bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of transcranial direct current stimulation (TDCS) intervention on resting state functional connectivity in early Alzheimer’s disease
Authors: Roy Ashika Anne , Joshi Himanshu , Havanur Setu , Rangarajan Subhashini K , Sreeraj Vanteemar S , Sinha Preeti , Narayanan Mariyappa , Janakiprasad Keshav K , Alladi Suvarna , Sinha Sanjib , Saini Jitender , PT Sivakumar , Varghese Mathew , Venkatasubramanian Ganesan , John John P 
Published: December 2021

AbstractBackgroundWorking memory and executive function deficits are the characteristic features of Mild Cognitive Impairment and mild Alzheimer’s Disease (mild AD). Studies exploring the alterations in working memory and executive functions show disrupted functional connectivity in Dorsolateral Pre Frontal Cortices (DLPFC) and Angular Gyrus (AG). Transcranial direct current stimulation (tDCS), by stimulating these brain regions, can alter resting‐state functional connectivity (rs‐FC) and has emerged as a safe and non‐invasive technique that has the potential to enhance neuroplasticity and cognitive improvement.MethodWe investigated the effect of anodal stimulation at the left DLPFC and cathode placed at the right supra‐orbital area to observe the rsFC changes in patients with MCI and mild AD (n=12; Age=67.58 ± 8.59 years, Gender ratio 1:1, formal years of education= 14.58±3.55 years, Hindi mental Status examination=26.91±3.1), who attended the outpatient services of Geriatric Clinic and Services, after due approval from institute ethics committee NIMHANS. The resting‐state functional magnetic resonance imaging (rsfMRI) acquisitions were performed before and after the ten sessions of tDCS, each session lasting 20 minutes. Investigations were performed on subregions of DLPFC (left Superior Frontal Gyrus (LSFG), Right SFG, left Middle Frontal Gyrus (LMFG) and Right MFG) and Angular Gyrus (Right Angular Gyrus (RAG) and Left AG), chosen a priori as seeds for the seed based FC (sbFC) analysis after correcting for the influences of age and gender using CONN 18b toolbox. Spherical masks of size 5 mm diameter were also created for the above‐mentioned seeds.ResultThe pre‐post tDCS comparisons of sbFC showed significant (FDR; p<0.05) reduction of rsFC in patients with MCI and mild AD at right supramarginal gyrus, right angular gyrus, right frontal pole (for Seed‐RAG, Voxel‐ whole brain), supramarginal gyrus (for Seed‐RAG, Voxel‐ RAG), and Middle Temporal gyrus, left Temporo‐Occipital part (for Seed‐ RSFG, Voxel‐ whole brain) as shown in Figure 1 a, b, and c respectively (Refer Table 1).ConclusionThe results support that anodal stimulation using tDCS at left DLPFC may lead to the reduction of aberrantly increased functional connectivity between brain regions involved in working memory and executive functions in MCI and mild AD.
A novel antibody‐free mass spectrometry panel of CSF biomarkers for synaptic dysfunction
Authors: Nilsson Johanna , Cousins Katheryn A.Q. , Gobom Johan , Portelius Erik , Chen‐Plotkin Alice , Shaw Les M. , Grossman Murray , Trojanowski John Q. , Zetterberg Henrik , Blennow Kaj , Brinkmalm Ann 
Published: December 2021

AbstractBackgroundOne of the earliest events and the best correlate to cognitive decline in neurodegenerative diseases, such as Alzheimer’s disease (AD), is synaptic dysfunction and degeneration. Thus, identifying and validating new biomarkers capable of quantifying synaptic degeneration for use as prognostic biomarkers would be very valuable for diagnostic purposes. We have developed a novel assay in which 17 synaptic proteins are simultaneously quantified in cerebrospinal fluid (CSF). The proteins in the panel include but are not limited to: synucleins, neuronal pentraxins, SNARE proteins and neurogranin. In a pilot study, we previously observed that several of these proteins may serve as synaptic biomarkers for AD. In this follow‐up study we aimed to confirm our previous results as well as expand to other neurodegenerative disease such as frontotemporal lobar degeneration (FTLD) and disorders with α‐synuclein pathology.MethodSample preparation of 100 µL CSF samples was performed in a consecutive three‐step process constituting of stable isotope labeled peptide standards addition, tryptic digestion followed by purification by solid‐phase extraction. For quantification was micro‐high‐performance liquid chromatography‐mass‐spectrometry (triple quadrupole) used. A cross‐sectional study including controls (n=47), AD (n=63), FTLD (n=103) and α‐synuclein patients (n=22) was performed.ResultIn the study the most notable results were found for 14‐3‐3 zeta/delta, beta‐synuclein and the pentraxins. All three pentraxins (1, 2 and the receptor) were decreased compared to controls across all groups, while 14‐3‐3 zeta/delta was increased. Further, beta‐synuclein was seemingly specifically altered (increased) between controls and AD, while no difference was observed between controls and FTLD, and α‐synuclein patients.ConclusionWe have successfully developed a panel of novel CSF biomarkers for synaptic dysfunction. We present results suggesting that several synaptic proteins potentially could be used as biomarkers for synaptic dysfunction and degeneration in not only AD but also other neurodegenerative diseases such as FTLD and α‐synuclein pathologies.
The association between sleep and cognitive pre‐frailty in community‐dwelling older adults: A two‐year cohort study
Authors: Huang Tzu‐Hsin , Chen Yen‐Ching , Chen Ta‐Fu , Yeh Su‐Ling , Chiou Jeng‐Min , Chen Jen‐Hau 
Published: December 2021

AbstractBackgroundSleep has been related to cognition and frailty, respectively. Cognitive frailty, the co‐existence of mild cognitive impairment (MCI) and physical frailty, has been proposed in 2013 and its relation with sleep remains unclear. To predict cognitive frailty in the preclinical stage, this study aimed to explore the relationship between sleep and cognitive pre‐frailty in non‐demented older adults.MethodThis study is part of the ongoing Taiwan Initiative for Geriatric Epidemiological Research. After exclusion of participants with specific conditions and loss to follow‐up, 324 older adults from the senior health checkup program of National Taiwan University Hospital were included at baseline (2015‐2017). Outcome of this study was the coexistence of MCI and pre‐frailty (cognitive pre‐frailty) and were assessed at baseline and two‐year follow‐up (2017‐2019). Global and domain‐specific cognition were assessed by Taiwanese version of Montreal Cognitive Assessment and a battery of neuropsychological tests, respectively. Pre‐frailty was defined as the existence of one or two out of five conditions using modified Fried’s frailty phenotype. Sleep variables was available at baseline, which included global sleep quality [assessed by Pittsburgh Sleep Quality Index (PSQI), score range: 0‐21)], sleep duration (in hours), and daytime sleepiness (assessed by Epworth Sleepiness Scale, ESS, score range: 0‐24). Generalized linear mixed model was utilized to assess the association between sleep and cognitive pre‐frailty over 2 years adjusting for age, sex, years of education and other important covariates.ResultParticipants’ mean age was 75.2 years at baseline. Prevalence of cognitive pre‐frailty was 1.85% at baseline and 2.55% at two‐year follow‐up. Instead of a linear relationship, we found a non‐linear association between sleep and cognition. When mean PSQI score and mean sleep duration deviated from the corresponding sample mean (PSQI score: 6.3; sleep duration: 6.2 hours), the severity of cognitive pre‐frailty increased [quadratic PSQI score: adjusted odds ratio (aOR)=1.02, 95% confidence interval (CI)=0.01‐0.04; quadratic sleep duration: aOR=1.15, 95% CI=0.04‐0.23]. No significant association was found between daytime sleepiness and cognitive pre‐frailty.ConclusionThis study found a nonlinear association of global sleep quality and sleep duration with cognitive pre‐frailty over two years in the community‐dwelling older adults.
Gender minority BIPOC adults in the U.S. report greater subjective cognitive decline
Authors: Cicero Ethan , Wharton Whitney , Flatt Jason D 
Published: December 2021

AbstractBackgroundThere is limited research investigating risk of cognitive impairment and Alzheimer’s disease and related dementia (ADRD) among gender minority (GM) adults (i.e. transgender, non‐binary). To‐date, no study has examined these cognitive challenges among GM who identify as Black, Indigenous, or People of Color (BIPOC). The health and social inequities experienced by GM BIPOC are linked to an increased risk of cognitive impairment in cisgender (CG) adults. Subjective cognitive decline (SCD), a self‐reported experience of worsening memory or thinking, may be one of the first clinical manifestations of ADRD.Method2015‐2019 Behavioral Risk Factor Surveillance System data, representing 33 states that assessed SCD and gender identity, were used to create a 1:4 matched analytic sample (1GM matched to 2CG males and 2CG females on U.S. state, age, race) to examine SCD among GM BIPOC (N=129), GM White (N=324), CG BIPOC (N=513), and CG White (N=1296) adults aged 45‐65. Logistic regression and adjusted odds ratios were used to determine SCD and SCD‐associated functional limitations prevalences and test for differences in prevalence and demographic characteristics.ResultSCD prevalence was highest among GM BIPOC (26.36%) and GM White (17.90%), followed by CG BIPOC (12.28%) and CG White (9.72%). The odds of SCD were 1.64‐3.32 times higher in GM BIPOC relative to the other groups. There were no differences in prevalence of SCD‐associated limitations. After accounting for demographic characteristics, GM BIPOC adults were nearly twice as likely to report SCD when compared to both CG BIPOC (CL: 1.06–3.02, P=0.0283) and CG White adults (95% CL: 1.22–3.20, P=0.0059).ConclusionPast research highlights that BIPOC adults suffer from ADRD at higher rates than Whites. When considering the intersection of GM status and identifying as BIPOC, we found that SCD prevalence was highest among GM BIPOC and GM BIPOC had higher odds of SCD when compared to CG BIPOC. Additional studies are needed to understand correlates and modifiable risk factors of cognitive impairment among GM BIPOC adults. This understanding is necessary for identifying GM adults at higher risk for cognitive impairment, reducing ADRD risk, and improving care and quality of life for this understudied population.
Living with and caring for: Experiences of dementia within LGBTQ2+ communities in Canada
Authors: Stinchcombe Arne 
Published: December 2021

AbstractBackgroundWith an aging Canadian population, the number of people living with Alzheimer’s disease and related dementias (ADRD) is expanding. Older members of lesbian, gay, bisexual, transgender, queer, and two‐spirit (LGBTQ2+) communities have expressed distinct concerns related to developing and living with dementia, often stemming from their sexual and/or gender minority identities. There continue to be gaps in our knowledge about LGBTQ2+ persons with dementia and caregivers. The purpose of this study was to examine the lived experiences of LGBTQ2+ persons with dementia and LGBTQ2+ caregivers.MethodIn‐depth semi‐structured interviews with persons with dementia and caregivers (n=7) were conducted. Data were analyzed using a constructivist grounded theory approach.ResultThrough analysis, findings identified were related to LGBTQ2+ identities, adaptation, relationships, and stigma.ConclusionThe findings highlight the importance of inclusive policy and practice approaches to support LGBTQ2+ persons with dementia and caregivers.
Development and analytical characterization of novel tau Simoa assays targeting full‐length tau in CSF and mid‐tau in CSF and plasma
Authors: Vanbrabant Jeroen , Stoops Erik , Mauroo Kimberley , Bjerke Maria , Engelborghs Sebastiaan , Graham Danielle , Czerkowicz Julie , Rubel Carrie E. 
Published: December 2021

AbstractBackgroundBiofluid markers of neurodegeneration and neural injury have great potential to elucidate disease mechanisms and accelerate development of experimental therapeutics. Cerebrospinal fluid (CSF) tau and phosphorylated tau are established biomarkers for AD, while plasma (N‐terminal) tau and phosphorylated tau (p‐tau) are being evaluated as complementary markers in a more accessible biofluid.Tau is present in CSF and plasma in both full‐length and truncated forms, with great interest in characterizing and advancing these different forms as biomarkers to support clinical development. To contribute to the emerging research on tau fragments as biomarker, novel ultra‐sensitive immunoassays were developed targeting low‐abundant, non‐truncated full‐length (FL) tau in CSF and a mid‐region tau fragment in CSF and plasma.MethodSimoa assays were developed using monoclonal antibodies (mAbs) targeting mid‐region tau epitopes or epitopes on full‐length tau.Resulting assays were qualified and partially validated for analytical performance parameters: measuring range, specificity, repeatability, reproducibility and parallelism were assessed. Reagent and analyte stability were investigated by assessing hold time and freeze/thaw (F/T) stability. Paired clinical routine CSF and plasma samples were analysed (20 controls and 20 AD based upon CSF Aβ1‐42, t‐tau and p‐tau(T181) profile).ResultFL‐ and mid‐tau Simoa assays were analytically characterized, upscaled to bulk volumes and partially validated. Both assays had acceptable repeatability and reproducibility (%CV <20%) for plasma and/or CSF. Parallelism was within acceptance criteria (ACC of 75‐125%; %CV <20%) for FL‐tau in 4 CSF samples and for mid‐tau in 4 CSF and 4 plasma samples. Analyte stability was demonstrated up to 5 F/T cycles and for a hold‐time of 24h at 21°C with a %CV<20%. Testing of clinical samples showed an increased CSF FL‐ (p<0.005) and mid‐Tau (p<0.0001) concentration in AD versus controls, whereas plasma mid‐tau did not increase.ConclusionA novel CSF assay for full length tau and a novel CSF/plasma assay for the mid‐tau fragment was developed, qualified and partially validated. The generated data indicated well‐performing tau assays available as RUO kits in pre‐clinical and clinical use in drug development programs.
Greater diffusion restriction in white matter tracts in preclinical AD
Authors: Benitez Andreana , Jensen Jens H. , Falangola Maria F. , Spampinato Maria Vittoria , Rieter William J. , Nietert Paul J. , Fountain‐Zaragoza Stephanie , Keith Kahtryn , Dhiman Siddhartha , Helpern Joseph A. 
Published: December 2021

AbstractBackgroundThe Alzheimer’s Continuum is biologically defined by beta‐amyloid deposition, encompassing individuals with or without other biomarker or clinical changes (Jack et al., 2018). Beta‐amyloid deposition is superimposed upon white matter degeneration in aging, but the degree to which these co‐occurring changes are characterized in vivo in the preclinical stage is less understood. The goal of this study was to use Diffusional Kurtosis Imaging (Jensen & Helpern, 2010) and biophysical modeling (Fieremans et al., 2011) to detect and describe amyloid‐related white matter changes in preclinical AD.Method141 cognitively unimpaired older adults ages 45 to 85 completed 3T brain MRI, amyloid PET (florbetapir, F18), and standard clinical and neuropsychological procedures (Besser et al., 2018). 51 had amyloid PET mSUVr values ≤ 1.21 and were designated as being on the Alzheimer’s Continuum (AB+); all other subjects were AB‐. DKI data were pre‐processed (Ades‐Aron et al., 2018), maps were computed using in‐house scripts (https://github.com/m‐ama/PyDesigner), and tensor‐based registration was performed using DTI‐TK (Zhang et al., 2007) as integrated with TBSS (Smith et al., 2006). Voxelwise and region of interest analyses of skeletonised maps were conducted to determine differences between AB+ and AB‐ groups, covarying for age, on conventional diffusivity (i.e. MD, FA) and biophysical modeling metrics that indicate extra‐axonal myelin/gliotic changes (i.e. D
e,⊥) and changes in axonal density (i.e. AWF).ResultVoxelwise analysis indicated significantly greater diffusion restriction (i.e. lower MD, higher FA) in AB+ versus AB‐ subjects, with medium‐to‐large effect sizes (age‐adjusted |d|= 0.6 to 0.8). Region of interest analyses of the corpus callosum corroborated these findings, suggesting that these differences occur in late‐myelinating (genu) but not early‐myelinating (splenium) tracts (Fig. 1.B). This effect was likely driven by changes in the extra‐axonal space (i.e. lower D
e,⊥ in AB+).ConclusionThe Alzheimer’s Continuum in preclinical AD is associated with greater diffusion restriction in white matter, preferentially in regions that myelinate later in life. Potential mechanisms include myelin breakdown and repair, oligodentritic activation, and inflammation (i.e. microgliosis, astrocytosis), suggesting non‐amyloid pathological changes upon which to focus disease monitoring or treatment development at the very earliest stages of disease.
Comparison of the prognostic value of cerebrospinal fluid and plasma neurofilament light in predicting longitudinal decline in white matter integrity among older adults
Authors: Moore Elizabeth E. , Shashikumar Niranjana , Pechman Kimberly R. , Bell Susan P. , Gifford Katherine A. , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2021

AbstractBackgroundCerebrospinal fluid (CSF) neurofilament light (NFL) is a biomarker of neuroaxonal injury associated with cognitive decline, neurodegeneration, and white matter damage. Recent advances allow for plasma measurement of NFL, increasing accessibility of this biomarker. However, it is unknown if CSF and plasma NFL have similar prognostic value for predicting white matter damage. This study relates baseline CSF and plasma NFL concentrations to longitudinal change in white matter integrity in older adults.MethodVanderbilt Memory & Aging Project participants free of dementia at baseline (n=147, 72±6 years, 32% female) underwent baseline fasting lumbar puncture for CSF sampling and venous blood draw for plasma sampling. Participants completed serial 3T diffusion tensor imaging to assess white matter microstructural integrity at baseline, 18‐months, 3‐years, and 5‐years (follow‐up 4.3±1.3 years). Voxel‐wise linear mixed effects models with follow‐up time interaction terms related baseline CSF and plasma NFL separately to white matter microstructural trajectory, adjusting for baseline demographic and health variables, apolipoprotein E‐ε4 status, diagnosis, and follow‐up time. Follow‐up models tested interactions with diagnosis, amyloid‐β (Aβ), and phosphorylated tau (p‐tau).ResultCSF and plasma NFL were correlated (r=0.50, p<0.001). In the entire sample, CSF NFL related to faster white matter microstructural integrity decline in frontal, parietal, occipital, and subcortical regions (corrected p‐values<0.05). Plasma NFL related to faster white matter microstructural integrity decline in frontal and subcortical regions (corrected p‐values<0.05). CSF (largest β=5.7x10‐9) and plasma (largest β=3.1x10‐7) associations were similar in strength. CSF NFL interacted with diagnosis and Aβ (corrected p‐values<0.04), with associations driven by MCI and Aβ negative participants. Plasma NFL interacted with Aβ and p‐tau (corrected p‐values<0.04), with associations driven by Aβ and p‐tau negative participants.ConclusionAmong older adults, increased baseline CSF and plasma NFL concentrations predicted faster longitudinal decline in white matter integrity. While CSF NFL may relate to more widespread future white matter damage compared to plasma, plasma NFL could be an accessible biomarker for assessing future risk of white matter damage, particularly in individuals without Aβ or p‐tau pathology. CSF NFL may be a better prognostic biomarker in individuals with MCI, whereas plasma NFL has similar prognostic ability across diagnostic groups.
Menopause moderates sex differences in tau PET signal: Findings from the Framingham Study
Authors: Buckley Rachel F. , O’Donnell Adrienne , McGrath Emer R. , Jacobs Heidi I.L. , Satizabal Claudia L. , Ghosh Saptaparni , Rubinstein Zoe B. , Murabito Joanne M. , Sperling Reisa A. , Beiser Alexa S. , Seshadri Sudha 
Published: December 2021

AbstractBackgroundCognitively‐normal (CN) older women exhibit elevated tau‐PET signal in medial temporal and neocortical regions compared with men. The effect of menopause on tau deposition remains unclear. We explored menopausal status as a moderator of sex differences in tau deposition in middle‐aged adults.Method273 CN (Age=55yrs(±8), Female(n)=134, Post‐menopausal(n)=70) from the Framingham Study 3rd generation cohort underwent 18F‐Flortaucipir (FTP)‐PET and/or 11C‐Pittsburgh Compound‐B (PiB)‐PET scans. We examined FTP‐PET signal in four a priori regions that demonstrate large sex differences in CN older adults (entorhinal, rostral middle frontal, inferior parietal and lateral occipital). FTP‐PET and global PiB‐PET signal were referenced to cerebellar grey. Linear regression examined sex differences in each ROI, adjusting for age and PET camera. Separate models examined menopausal status (post‐menopause/pre‐menopause females), menopausal age (≤|>50 years), and interactions with APOEε4. Sensitivity analyses included age‐matched males (‘pseudo‐premenopausal’/‘pseudo‐menopausal’) against the menopause groups to account for confounds with chronological age.ResultMiddle‐aged females exhibited higher FTP‐PET signal in the inferior parietal, rostral middle frontal and lateral occipital regions than males by ∼0.04SUVr (p<0.009; Fig. 1). No sex or menopause differences were evident in PiB‐PET. Post‐menopausal females exhibited higher FTP‐PET signal in the lateral occipital lobe than pre‐menopausal (p=0.05; Fig. 2). Menopause age≤50 years corresponded with higher lateral occipital and rostral middle frontal FTP‐PET signal than >50years (p<0.05; Fig. 2). Post‐menopausal females maintained higher signal in lateral occipital, inferior parietal and rostral middle frontal regions compared with even age‐matched ‘pseudo‐menopausal’ males (Table 1). Finally, a significant menopause*APOEε4 interaction suggested that the menopause effect was only evident in APOEε4 non‐carriers, localized to the parietal lobe (p∼0.03; Fig. 3).ConclusionSex differences in tauopathy are apparent in CN individuals approximately 20 years earlier than previously demonstrated. Our findings suggest that sex differences are exacerbated by menopause, particularly when the age‐at‐menopause is below 50 years. Chronological age did not appear to confound the results, as age‐matched males exhibited significantly lower tau signal. Finally, the effect of APOEε4 carriership may ameliorate menopause effects; only pre‐menopausal APOEε4 non‐carriers appeared to exhibit protective effects of circulating estradiol relative to post‐menopausal non‐carriers. Future work will need to identify direct hormonal contributions, the impact of surgery and hormone‐therapy.