bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing reactive astrogliosis in Parkinson’s brain with astroglial tracers BU99008 and deprenyl
Authors: Rocha Filipa Monteiro , Nordberg Agneta K , Kumar Amit 
Published: December 2023

AbstractBackgroundThe knowledge regarding the role of reactive astrogliosis in Parkinson’s disease (PD) is still at the surface level, however, a few in vivo PET studies have speculated that reactive astrogliosis could be an early event in PD pathology. Moreover, a direct link between α‐synuclein pathology and astrocytes in PD has been also shown, where astrocytes play a key role in α‐synuclein propagation by shuttling α‐synuclein between neurons and astrocytes. The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) (targeting MAO‐B) and 11C‐BU99008 (detect imidazoline‐2‐binding sites (I2Bs)), which we believe is crucial to explore the role of reactive astrogliosis, including astrocytic heterogeneity in PD. Hence, we used a multi‐tracer approach to understand the role of reactive astrogliosis and to validate its reliability as a potential biomarker in PD and related synucleinopathies.MethodWe used specialized postmortem saturation radioligand binding assay and small frozen human brain section autoradiography in PD and controls (CN) brains.ResultThe 3H‐BU99008 and 3H‐DED saturation binding studies in the frontal cortex (FC) brain homogenate (BH) of PD (n = 2‐3) and CN (n = 2) cases demonstrated relatively higher 3H‐DED binding as compared to 3H‐BU99008 with following Bmax (binding‐density) and Kd values: 3H‐BU99008 CNBmax – 59.1fmol/mg, Kd‐ 2.9nM vs. PDBmax – 51.6fmol/mg, 2.3nM; 3H‐DED CNBmax – 190.6fmol/mg, Kd‐ 2.7nM and PDBmax –244.2fmol/mg, Kd‐ 6.7nM. 3H‐BU99008 binding in the Cau in PD was ∼3‐fold higher than in CN. In contrast, the 3H‐DED binding between CN and PD brains in the Cau BH was almost comparable. Interestingly, qualitative, and semi‐quantitative assessment of small frozen brain section autoradiographies showed increased specific binding of 3H‐BU99008 and 3H‐DED in PD (n = 4) frontal & temporal cortices as compared to CN (n = 2‐3). In Cau, 3H‐BU99008 again showed higher binding than CN whereas 3H‐DED binding was comparable to CN, further complementing our saturation data.ConclusionThe first study to assess reactive astrogliosis signature in postmortem PD brains with astroglial tracers BU99008 and DED. The findings clearly highlight regional differences in BU99008 and DED binding in PD brains and suggest increased reactive astrogliosis at the end stages of the disease warrants further investigation.
Geographic bias in hand preference within posterior cortical atrophy
Authors: Chapleau Marianne , Seaman Julia , Allen Isabel Elaine , Bogley Rian , Montembeault Maxime , Miller Bruce L , Tempini Maria Luisa Gorno , La Joie Renaud , Rabinovici Gil D. , Miller Zachary ,   International PCA Work Group
Published: December 2023

AbstractBackgroundPosterior cortical atrophy (PCA) is a neurodegenerative disorder of visuospatial and visuoperceptual impairment with high association to underlying Alzheimer’s disease (AD) pathology. In contrast to typical amnestic AD, risk factors for PCA remain largely unknown. Previously, we observed higher rates of neurodevelopmental differences in PCA, including an increased prevalence of non‐right‐handed individuals (left‐handed, ambidextrous, and/or forced‐right‐handed) compared to the general population. Non‐right‐handedness has been associated with many neurologic and psychiatric conditions, and we have found is overrepresented in early and non‐amnestic forms of AD. In this study, we sought to investigate handedness within an international PCA cohort.MethodWe contacted 55 research centers conducting PCA research identified in a literature review (n = 1353 papers), as well as additional sites recruited through the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Atypical AD Professional Interest Group (n = 7 sites) requesting de‐identified, single‐subject data from PCA patients. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected from 1121 participants evaluated at 34 sites in 16 countries. In this sub‐project, the sample size was restricted to the 901 PCA participants with reported handedness. Descriptive analyses were performed across the entire cohort and across three different geographic levels: by 1) center, 2) country/region, and 3) continent. Statistical analyses were restricted to the continental view given sample size constraints.ResultWithin the total consortium PCA cohort, 10.3% (93/901) were non‐right‐handed. Figure 1 shows the distribution of non‐right‐handedness across country/region. Comparisons across continents revealed differences in handedness (p = 0.04, Yate’s corrected). Sample sizes in Asia, Australia, and South America did not permit comparisons of observed vs. expected rates of non‐right‐handedness, whereas Europe displayed significantly less and North America significantly more non‐right‐handedness than expected (p = 0.04 and p = 0.02, respectively, employing a 10% non‐right‐handedness rate for the general population).ConclusionWithin the international PCA consortium, differences in hand preference presented across centers in a manner that could not be explained by normal variation in the data. Uncovering this global bias in hand preference not only holds relevance towards understanding the etiology of PCA but may have implications for neuroscience research more broadly.
Levels of activating transcription factor 6 alpha (ATF6α) in Alzheimer’s disease
Authors: Chauvet Mariana Gomes , Isaac Alinny Rosendo , Ferreira Sergio T. , Lourenco Mychael V. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. More than 40 million people currently suffer from AD, and such prevalence tends to increase considerably in the coming decades due to increased human longevity. Nonetheless, despite intense research efforts, no therapy has yet proven effective in attenuating or reversing the progression of AD. The unfolded protein response (UPR) is an adaptive signaling mechanism that aims to maintain cell viability under protein folding stress. The accumulation of misfolded proteins is associated with several neurodegenerative diseases, such as AD, leading to synaptic loss and neuronal death. UPR activation depends on stress sensors such as ATF6α (activating transcription factor 6 α). Recently, ATF6α factor gained importance as a therapeutical target in some disorders and pharmacological activation of this pathway has already been shown to be protective in heart disease. Nonetheless, the association between the ATF6α pathway and AD is not fully understood yet. Here we investigated whether dysfunctional ATF6α associates with AD.MethodATF6α protein levels were measured in postmortem tissue from the cerebral cortex and in hippocampus of APP/PS1 transgenic mouse model of amyloid patholy by western blotting. ATF6α mRNA expression was analysed using an online database (Aging, dementia and TBI study from the Allen Institute.ResultInitial results using postmortem tissue from the cerebral cortex suggested that ATF6α protein levels are reduced in AD patients. Using an online database (Aging, dementia and TBI study from the Allen Institute), we found reduced ATF6α mRNA expression, in relation to the Braak scale of tau pathology in the parietal neocortex and hippocampus. Conversely, we found increased ATF6α protein levels in the hippocampus of APP/PS1 transgenic mouse model of amyloid pathology.ConclusionTogether, our initial results suggest that ATF6α may be differentially altered in AD. Further investigation of the ATF6α pathway in AD may offer a novel therapeutic perspective for cognitive decline.
Multiomic analyses suggest a divergent aging trajectory in dementia
Authors: Coenen Loet , de Vries Helga E , Middeldorp Jinte 
Published: December 2023

AbstractBackgroundAging is the main risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD) and other forms of dementia. Both aging and dementia have been shown to leave a molecular signature in the plasma proteome. Understanding how the Dementia Plasma Proteome (DPP) diverges from the Aging Plasma Proteome may provide insights in pathological changes in the brains of dementia patients, or resilience mechanisms in the brain of cognitive healthy individuals. Here, we provide a more detailed overview on the aging trajectories of the DPP across ‘normal agers’ and dementia patients using a multiomic analysis approach.MethodUsing publicly available datasets such as the Human Protein Atlas, GTEx, and the Aging, Dementia and TBI study, we aim to link changes observed in the plasma to age‐associated changes in the brain and AD pathology. For this, we used publicly available databases. Using immunohistochemistry, we attempt to validate our findings in brain tissue.ResultWe show that differences in expression levels of proteins belonging to the DPP (Dementia Proteins) between non‐demented controls and demented cases are positively associated to previously identified aging associations. Furthermore, we show that Dementia Proteins are preferentially expressed in the brain and among multiple brain cell types, such as neurons, oligodendrocyte precursor cells and astrocytes. Expression trajectories during aging of brain‐expressed Dementia Proteins in the healthy brain appear largely similar as identified in the aging plasma proteome. However, we identified several proteins displaying differential aging trajectories in the brain of demented patients. Lastly, we present how these altered aging trajectories associate to several pathological measures, such as levels of Tau and Amyloid beta.ConclusionThese results suggest differences in aging trajectories between non‐demented controls and dementia patients, which may be reflected in both the plasma and in brains of dementia patients. Together, these results may provide novel insights in proteins associated with dementia‐associated pathology and their contributions to the disease progression. Future studies are needed to further validate these findings and to discover the underlying mechanisms.
Associations between insulin‐like growth factor‐1 and executive function in normoglycemia, prediabetes, and type 2 diabetes mellitus
Authors: Ryoo Si Won , Anita Natasha Z. , Perlman George , Xiong Lisa Y. , Wu Che‐Yuan , Mitchell Jane , Swardfager Walter 
Published: December 2023

AbstractBackgroundThe relationship between insulin‐like growth factor‐1 (IGF‐1) and cognition has been studied in healthy individuals, yet the results have been inconclusive. The aim of this study was to determine whether the association between IGF‐1 and executive function differs in individuals with normoglycemia, prediabetes, and type 2 diabetes mellitus (T2DM).MethodThe Midlife in the United States (MIDUS) study used the Brief Test of Adult Cognition by Telephone (BTACT) to assess cognitive function. A composite z‐score for executive function was created from the following tests: Digits backward span, category fluency, number series, backward counting, and Stop and Go Switch Task (SGST). IGF‐1 levels were measured from fasting blood samples using an immunochemiluminescent assay. Normoglycemia was defined as individuals without a physician diagnosis of diabetes and glycated hemoglobin (HbA1c) < 5.6%. Prediabetes was defined as those without a physician diagnosis of diabetes and HbA1c between 5.7%‐6.4%. T2DM was defined as anyone with a physician diagnosis of diabetes, or HbA1c ≥6.5%, or use of oral hypoglycemic medication. Multiple imputation was used to handle missing covariate data. A linear regression model controlling for demographic factors, homeostatic model of insulin resistance (HOMA‐IR), C‐reactive protein (CRP) levels, exercise, smoking, sleep disturbance, alcohol intake and medication use, was used to determine the cross‐sectional association between IGF‐1 and executive function across subgroups.ResultThe MIDUS dataset included 447 normoglycemia (47.0% female, mean age 53.4±9.6), 467 prediabetes (57.4% female, mean age 56.8±10.6), and 271 T2DM participants (53.1% female, mean age 57.5±9.8). In participants with prediabetes, IGF‐1 levels were associated with better executive function (β = 0.126, p = 0.007), particularly in males (β = 0.258, p<0.001). This association was absent in individuals with normoglycemia or T2DM. Compared to males with prediabetes, the opposite trend was observed in males with T2DM (β = ‐0.181, p = 0.062).ConclusionThe findings of this study suggest that the association between IGF‐1 and executive function may be influenced by insulin resistance or T2DM. Gaining a better understanding of why the associations differ in T2DM compared to prediabetes may explain the inconsistency observed in the literature and help elucidate the mechanism behind cognitive decline in T2DM.
Characterising the D409V/WT mouse as a novel model of Lewy body dementia
Authors: Sander Millie , Brown Jonathan T , Lunnon Katie , Ballard Clive G 
Published: December 2023

AbstractBackgroundThe overlap in both pathological and symptomatic traits observed among Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients make accurate diagnosis difficult. Novel models to further study DLB are therefore imperative, and previous research suggests mice with heterozygous mutations in the GBA gene (D409V/WT) to be a viable option. These mice display age‐related cognitive decline and α‐synuclein deposition in the brain (Clarke et al., 2019), and our prior work found there to be significant atrophy in the brain by 12 months of age.MethodWe aimed to further characterise disease‐associated pathology exhibited by these mice. Cortical thickness and vesicle size was measured among mice of 3, 6, 9, 12, and 18 months of age in order to assess atrophy progression with age. Neuronal firing in the medial septum was measured at both baseline and following application of NMDA – a drug used to elicit neuronal activity. Firing rate and latency to reach peak NMDA response were used to assess neuronal dysfunction. Finally, differential expression and weighted gene co‐expression network analysis (WGCNA) was conducted to assess transcriptomic changes in the medial septum. All studies used wild‐type littermates as controls.ResultAge‐associated cortical thinning and ventricle enlargement were observed, with all six measures reaching statistical significance by 12 months of age. Although latency to reach peak neuronal firing showed no difference between groups, firing rate was significantly reduced in D409V/WT mice across all conditions. Differential expression analysis found significant downregulated genes in the medial septum of the D409V/WT mice compared to the WT controls, and WGCNA analysis found various clusters of genes to be associated with both genotype and sex.ConclusionThese results present examples of DLB‐associated pathology exhibited by the D409V/WT mice, supporting their potential as a novel model of disease. However, further characterisation is needed in order for these mice to be considered a reliable model, and to be employed in wide‐scale research.References: Clarke, E. et al. (2019) ‘Age‐related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia’, Neurochemistry International, 129. https://doi.org/10.1016/j.neuint.2019.104502.
Dyslexia phenotypes in Chinese‐speaking individuals with Primary Progressive Aphasia
Authors: Tee Boon Lead , Tempini Maria Luisa Gorno , Chen Lorinda Li‐Ying Kwan , Lo Raymond Y. , Chen Ta‐Fu , Tsoh Joshua , Yan Connie TY , Chan Andrew LT , Lu Chien Jung 
Published: December 2023

AbstractBackgroundThere are more than 7,000 living languages worldwide with wide heterogeneities in their linguistic features. Varying dementia symptomatology has been noted across speakers of different languages. Chinese languages adopt logographic scripts that contrast greatly from Indo‐European languages with alphabetic writing systems. For instance, Chinese characters have weak grapheme‐phoneme correspondence, with only 19‐ 39% pronounced per their phonetic components. Chinese characters also have 20 different spatial configurations with varying visuospatial complexity and abundant heteronyms. Past literature has focused on the reading presentations of primary progressive aphasia (PPA) patients that adopt Indo‐European languages. This study outlined the reading presentations of Chinese‐speaking PPA patients.MethodThe CLAP (Chinese Language Assessment for PPA) battery is designed to characterize the neurolinguistics features of Chinese‐speaking PPA individuals. In CLAP character reading test, participants are tasked to read aloud 50 Chinese characters that vary in lexicality (pictographic, regular compound, and irregular compound characters), character frequency and concreteness. Voxel‐based morphometry(VBM) was performed to examine the neural basis of reading performance. Participants are also tasked with reading pairs of compound words with heteronyms (e.g., “bow tie” vs “bow down).ResultsA total of 15 Mandarin‐speaking controls and 38 PPA individuals [6 nonfluent variant (nfv) PPA, 9 semantic variant (sv) PPA and 23 logopenic variant (lv) PPA] completed CLAP reading task. In character reading test, svPPA scored significantly lower than controls and nfvPPA (pictographic: p = 0.026; regular compound: p = 0.007; irregular compound characters: p<0.001). Regardless of lexicality, the reading score significantly correlated with volumetric changes over left temporal pole. While over‐regularization errors/surface dyslexia was the most common reading error across control and PPA groups, it was not specific to svPPA (p = 0.109). Conversely, on heteronym word reading test, svPPA and lvPPA scored significantly lower in accuracy, with over‐regularization errors more frequently noted in svPPA group.ConclusionContrary to English svPPA patients that struggled specifically with irregular word reading and showed frequent surface dyslexia, Chinese PPA patients showed no variant‐specific differences across lexicality, and svPPA‐specific over‐regularization phenomenon were found at the lexical (i.e., heteronym‐reading) and not sub‐lexical reading. Diagnostic criteria for PPA syndrome vary with languages and should ideally be tailored linguistically.
Repurposing verbal fluency: Word‐property analysis reveals neurocognitive markers of Hispanics with Alzheimer’s disease and mild cognitive impairment
Authors: Garcia Adolfo M , Ferrante Franco , Pérez Gonzalo , Migeot Joaquín , Ibanez Agustin 
Published: December 2023

AbstractBackgroundThough central to dementia assessments, verbal fluency tasks are suboptimally exploited. Performance is typically measured by counting valid responses. This precludes insights on which word types are least accessible to patients, while failing to discriminate among disorders. Alternatively, each word can be decomposed into relevant properties that drive semantic memory retrievability. Recently, our team has combined objective lexical measures with multimodal imaging to examine whether this approach is sensitive to Hispanics with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), vis‐à‐vis others with behavioral variant frontotemporal dementia (bvFTD).MethodIn Experiment‐1, we recruited 32 AD patients and 32 bvFTD patients, matched with 27 HCs. Experiment‐2 involved 60 persons with MCI and 60 matched HCs. Participants performed phonemic and semantic fluency tasks. We counted valid responses and, using normative databases, extracted quantitative data of six word properties: frequency (occurrences in everyday use), granularity (conceptual specificity), neighborhood (words with similar phonological structure), length (number of syllables), familiarity (subjective recognizability), and imageability (ease of mental visualization). We examined whether these variables were robust to discriminate between groups (via ANOVAs), identify individuals from each cohort (via linear regressions), and capture cognitive, neuroanatomical, and functional connectivity disruptions.ResultsIn Experiment‐1, while both patient groups produced fewer valid responses than HCs, only AD patients showed distinct word properties (higher frequency, lower granularity, more phonological neighbors). Multivariate word properties robustly identified individual AD (but not bvFTD) patients from HCs (AUC = .89), driven by the abovementioned properties. These features correlated with executive outcomes only in AD, and they predicted patients’ anatomical and functional disruptions along temporal, frontal, and cingulate regions. In Experiment‐2, the same word properties differentiated MCI individuals from HCs, with multivariate classification reaching an AUC of .75. These features correlated with the volume of, and connectivity between, temporal and frontal regions that partly overlapped with those observed in AD.ConclusionVerbal fluency tasks can be repurposed to reveal condition‐specific markers of persons with and at increased risk for AD. New avenues emerge towards scalable, low‐cost assessment of Hispanics and, potentially, other underrepresented populations.
Objectively‐determined parental history of dementia is associated with increased posterior white matter hyperintensity volume
Authors: Lippert Rafael V. , Turney Indira C , Lao Patrick J. , Pyne Jeffrey , Kraal A.Zarina , Alshikho Mohamad J , Berroa Joncarlos , Gutierrez Jose , Mayeux Richard , Manly Jennifer J. , Brickman Adam M. 
Published: December 2023

AbstractBackgroundCerebrovascular disease is associated with risk for dementia and possibly Alzheimer’s disease (AD) pathogenesis. Most people diagnosed with AD have mixed pathology, including plaques, tangles, and cerebrovascular disease. Because parental history of dementia is a strong risk factor for AD, studying the extent to which markers of cerebrovascular disease in midlife aggregate with parental history of dementia can provide insight into how risk for dementia is transmitted from one generation to the next. We previously showed that white matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, is associated with genetic risk, diagnosis, and progression of AD, particularly when distributed in posterior areas. Here, we examined if parental history of dementia, determined via prospective evaluation, is associated with regional distribution of WMH in middle age.MethodSix hundred thirty‐eight middle‐aged participants (mean±SD age = 54.4±10.5, 65% women, 70% Latinx, 21% Black, 9% non‐Latinx White) in the Offspring Study received MRI; regional WMH volumes were derived with in‐house software. Offspring Study participants are the adult children of participants in the Washington Heights Inwood Columbia Aging Project (WHICAP), a community‐based longitudinal study of cognitive aging and dementia in which participants are evaluated and diagnosed prospectively. A mixed design general linear model evaluated the severity and regional distribution of WMH between Offspring participants with and without parental history of dementia.ResultOf the Offspring participants included, 214 (34%) had a parent in WHICAP with a diagnosis of dementia. Offspring participants with a parental history of dementia had increased WMH (main effect of parental diagnosis: F = 3.58, p = 0.05), which varied by region (Parental Diagnosis x Region: F = 2.71, p = 0.04). There was greater WMH with parental diagnosis in parietal (t = 2.18, p = 0.02) and occipital (t = 3.05, p = 0.003) but not in frontal (t = 1.36, p = 0.17) or temporal (t = 0.25, p = 0.79) lobes.ConclusionMiddle‐aged adults with parental history of dementia have increased WMH volume, particularly in posterior brain regions, an anatomical pattern associated with risk and progression of AD. The results highlight the possibility that cerebrovascular disease is a core feature of AD, as WMH severity and parental history of dementia aggregate together.