bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synaptic dysfunction, Tau pathology and Neurodegeneration
Authors: Soares Carolina , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Aguzzoli Cristiano Schaffer , Rohden Francieli , Ferrari‐Souza João Pedro , Zalzale Hussein , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundTau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration in the same brain regions. Our study aims to map in the brain the association of synaptic markers with tau and degeneration.MethodWe evaluated 147 individuals from the TRIAD cohort with CSF GAP43, SYT1, SNAP25, neurogranin (Ng), ptau217, neurofilament light protein (NfL) quantification, as well as tau positron emission tomography (PET), magnetic resonance imaging, and clinical assessments. One‐way ANOVA tested group differences on synaptic levels. Spearman correlation tested the association among synaptic proteins. Linear regressions tested the association between biomarkers. Voxel‐based morphometry (VBM) was considered as an index of neurodegeneration.ResultWe observed an increase in synaptic markers across age and the AD spectrum, reaching a plateau when cognition is affected (Figure 1A). Among the synaptic markers, SNAP25 showed the greatest magnitude of change, on average, between young, aged cognitively unimpaired, mild cognitive impaired, and AD individuals (mean 62.44%). (Figure 1B‐C). In addition, we found that all synaptic markers are significantly intercorrelated (Figure 1D). Moreover, CSF ptau217 correlated with all synaptic biomarkers, GAP43 (β = ‐044), SYT1 (β = ‐0.41), SNAP25 (β = ‐0.59) and Ng (β = ‐0.25). Conversely, CSF NfL was strongly but only correlated with GAP43 (β = 0.62) (Figure 2). Voxel‐wise correlation revealed that tau tangles measured by [18F]‐MK6240 PET, was positively associated with SNAP25 in AD‐related regions, and VBM was associated with all synaptic markers, but more closely with GAP43. Furthermore, the interaction between synaptic markers and temporal meta‐ROI [18F]‐MK6240 on VBM was significant for Ng and GAP43 (Figure 3).ConclusionOur results support a heterogenous role of synaptic markers in the AD continuum and suggest that synaptic dysfunction in the presence of tau pathology may not be driving atrophy.
Sulfanegen, a 3‐mercaptopyruvate sulfurtransferase substrate, as a therapeutic option for Alzheimer’s disease
Authors: More Swati S , Rao Swetha Pavani , Xie Wei , Kwon Christopher , Juckel Nicholas , Vince Robert , Lee Michael K 
Published: December 2023

AbstractBackgroundThe oxidative stress evident in the Alzheimer’s disease (AD) brain leads to compromised 3‐mercaptopyruvate sulfurtransferase (3MST) function, one of the endogenous hydrogen sulfide (H2S) producing enzymes.1,2 Impaired 3MST function is expected to contribute toward potentiation of oxidative stress by depleting cellular glutathione (GSH) stores, and exacerbation of AD pathology by enhancing Aβ aggregation resulting in neurodegeneration. Preclinical studies with H2S donors such as NaSH have been promising,3,4 however further clinical translation efforts are thwarted due to their poor chemical stability, bioavailability, and dose‐limiting toxicities. We have developed a stable, bioavailable prodrug of 3MST substrate 3‐mercaptopyruvate, named sulfanegen, which can supplement the enzymatic reaction releasing H2S.2 Thus provision of sulfanegen could prove beneficial in mitigating AD‐related neurodegenerative consequences.MethodAged, symptomatic cohorts APP/PS1 mice (7 and 12 month old) were treated with saline (N = 8) or sulfanegen (75 mg/kg, i.p., N = 8) for 12 weeks. Cognitive behavioral assessments (T‐maze) were conducted 10‐11 weeks after treatment initiation. Equal numbers of both sexes of mice were used as much as possible. The harvested brain tissues were analyzed biochemically for cortical/hippocampal Aβ1‐42 burden, oxidative stress and inflammatory markers (protein carbonyls, lipid peroxidation, glutathione assay, TNF‐α and IL6. Quantitative stereological analysis of Aβ pathology, neuroinflammation and progressive neurodegeneration were also conducted.ResultTreatment of symptomatic Alzheimer’s mice with sulfanegen prevented cognitive impairment resulting from AD pathology (Figure 1).2 This was corroborated by reduced brain amyloid load as well as the reversal of oxidative stress and neuroinflammation. Neuropathological analysis also displayed modest, but significant effect of sulfanegen on Aβ levels, reactive astrogliosis and microglial reactivity. More importantly, sulfanegen caused attenuation of progressive degeneration of noradrenergic system in the LC. Additionally, administration of sulfanegen supplemented brain 3MP levels, resulting in restoration of brain 3MST function.ConclusionCollectively, our results show that the provision of a 3MST substrate, sulfanegen, exhibits neuroprotective effects, along with restoration of cognitive function in an AD mouse model. This study suggests an important role of 3MST in AD pathophysiology and potential therapeutic utility of sulfanegen as a disease‐modifying treatment.
Distinct Neural Correlates of Anxiety and Depression in Subjective Cognitive Decline versus Healthy Aging, a Microstructural Diffusion MRI Study
Authors: Flaherty Ryn , Sui Yu Veronica , Masurkar Arjun V. , Rusinek Henry , Lazar Mariana 
Published: December 2023

AbstractBackgroundA common criticism of considering Subjective Cognitive Decline (SCD) as a preclinical stage of Alzheimer’s Disease is that it may be explained by depression or anxiety1. We used NODDI, a diffusion microstructural model2, to explore the pathophysiology of depression and anxiety in SCD versus controls.Method325 participants in the Cam‐CAN study 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the NODDI metric Intracellular Volume Fraction (ICVF) were completed using MRTrix3, AMICO and MATLAB. The hippocampal cingulum bundle and fornix regions of interest (ROIs)4 were extracted from the ICBM‐DTI‐81 atlas. Depression and anxiety were assessed using the Hamilton Anxiety and Depression Scale (HADS). Linear regression models were completed in R. Gender and age were included as nuisance variables.ResultThere were no differences in gender or age distribution between cohorts, however participants with SCD were more depressed and anxious on average (Table 1). There was a significant interaction effect between depression and cohort in the fornix (Figure 1), as well as between anxiety and cohort in the hippocampal cingulum (Figure 2). In post‐hoc analyses, only the SCD group showed a correlation between depression and ICVF in the fornix (Figure 1) while only controls showed a correlation between anxiety and ICVF in the hippocampal cingulum (Figure 2), indicating different pathophysiology underlying psychiatric symptoms in the two groups.ConclusionAnxiety and depression appear to be associated with different microstructural features in SCD versus controls, suggesting anxiety and depression in SCD is a phenomenon distinct from anxiety and depression in healthy aging. Future work will explore the relationship between anxiety and depression and risk of conversion to mild cognitive impairment.1. Mitchell AJ, Beaumont H, Ferguson D, et al. Acta Psychiatrica Scandinavica. 2014;130(6):439‐51.2. Daducci A, Canales‐Rodriguez EJ, Zhang H, et al. Neuroimage. 2015;105:32‐44.3. Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25.4. Kantarci K. Frontiers in Aging Neuroscience. 2014;6.
The contribution of leisure activities to cognitive health in adults with chronic stroke
Authors: Hernández‐Gamboa Rebeca , Dao Elizabeth , Falck Ryan S , Liu‐Ambrose Teresa 
Published: December 2023

AbstractBackgroundStroke doubles one’s risk for dementia. Therefore, stroke survivors represent a target population in need of intervention strategies to promote cognitive function and prevent dementia. Engagement in leisure activities, such as social, physical, and cognitive enrichment activities, are beneficial for healthy cognitive aging. Thus, we hypothesize that higher levels of leisure activities are associated with better cognitive performance in adults with chronic stroke and may be a promising approach to promoting cognitive health post‐stroke.MethodA cross‐sectional analysis of baseline data from the Vitality study – a randomized controlled trial examining the effects of exercise training or complex mental and social activities on cognitive function in community dwelling older adults (aged 55+ years) living with chronic stroke (i.e., stroke sequelae ≥1 year). Our primary cognitive outcome was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale‐Plus (ADAS‐Cog Plus: 13‐item ADAS‐Cog and additional cognitive tests). We indexed participation in leisure activities using the Nottingham Leisure Questionnaire (NLQ); this questionnaire is specific for stroke survivors. We first investigated the bivariate correlation between leisure activities and ADAS‐Cog Plus score, and then performed multiple regression analyses to examine the independent contribution of leisure activities to explain variance in ADAS‐Cog‐Plus scores, after controlling for age, sex, education, and Montreal Cognitive Assessment (MoCA) score.ResultForty‐three females and 72 males were included in this analysis (mean age = 70.69 ±8.68, MoCA = 21.83±4.20, and NLQ = 22.84±7.26). Higher NLQ score was significantly associated with better ADAS‐Cog Plus score (r = ‐0.31; 95% CI: [‐0.47 ‐0.14]; p< 0.001). Importantly, the multiple linear regression indicated that higher NLQ scores were independently associated with better ADAS‐Cog Plus performance (b = ‐0.02 ± 0.007; p = 0.01). The adjusted R2 for the model including NLQ was significantly higher than the model without NLQ scores (F = 6.45, p<0.05).ConclusionOur findings suggest that higher levels of leisure activities are associated with better cognitive performance in adults living with chronic stroke. Future studies should explore the types of leisure activities that are most beneficial to preserve cognition and prevent dementia onset post stroke. Different physical and cognitively demanding activities may differentially affect cognitive function.
White Matter Correlates of Speech in Cerebrovascular Disease
Authors: Broberg Dana N , Haddad Seyyed MH , Aveni Katharine , Havens Alexander , Orange Joseph B , McLaughlin Paula , Binns Malcolm , Roberts Angela C , Bartha Robert 
Published: December 2023

AbstractBackgroundAnalyses of spoken discourse (speech beyond single words or sentences) can detect cognitive impairment in cerebrovascular disease (CVD) [Roberts, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and visible white matter damage detected using structural magnetic resonance imaging (MRI) and potential early‐stage damage in normal‐appearing white matter (NAWM) detected using diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered speech.MethodSpoken discourse and 3T MRI data were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n = 127). Spoken discourse analyses were completed previously [Roberts et al., 2021]. White matter hyperintensities (WMH) and the NAWM portions of the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculus (UNC) were segmented in each hemisphere (Figure 1). Mean values of fractional anisotropy (FA) and mean diffusivity (MD) within NAWM, and normalized WMH volume were calculated for each of the white matter tracts. Three canonical correlation analyses examined associations between 10 spoken discourse measures and the imaging metrics (WMH volume, FA, MD) in each tract.ResultCanonical correlations were significant for FA (rc
= 0.51, p<0.05) and MD (rc
= 0.56, p<0.05) but not WMH volume (rc
= 0.42, p = 0.69). Among the white matter tracts, the strongest canonical loadings were seen for FA and MD in the left SLFp (FA: 0.80; MD: ‐0.61) and left SLFt (FA: 0.60; MD: ‐0.40) (Figure 2). Higher FA and lower MD in the left SLFp and left SLFt were associated with fluency, information content, and syntax performance.ConclusionSpoken discourse performance was associated with microstructural integrity of NAWM but not visible white matter damage. These results suggest that DTI metrics provide a more relevant assessment of white matter tract function in relation to speech than a volumetric measure of tract lesion load. Of the white matter tracts investigated in this study, spoken discourse performance in CVD was most strongly linked to white matter microstructure in the parietal and temporal endings of the left superior longitudinal fasciculus.
Increased CSF GAP‐43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Authors: Franzmeier Nicolai , Dehsarvi Amir , Steward Anna , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Wanger Fabian , Brendel Matthias , Ewers Michael , Moscoso Alexis , Blennow Kaj , Zetterberg Henrik , Schöll Michael 
Published: December 2023

AbstractBackgroundAnimal and in vitro studies of Alzheimer’s disease (AD) found that tau spreads trans‐synaptically in an activity‐dependent manner, suggesting that synapses are key routes for tau spread. Importantly, amyloid‐beta (Ab) induces synaptic remodeling and aberrant synaptic activity, which may accelerate trans‐synaptic tau spread. In AD patients, we found previously that PET‐assessed tau spreads from circumscribed epicenters across functionally connected brain regions. Yet, it remains unclear whether connectivity‐associated spread of tau in AD is accelerated by Ab‐related synaptic changes. The presynaptic growth‐associated protein 43 (GAP‐43) is implicated in synaptic plasticity and is consistently increased in cerebrospinal fluid (CSF) in AD, suggesting that GAP‐43 captures deviations in synaptic integrity such as aberrant synaptic activity. We therefore tested whether higher GAP‐43 is associated with faster Ab‐related tau spread.MethodsWe included longitudinal [18F]Flortaucipir tau‐PET (follow‐up∼3.21±1.48yrs), baseline [18F]Florbetapir amyloid‐PET and CSF GAP‐43 from 93 subjects (i.e., cognitively normal [CN] controls Ab‐, n = 54; CN/Mild Cognitive Impairment Ab+, n = 33/21). To model connectivity‐associated tau spread, we determined a connectivity template across 200 cortical regions (i.e., Schaefer atlas) using 3T multi‐band resting‐state fMRI in 42 age‐ and sex‐matched Ab‐/tau‐ controls. All statistical models were controlled for age, sex and diagnosis.ResultsUsing linear regression, we found that higher CSF GAP‐43 levels were associated with faster Ab‐related tau‐PET increase in pre‐defined ROIs (centiloid x GAP‐43 interaction, global/temporal‐meta‐ROI: b = 0.0019/0.0028; p = 0.009/0.007, Fig.1) as well as in the personalized Q1 ROI (b = 0.0024; p = 0.004) that summarizes regions most closely connected to subject‐specific tau epicenters with highest baseline tau‐PET (Fig.2A). Importantly, this centiloid x GAP‐43 interaction decreased across regions less strongly connected to tau epicenters (Q2/Q3/Q4: b = 0.0017/0.0008/0.0002; p = 0.009/0.080/0.344, Fig.2B‐D, 3A). Further, we quantified subject‐specific connectivity‐associated tau spread (i.e., the regression‐derived association between epicenter connectivity and tau‐PET increase in remaining brain regions). Here, higher CSF GAP‐43 was associated with a stronger association between Ab and connectivity‐associated tau spread (centiloid x GAP‐43 interaction, b = ‐0.0031; p = 0.037, Fig.3B).ConclusionsHigher CSF GAP‐43 is associated with faster Ab‐related tau spread across interconnected brain regions in AD, suggesting that AD‐related synaptic abnormalities are associated with accelerated tau spread rendering synaptic changes a potential treatment target to attenuate tau spreading.
ATH‐1105, a small molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP‐43 protein pathology in ALS and frontotemporal dementia‐relevant preclinical models
Authors: Johnston Jewel L , Berthiaume Andrée‐Anne , Reda Sherif , Kleist Kayla N. , Setti Sharay E. , Wu Wei , Church Kevin J. 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative disorder marked by loss of neurons in the frontal and temporal lobes, leading to cognitive and behavioral changes. Common pathological features include neuroinflammation and intracellular inclusions of TDP‐43, which are found in approximately 50% of people with FTD. Positive modulation of the hepatocyte growth factor (HGF)/MET system has been shown to protect against several drivers of neurodegeneration and may represent a therapeutic strategy for FTD. Here, we assess the effects of ATH‐1105, a small molecule positive modulator of HGF/MET, in preclinical models that capture components of FTD, including neurodegeneration, inflammation, cognitive impairment, and TDP‐43 pathology.MethodTo evaluate the neurotrophic effects of ATH‐1105, neurite length and synaptic count were measured in rat hippocampal neurons after treatment with ATH‐1105. The neuroprotective effects of ATH‐1105 were assessed in rat cortical neurons subjected to neurotoxic insults including 1‐methyl‐4‐phenylpryidinium, glutamate, lipopolysaccharide (LPS), or hydrogen peroxide. Anti‐inflammatory effects of ATH‐1105 were evaluated by measuring secreted proinflammatory cytokines in LPS‐stimulated THP‐1 differentiated macrophages. To assess pro‐cognitive effects after neuroinflammatory insult, adult mice received a single intraperitoneal injection of LPS followed by daily doses of ATH‐1105 for 14 days. Cognitive performance was assessed in the T‐maze spontaneous alternation task. Finally, Prp‐TDP43A315T mice, a model of ALS/FTD, were given daily oral treatment with 20 mg/kg ATH‐1105 or vehicle for two months, starting from one month of age. Plasma was evaluated for levels of proinflammatory cytokines and neurofilament light chain. At study termination, TDP‐43 inclusions in the sciatic nerve were measured by immunohistochemistry.ResultTreatment with ATH‐1105 increased neurite outgrowth and synaptic count in primary hippocampal neurons and protected against all cytotoxic insults in primary cortical neurons. ATH‐1105 mitigated cytokine release in LPS‐stimulated THP‐1 macrophages and attenuated LPS‐induced cognitive impairment in vivo. In TDP‐43A315T mice, treatment with ATH‐1105 reduced plasma biomarkers of inflammation and neurodegeneration. Additionally, after two months of treatment, ATH‐1105 reduced intra‐axonal TDP‐43 inclusions in the sciatic nerve.ConclusionThe data presented provide preliminary evidence that ATH‐1105 is protective against several pathological mechanisms common to FTD, including TDP‐43 protein pathology, and support its continued evaluation as a therapeutic for FTD.
Hearing symptom profiles in Alzheimer’s disease and frontotemporal dementia
Authors: Johnson Jeremy , Levett Benjamin , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Jiang Jessica , Bamiou Doris‐Eva , Hardy Chris JD , Warren Jason D 
Published: December 2023

AbstractBackgroundHearing loss has emerged as a marker of cognitive decline and potential treatment target in dementia, however the symptom profiles that characterise hearing impairment in different dementia syndromes are poorly characterised. Beyond sound detection, these diseases impair aspects of auditory perception that are crucial for communication in daily life. Here we addressed changes in everyday hearing function in Alzheimer’s disease and frontotemporal dementia syndromes, using standardised auditory symptom questionnaires completed by patients’ caregivers.MethodPrimary caregivers for patients with Alzheimer’s disease (n = 20), logopenic variant primary progressive aphasia (n = 8), nonfluent variant primary progressive aphasia (n = 13), semantic variant primary progressive aphasia (n = 13) and behavioural variant frontotemporal dementia (n = 18) completed the Hearing Impairment Impact – Significant Other Profile, adapted Amsterdam Inventory for Auditory Disability and Khalfa Hyperacusis questionnaires. The Amsterdam Inventory for Auditory Disability was also completed by 15 healthy age‐matched individuals. No participant had a past history of significant otological disease.ResultScores on the Hearing Impairment Impact – Significant Other Profile and Khalfa Hyperacusis Questionnaire respectively demonstrated greater carer burden and increased sensitivity to sound in the behavioural variant frontotemporal dementia group compared with the Alzheimer’s disease group. On the Amsterdam Inventory for Auditory Disability, multi‐domain hearing difficulties were endorsed for the behavioural variant frontotemporal dementia and primary progressive aphasia groups relative to healthy controls, and total scores in the logopenic and semantic variant primary progressive aphasia groups were significantly worse than both the healthy control and Alzheimer’s disease groups. Syndromic groups showed differentiable hearing profiles across hearing domains.ConclusionMajor dementia syndromes have distinct profiles of everyday hearing difficulty, and patients with frontotemporal dementia and progressive aphasia syndromes may have particularly marked (albeit often unrecognised) changes in their hearing. These findings should motivate the development of bespoke auditory tests to assess central hearing function and personalised hearing management strategies in these diseases.