bluuebunny/crossref_metadata_2025_split huggingface dataset:
Social cognition provides early distinction between phenocopy syndrome of behavioural variant frontotemporal dementia and behavioural variant frontotemporal dementia
Authors: van Engelen Marie‐Paule E. , Louwers Paulette , Gossink Flora T , Krudop Welmoed A. , de Boer Sterre C.M. , Dols Annemiek , Schouws Sigfried , Scheltens Philip , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. 
Published: December 2021

AbstractBackgroundPatients displaying clinical features of bvFTD but lacking abnormalities on neuroimaging in the absence of clinical progression over time are considered to represent the phenocopy syndrome of bvFTD (phFTD). Clinical overlap between bvFTD and phFTD hampers their diagnostic distinction whereas it is essential to provide adequate treatment and prognosis. We aimed to assess whether there are differences in patient characteristics and caregiver‐reported symptoms between phFTD and bvFTD that can provide tools for early distinction.MethodWe compared phFTD with probable/definite bvFTD with respect to patient characteristics and caregiver‐reported symptoms, that comprised the domains behaviour, global cognitive functioning, social cognition and ADL. Total test scores were compared between groups followed by multiple logistic regression analysis. ROC curves were plotted to assess diagnostic value.ResultA total of 53 patients were included (n = 28 phFTD, n= 25 bvFTD). Compared to bvFTD, phFTD patients performed better in terms of social cognition yet had more behavioural symptoms and worse ADL performance reported by the caregiver. When combining social cognition, behavioural symptoms and ADL performance we found a sensitivity and specificity of 85.71% and 80.0% for a diagnosis of phFTD.ConclusionSocial cognition was spared in phFTD compared to bvFTD patients implying to be a valuable tool in distinguishing phFTD from bvFTD. Worse ADL performance and increased behavioural symptoms reported by caregivers in phFTD is remarkable and indicates further research is needed to asses if patient‐based tools are superior to caregiver‐based tools when suspecting phFTD.
Blood phosphorylated tau 181 predicts early, preclinical brain amyloid deposition
Authors: McGrath Emer R. , Beiser Alexa S. , Yang Qiong , Ghosh Saptaparni , DeCarli Charles S. , Himali Jayandra J. , O’Donnell Adrienne , Satizabal Claudia L. , Johnson Keith A. , Tracy Russell P. , Seshadri Sudha 
Published: December 2021

AbstractBackgroundPlasma phospho‐tau181 is a promising new biomarker for Alzheimer’s disease (AD) with greater specificity than t‐tau and greater convenience compared to cerebrospinal fluid or neuroimaging biomarkers. However, its association with regional brain cortical amyloid and tau deposition is not well characterized. We evaluated 1) the association between plasma p‐tau181 levels and regional cortical amyloid and tau deposition and 2), determinants of circulating phospho‐tau181 levels.MethodPlasma p‐tau181 levels were measured in 52 [48% women, mean age 64.4 (SD 5.5)yr] cognitively normal Framingham Heart Study Offspring cohort participants at examination cycle nine (2011‐2014) who subsequently underwent 11C‐Pittsburgh Compound‐B (PiB)‐PET and/or 18F‐Flortaucipir (FTP)‐PET scans. We related phospho‐tau181 levels to PiB‐PET (composite of frontal, lateral temporal and parietal and retrosplenial cortices [FLR], as well as individual cortical regions) and FTP‐PET (entorhinal, inferior temporal and precuneus regions). Additionally, we compared p‐tau181 with plasma neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) in predicting brain amyloid deposition.ResultThe mean time from plasma biomarker measurement to brain‐PET was 6.8 (SD 0.6)yr. On linear regression analysis adjusted for age, sex and time to PET, log p‐tau181 was associated with increased FLR (SE, 1.24±0.30, p<0.0001), precuneus (1.35±0.30, p<0.001), superofrontal (1.10±0.31, p=0.001), superotemporal (1.24±0.30, p<0.001) and insular amyloid deposition (1.17±0.31, p<0.001). Plasma p‐tau181 was not associated with tau‐PET deposition in the entorhinal (‐0.31±0.63, p=0.63), inferotemporal (‐0.19±0.64, p=0.77) or precuneus (‐0.05±0.64, p=0.94) regions, n=21 with available tau‐PET. Log NFL (1.30±0.49, p=0.01) and GFAP (1.46±0.39, p<0.0001) showed univariate associations with FLR amyloid deposition. On multivariable analysis adjusting for age, sex, apoE4 allele, AD polygenic risk score and all three biomarkers, p‐tau181 (0.92±0.31, p=0.005) and GFAP (0.92±0.41, p=0.03), but not NFL (0.25±0.51) remained associated with FLR amyloid deposition. Total cholesterol was the only vascular risk factor associated with circulating p‐tau181 levels (‐0.004±0.001, p=0.01).ConclusionElevated plasma phospho‐tau181 is associated with preclinical cortical amyloid (but not tau) deposition in a relatively young, cognitively normal sample. Circulating levels of p‐tau181 appear to be independent of vascular risk factors, highlighting the potential of phospho‐tau181 as a robust and generalizable blood‐based biomarker for AD dementia in a community‐based setting. Additional studies replicating our findings are warranted.
CSF amyloid, tau, and neurodegeneration biomarkers are associated with longitudinal cognitive decline in preclinical AD
Authors: Cody Karly Alex , Betthauser Tobey J. , Hulle Carol A. , Koscik Rebecca L. , Jonaitis Erin M. , Clark Lindsay R. , Chin Nathaniel A. , Okonkwo Ozioma C. , Bendlin Barbara B. , Asthana Sanjay , Suridjan Ivonne , Kollmorgen Gwendlyn , Zetterberg Henrik , Carlsson Cynthia M. , Blennow Kaj , Johnson Sterling C. 
Published: December 2021

AbstractBackgroundThis work examined heterogeneity in cognitive trajectories between amyloid(A) and tau(T) cerebrospinal fluid (CSF) stratified biomarker groups in late‐middle‐aged, initially cognitively unimpaired individuals. Additionally, candidate biomarkers of neurodegeneration were investigated for potential added value in predicting cognitive decline.MethodIndividuals (N=535) recruited from Wisconsin Alzheimer’s Disease Research Center (n=301) and Wisconsin Registry for Alzheimer’s Prevention (n=234) underwent a lumbar puncture and serial (1 to 9) cognitive assessments (Table 1). CSF biomarkers were measured using the exploratory Roche NeuroToolKit assays (Roche Diagnostics International Ltd). Four biomarker groups (A‐T‐, A‐T+, A+T‐ and A+T+) were established based on combinations of CSF Aβ42/40 and p‐tau biomarker positivity, where (A) and (T) positivity was determined as CSF Aβ42/40≤0.046 and CSF p‐tau≥24.8 pg/mL. Decline on a Preclinical Alzheimer’s Cognitive Composite (PACC‐3) was investigated using linear mixed effects models (including subject‐specific random intercepts and age‐related slopes) adjusting for sex, education, cohort, and the number of prior exposures to the cognitive battery. In primary analyses, the predictors of interest included the biomarker group and its interaction with age to investigate whether longitudinal PACC‐3 trajectories differed between biomarker groups. Secondary models added one of the following biomarkers for neurodegeneration and its interaction with age: neurofilament light chain (NfL), neurogranin, or alpha‐synuclein. Models were compared against the primary model using the Akaike information criterion and log likelihood ratio tests.ResultThe results from the primary model indicated a significant biomarker group×time interaction (P<.001, Figure 2). Tukey‐adjusted pairwise comparisons indicated that the A+ groups (A+T‐ and A+T+) had significantly different PACC‐3 trajectories compared with the A‐T‐ group (P<.0001, Figure 2). Comparison of the simple age‐related slopes suggest that the A+T+ group was declining approximately 3.6 times faster compared with those without elevated biomarkers. Higher NfL, but not neurogranin or alpha‐synuclein, was associated with PACC‐3 decline after accounting for AT(+/‐) status (Table 2).ConclusionIn this preclinical sample, cognitive decline was evident in A+ groups. Secondary analyses suggest that NfL may contribute additional value to the AT(neurodegeneration) framework in explaining cognitive decline before the onset of dementia.
Interaction of obstructive sleep apnea severity and amyloid burden on novel plasma biomarkers of tau and neurofilament light protein in community‐dwelling cognitively normal older‐adults
Authors: Bubu Omonigho Michael M. , Umasabor‐Bubu Ogie Queen , Williams Ellita T. , Turner Arlener D. , Williams Natasha , Jean‐Louis Girardin A. , Osorio Ricardo 
Published: December 2021

AbstractBackgroundRecent evidence suggest that plasma Tau and neurofilament light (NfL) have high potential as markers of neurodegeneration in Alzheimer disease (AD). Obstructive sleep apnea (OSA) severity increases AD risk and is associated with well‐validated markers of AD pathology in cognitively normal older‐adults. We determined the independent and combined effects of OSA severity and amyloid burden on plasma levels of Tau, and NfL, in community‐dwelling cognitively normal older‐adults.MethodCross‐sectional analysis of baseline data from 70 community‐dwelling cognitively normal older‐adults, selected from ongoing NYU prospective longitudinal studies on memory, sleep and aging. CSF‐Aβ42 (measured using ELISA) quantified amyloid burden. OSA severity was defined using AHI4%. Levels of plasma Tau and NfL were determined using single molecule array (SIMOA) technology ultra‐sensitive assays. Associations of OSA severity and plasma Tau and NfL were assessed using Pearson correlation analysis. The interactive associations of OSA severity and CSF‐Aβ42 levels on plasma Tau and NfL was assessed using generalized linear models. Analyses were adjusted for age, sex, BMI, education and APOE4.ResultOf the 70 participants, 42 (60%) were women. Mean (SD) age was 68.7 (7.1) years. Mean (SD) AHI was 11.4/hr. (13.7) {29 (40%) had AHI <5, 20 (25%) had AHI: 5 to ≤ 15, 11 had AHI: 15 to ≤30 and 10 had AHI >30}. Independent of CSF‐Aβ42, OSA severity was not associated with plasma Tau (r=.11, p‐value=.38), or plasma NfL (r=.05, p‐value=.67). The interactive associations of OSA severity and CSF‐Aβ42 levels on plasma Tau (β =0.042; 95% CI, 0.013 to 0.070) and NfL (β = 0.055; 95% CI, 0.022 to 0.089) were significant, P < .05 for all. The analysis was not powered for generating dichotomized strata specific (i.e. OSA+/Aβ+, OSA+/Aβ‐, OSA‐/Aβ+ and OSA‐/Aβ‐) estimates.ConclusionIn this sample of cognitively normal older‐adults, OSA severity was not associated with plasma levels of Tau and NfL. However, β estimates of the interactive associations of OSA severity and CSF‐Aβ42 levels suggest that their combined effect is associated with higher plasma levels of Tau or NfL. Larger cohorts are necessary to delineate mechanisms and examine for OSA/Aβ strata‐specific estimates.
Pilot study of genome‐wide differences in DNA methylation among older adults with normal cognition and mild cognitive impairment, with and without neuropsychiatric symptoms
Authors: Vyas Chirag M. , Gatchel Jennifer R. , Sadreyev Ruslan I. , Kang Jae Hee , Mischoulon David , Reynolds Charles F. , Chang Grace , Manson JoAnn E. , DeVivo Immaculata , Blacker Deborah , Okereke Olivia I 
Published: December 2021

AbstractBackgroundGenome‐wide DNA methylation assay (DNAm) reflects epigenetic aging and differences in gene expression, and may help to elucidate the role of systemic aging in cognitive decline. Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and may increase the risk of progression to dementia. However, few investigations have addressed whether genome‐wide differences in DNA methylation underlie presentations of NPS in MCI.MethodWe included 45 older participants (mean age=70 years) from a depression prevention ancillary study (VITAL‐DEP) to the VITamin D and OmegA‐3 TriaL. We defined 3 groups: cognitively normal (CN; n=20); amnestic MCI (aMCI; n=16); non‐amnestic MCI (naMCI; n=9). Genomic DNA was extracted from leukocytes; DNA methylation was assayed using Illumina MethylationEPIC (Methyl850K chip). DNAm age metrics were computed using Horvath methods; genome‐wide differential methylation was examined among the 866,836 CpG sites in MethylationEPIC. Annotations were performed using Gene Ontology (GO) databases and tools.ResultThe sample was balanced by age and sex across cognitive groups (CN and MCI). Participants with MCI had higher DNAmAge compared to those with CN [median (interquartile range): 66.4 (63.5‐71.1) vs. 65.3 (63.4‐69.2)]. Comparing MCI vs. CN, there were 48 CpG sites at p<1x10‐4, but not genome‐wide‐significant, suggesting possible differential methylation in novel genes. For example, over‐representation analysis revealed genes associated with dysregulation of the tight junction (ACTR3, TUBA4A, JUN) and one‐carbon folate pathways (DPYD, GART), suggesting blood‐brain barrier dysfunction and metabolic dysregulation. Comparing MCI with vs. without NPS, there were 49 CpG sites at p<1x10‐4, but not genome‐wide significant. Top hits in GO suggested involvement of negative regulation of neuron projection development (KANK1, RAP1GAP2), activation of protein kinase C activity (PARD3, F2R), regulation of blood coagulation (STXBP5, F2R), and glycosaminoglycan degradation (HSPG2, HGSNAT). Functional annotations suggested involvement of important cellular pathways (e.g., serotonergic synapse, alpha‐linolenic metabolism, calcium signaling). Further, several identified genes had prior reports as summarized in the AlzGene database (e.g., PPP1R10, HSPG2).ConclusionGenome‐wide differential methylation in DNAm analysis suggested potential genomic variations in MCI vs. CN and in NPS among patients with MCI. If confirmed, such genomic biomarkers could inform development of targets in prevention studies.
Development of small‐molecule tau‐SH3 interaction inhibitors that prevent amyloid‐β toxicity
Authors: Roth Jonathan R , Rush Travis , Pugh Derian A , Dean Hunter B , Cochran J. Nicholas , Thompson Samantha J , Aldaher Adam R , Mesina Jacob S , Ruiz Pedro , Pathak Vibha , Wu Mousheng , Bostwick J Robert , Suto Mark J , Augelli‐Szafran Corinne E , Roberson Erik D. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia and lacks disease‐modifying treatments. Tau‐based therapies are attractive and Tau reduction prevents amyloid‐induced dysfunction in preclinical AD models. Tau reduction also prevents amyloid‐independent dysfunction in diverse disease contexts, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau’s interaction with SH3 domain containing proteins likely underlie mechanisms of amyloid‐induced dysfunction, so we targeted their interaction as a therapeutic strategy.MethodWe previously designed a peptide Tau‐SH3 interaction inhibitor based on the region of Tau that binds FynSH3, and determined that it prevented amyloid‐induced dysfunction in primary neurons. We next completed a high‐throughput screen to identify compounds that inhibit Tau‐Fyn interaction. Here, we studied a top hit from that screen, generated and characterized a series of daughter compounds, and tested whether the compounds prevented amyloid‐induced dysfunction in primary neurons.ResultThe hit compound, SR31627, prevented amyloid‐β toxicity in primary neurons. The medicinal chemistry program resulted in lead compound SR42667, which had five‐fold improved potency and improved drug‐like properties. We found that SR42667 binds Tau, is cell‐permeable, and prevents amyloid‐induced dysfunction.ConclusionWe demonstrate that Tau‐SH3 interactions can be targeted using small molecule inhibitors and that these inhibitors have efficacy for blocking amyloid‐induced dysfunction.
The relationship between subjective hearing impairment and mild behavioral impairment – A study of older adults without dementia in the COMPASS‐ND Study
Authors: Guan Dylan X. , Gosselin Penny , Chen Hung‐Yu , Pichora‐Fuller M. Kathleen , Phillips Natalie , Smith Eric E. , Ismail Zahinoor 
Published: December 2021

AbstractBackgroundHearing loss and mild behavioral impairment (MBI) are both early warning signs of cognitive decline and dementia in older adults and have been recommended for use as non‐cognitive markers of dementia. To date, few studies have directly investigated the relationship between these two markers.MethodBaseline data from 219 non‐demented participants (10 cognitively normal; CN, 48 subjective cognitive decline; SCD, 161 mild cognitive impairment; MCI) in the COMPASS‐ND study (February 2020 release) were analyzed. Hearing impairment was measured in three ways: with a 10‐item self‐report measure using the Hearing Handicap Inventory for the Elderly – Screening Version (HHIE‐S), with a speech and noise test using the Canadian Digit Triplet Test (CDTT), and with screening audiometry using 2 discrete input levels at 2000 Hz to generate 6 hearing loss categories. Global and domain‐specific MBI burden was approximated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) with a published algorithm. Multivariable linear regressions were conducted to examine the association between the three hearing impairment measures and global MBI burden, adjusting for sex, age, education, hearing aid use, and Montreal Cognitive Assessment (MoCA) score or diagnosis. Multivariable logistic regressions were used to investigate whether the hearing variables could predict MBI domains.ResultHalf of all participants showed MBI symptoms (Figure 1). Greater self‐reported hearing impairment measured by the HHIE‐S was significantly associated with greater global MBI burden and the presence of apathy and affective dysregulation when controlling for global cognition or diagnosis (Table 1). These associations remained significant in analyses restricted to MCI alone. Performance on CDTT and screening audiometry, were not associated with global or domain‐specific MBI burden.ConclusionThe HHIE‐S, which was designed to capture the emotional and social aspects of hearing loss, was positively related to global MBI burden and more specifically to apathy and affect. Unlike audiometry and speech and noise measures, self‐reported measures of hearing impairment can be influenced by age, sex, other comorbidities, and social factors. Our findings underscore that value of self‐report measures of hearing impairment as distinct from audiometry and speech and noise measures in their association with behavioral impairment and as non‐cognitive markers of dementia.
Digital mobility outcomes to assess habitual physical activity in people with cognitive impairment: A systematic review
Authors: Ardle Ríona Mc , Jabbar Khalid Abdul , Din Silvia Del , Kerse Ngaire , Rochester Lynn , Callisaya Michele L 
Published: December 2021

AbstractBackgroundMaintaining habitual physical activity (HPA) is essential for people with dementia and mild cognitive impairment (MCI) to remain functionally independent. Therefore, physical activity interventions may complement care services and promote wellbeing and independence in this population. The advent of digital technology, such as wearable technology and ambient sensors, has enhanced our ability to objectively and reliably measure HPA in a cognitively‐impaired population. Digital technology can continuously and remotely capture a range of digital mobility outcomes important to independence, such as volume (i.e. amount of HPA), intensity (i.e. rate/magnitude of HPA), pattern (i.e. distribution of HPA over time) and variability (i.e. how regular or dynamic HPA is) of HPA. In order to inform clinical interventions and public health strategies for dementia, appropriate HPA outcomes must be quantified. The key aim of this review is to identify the digital tools and HPA outcomes used in community‐dwellers with dementia and mild cognitive impairment, and describe the volumes, intensities, pattern and variability of physical activity in this population.Method2975 article titles were systematically reviewed. Following title search, 266 abstracts were selected for abstract review. Seventy‐five articles are currently undergoing full text review.ResultThis review will report (1). digital technology used to assess HPA (e.g. accelerometers, infra‐red sensors), (2). the range of digital outcomes reported (e.g. steps per day, average ambulatory bout length), (3). key findings relating to the quantification of volume, intensity, pattern and variability of HPA in people with dementia and MCI, drawing comparisons to healthy older adults were applicable.ConclusionFindings from this review will be informative to future selection of digital mobility tools and outcomes to quantify HPA in people with dementia and MCI. The literature will be synthesized to identify the current state of research and identify gaps for future investigation. Recommendations will be made for the development of protocols to continuously and remotely assess HPA in people with cognitive impairment, and for identifying the most appropriate digital mobility outcomes to serve as clinical or interventional endpoints to monitor change in HPA in this population.
The roles atherosclerotic cardiovascular disease risk and depression on cognitive outcomes in Mexican Americans and non‐Hispanic whites
Authors: Marcela Marcela Davila , Large Stephanie E , Hope Michael , Hall James R , O'Bryant Sid , Johnson Leigh Ann 
Published: December 2021

AbstractBackgroundMexican Americans (MA) experience cognitive decline at younger ages and have higher rates of cardiovascular disease (CVD) than Non‐Hispanic whites (NHW). Persons who are depressed are more likely to have one or more risk factors for cardiovascular disease. The purpose of this study was to examine the impact of depression and Atherosclerotic Cardiovascular Disease (ASCVD) on cognitive function in MA and NHW.MethodData was collected from the Health and Aging Brain Study: Health Disparities (HABS‐HD) study. A total of 1094 participants who were classified as normal controls were stratified into 4 groups: no depression and low risk ASCVD (N= 684), no depression and high risk ASCVD (N= 222), depression and low risk ASCVD (N=140), and depression and high risk ASCVD (N=48). Depressive symptoms were assessed via Geriatric Depression Scale (GDS). ASCVD risk was calculated using a risk calculator. One‐way ANOVAs were conducted to examine differences in cognitive performance based on ASCVD risk and depression.ResultThe results showed that depressed NHW and MA males with a low ASCVD risk had significantly lower mean scores on Trail Making Test A than the non‐depressed with low ASCVD risk group (p < 0.006), (p < 0.017). Depressed MA males with high ASCVD risk had significantly lower mean scores on the MMSE than the non‐depressed low ASCVD risk group (p < 0.00). Depressed NHW females with low ASCVD risk had significantly lower mean scores on delayed memory than the non‐depressed low ASCVD risk group (p < 0.008). Depressed MA females with a high ASCVD risk demonstrated significantly lower mean scores on the COWA and SEVLT Trials 1‐5 and the non‐depressed low ASCVD risk group (p < 0.002), (p < 0.046).ConclusionThe results of this study indicated that depression and risk of ASCVD can impact cognitive functioning in different ways. In men depression impacted scores on Trails A. In MA women comorbid depression and high risk for ASCVD affect scores on the COWA and SEVLT. These findings support that medical comorbidities influence cognitive function. Future research directions include exploring the relationships between other CVD risk factors and depression.