (AUC) as 0.87. Combining visual memory test, the digital connection test‐1 and the clock puzzle‐1 to discriminate dementia, the AUC was 0.93 and was superior to the AUC of MMSE (AUC = 0.88).ConclusionCompared to traditional pencil‐paper tests, non‐verbal tests shown its potentials in screening dementia with fewer language limitation.
Cholinergic deficit induced memory retrieval deficit and hippocampal CaMKII‐alpha deregulation is counteracted by sub‐chronic agmatine treatment in mice
Authors: Ostovan Vahid Reza , Baberi Nahid , Farrokhi Majid Reza , Moezi Leila , Pirsalami Fatema , SoukhakLari Roksana , Moosavi Maryam 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is one of the most prevalent neurodegenerative disease characterized by brain cholinergic dysfunction. Evidence suggests the impairment of memory retrieval phase in AD. It has been shown that CaMKII‐α expressing neurons are selectively reduced in the hippocampus in AD brains. The present study aimed to investigate the effect of scopolamine on the memory retrieval phase and the hippocampal CaMKII‐α signaling. In addition, the effect of sub‐chronic administration of agmatine against scopolamine induced memory and possible hippocampal CaMKII‐α deregulation was investigated in mice.MethodAdult male NMRI mice were administered with agmatine at the doses of 5, 10, 20, 30 and 40 mg/kg/i.p. or saline for 11 days. Acquisition and retrieval tests of passive avoidance task were performed on days 10 and 11, respectively (30 Min following agmatine treatment). Scopolamine (1 mg/kg/i.p.) was administered once, 30 Min before retrieval test. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of CaMKII‐α and beta actin proteins.ResultThe results showed that scopolamine induced memory retrieval deficit and decreased the phosphorylated level of hippocampal CaMKII‐α. Sub‐chronic agmatine treatment at the dose of 40 mg/kg prevented scopolamine induced memory retrieval deficit and restored the level of hippocampal phosphorylated CaMKII‐α.ConclusionThis study suggests that hippocampal CaMKII‐α might play a role in scopolamine induced amnesia and sub‐chronic agmatine prevents the impairing effect of scopolamine on the retrieval phase of memory and the phosphorylation of hippocampal CaMKII‐α protein.
Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation: A case report
Authors: Fernandez Paulo Eduardo Lahoz , Cordeiro Anna Beatriz Perdigão , Bertolucci Paulo Henrique Ferreira 
Published: December 2023

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and personality changes. Findings show variation in the disease progression. Some patients show a rapid progression over a few years, and others show little or no changes over a decade (1) Mutations in the amyotrophic lateral sclerosis 2 (ALS2) gene cause autosomal recessive motor neuron diseases, including juvenile‐onset amyotrophic lateral sclerosis (JALS), and other associated disorders. (2) We present a rare case.MethodWe describe the clinical and imaging features of a man who presented a rare case of Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation.ResultA 63‐year‐old man presented a 10‐year history of insidious and slowly progressive behavioral changes. He showed reduced emotional responsiveness, with no concern since his wife had received a diagnosis of a malignancy. He followed with disinhibition, and impulsive actions such as excessive shopping with no payment, overspending, and socially inappropriate behavior. He also had a compulsive/ritualized behavior with stereotyped speech, and counting repeatedly steps. His medical family history was unremarkable. The neuropsychological evaluation showed impairment of executive functioning, MMSE 27/30. Neurological examination was normal. Brain MRI frontotemporal atrophy with a marked asymmetry in the right temporal lobe in sagittal, axial, and coronal sequences. CSF biomarkers showed elevated t‐tau with no other changes, and the genetic test showed an ALS2 heterozygous mutation., also counting repeatedly steps.ConclusionThe presence of the C9ORF72 mutation has been shown in slowly progressive FTD, however, other mutations such as ALS2 have not yet been reported with the following phenotype, as in this case (3)References:1. Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges JR. Can progressive and non‐progressive behavioural variant frontotemporal dementia be distinguished at presentation? J Neurol Neurosurg Psychiatry. 2009 Jun 1;80(6):591‐3.2. Sheerin UM, Schneider SA, Carr L, Deuschl G, Hopfner F, Stamelou M, et al. ALS2 mutations. Neurology. 2014 Mar 25;82(12):1065‐7.3. Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry. 2012 Apr;83(4):358‐64.
Speech changes in neurodegenerative diseases relate to clinical outcomes
Authors: Gumus Melisa , Koo Morgan , Bhan Aparna , Robin Jessica , Black Sandra E. 
Published: December 2023

AbstractBackgroundThe detection and characterization of speech changes may help in the identification of neurodegenerative diseases and have the potential to help with patient characterization and monitoring. Yet, there is limited research validating the presence of speech changes across different types of neurodegenerative disease. We report on the relationships between speech and other clinical assessments in the individuals with different dementia diagnoses and in comparison to healthy older adults.MethodWe analyzed speech recordings from 109 patients (52F, 57M; Age = 72.63± 8.61) who were diagnosed with various neurodegenerative diseases, including Alzheimer’s disease, Frontotemporal Dementia, and Vascular Cognitive Impairment, in a cognitive neurology memory clinic. Speech recordings of an open‐ended picture description task were processed using the Winterlight speech analysis platform which generates >500 acoustic and linguistic features. We investigated the linear relationship between the speech features and clinical assessments including the Mini Mental State Examination (MMSE), Western Aphasia Battery (WAB), and Mattis Dementia Rating Scale while controlling for age, sex and years of education. Speech features that were significantly associated with clinical measures were then included in group comparisons with healthy older adults (N = 74, ∼39F; Age = 61.31±7.29).ResultSpeech features including lexical and syntactic features were significantly correlated with clinical assessments in patients, across diagnoses. Lower MMSE scores were associated with the use of more familiar nouns (β = ‐1.60, p<.001). Similarly, increased impairment as assessed by the WAB was correlated with the use of higher frequency nouns (β = ‐0.01, p<.001). Patients used significantly more nouns (z = 6.25, p<.001) and shorter words (z = 8.33, p<.001) than the healthy older adults. Their speech duration was also significantly shorter (z = 7.98, p<.001) and they paused more (z = 5.19, p<.001).ConclusionSpeech changes representing decreased speech, with simpler vocabularies and syntax, were detectable in patients with different neurodegenerative diseases and correlated with clinical outcomes. These same speech patterns differed in patients with neurodegenerative disease compared to healthy older adults. Speech has the potential to be a sensitive measure for detecting cognitive impairments across various neurodegenerative diseases.
A case‐series comparison of semantic control in the logopenic variant primary progressive aphasia and Alzheimer’s disease
Authors: Henderson Shalom K , Rowe James B. , Ralph Matthew A Lambon 
Published: December 2023

AbstractBackgroundSemantic cognition requires both semantic representation (conceptual knowledge), and semantic control (the ability to shape and manipulate information for a particular context/task) (Lambon Ralph, Jefferies, Patterson, & Rogers, 2017). Prior investigations have contrasted the semantic representation loss in semantic dementia with semantic control deficits in post‐stroke semantic aphasia (SA) (Jefferies & Lambon Ralph, 2006; Thompson et al., 2022). The logopenic variant of primary progressive aphasia (lvPPA) has neuroanatomical commonalities with SA, including damage centred on the left temporoparietal and inferior frontal regions, and neuropsychological commonalities including executive and language impairments. Accordingly, we investigated whether lvPPA impairs semantic control.MethodWe compared 12 individuals with lvPPA, 9 with typical amnestic Alzheimer’s disease (AD), and 12 age‐matched healthy controls on a battery of verbal and non‐verbal semantic, language, memory and executive functioning tests.ResultThe lvPPA patients spanned multiple levels of performance across the different tests and showed the characteristic features of a semantic control deficit: (i) They showed impairments in tests that require greater semantic demand (e.g., semantic association knowledge test more than straightforward word‐picture matching); (ii) only lvPPA patients showed strong correlations between semantic and executive tests; (iii) an effect of item familiarity was not found in lvPPA patients; and (iv) both lvPPA and AD patients benefited from phonemic cueing on the Boston Naming Test.ConclusionLvPPA patients’ performance on semantic tests is similar to that of previously reported SA, suggesting an impairment of semantic control. Imaging analysis is underway and will be available at the AAIC conference.
References:Jefferies, E., & Lambon Ralph, M. A. (2006). Semantic impairment in stroke aphasia versus semantic dementia: a case‐series comparison. Brain, 129(Pt 8), 2132‐2147. https://doi.org/10.1093/brain/awl153
Lambon Ralph, M. A., Jefferies, E., Patterson, K., & Rogers, T. T. (2017). The neural and computational bases of semantic cognition. Nat Rev Neurosci, 18(1), 42‐55. https://doi.org/10.1038/nrn.2016.150
Thompson, H. E., Noonan, K. A., Halai, A. D., Hoffman, P., Stampacchia, S., Hallam, G., . . . Jefferies, E. (2022). Damage to temporoparietal cortex is sufficient for impaired semantic control. Cortex, 156, 71‐85. https://doi.org/10.1016/j.cortex.2022.05.022