bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel CSF inflammatory markers MIF and TREM‐1 are increased in Alzheimer’s disease
Authors: Hok‐A‐Hin Yanaika S. , van der Flier Wiesje M. , Lemstra Afina W. , Del Campo Marta , Teunissen Charlotte E. 
Published: December 2021

AbstractBackgroundThere is a lack of biomarkers reflecting Alzheimer‐relevant pathological processes such as inflammation, to improve Alzheimer’s differential diagnosis. Our recent discovery cerebrospinal fluid (CSF) proteomics study, revealed potential AD‐specific biomarkers related to inflammatory pathology, such as migration inhibitory factor (MIF) and triggering receptor expressed on myeloid cells 1 (TREM‐1). Here, we aimed to validate these findings including also samples from patients with dementia with Lewy Body (DLB) using a novel sensitive technology purposed for clinical implementation.MethodMIF and TREM‐1 levels were measured in CSF from patients with AD (n=38, 66 ± 6 years, 97% males), DLB (MIF: n=50, TREM‐1: n=40, 67 ± 7 years, 95% males) and controls (cognitively unimpaired, n=37, 66 ± 6 years, 95% males) using assays on the antibody‐based SimplePlex technology, in‐house validated for CSF analysis. Differences in protein levels between diagnostic groups and correlations to AD CSF biomarkers and mini‐mental state examination (MMSE) scores were tested by analysis of covariance (corrected for age and sex) and Spearman correlations. An optimal prediction panel was identified using backward elimination logistic regression analysis with likelihood ratio and ROC analyses.ResultCSF MIF levels were increased in AD (1.2‐fold, p=0.002) and DLB (1.14‐fold, p=0.036) compared to controls (figure 1A). MIF levels correlated with total‐ and phosphorylated‐Tau (t‐Tau, ρ=0.670, p<0.001; p‐Tau, ρ=0.686 p<0.001) and Amyloid‐beta 42 (Aβ42, ρ=‐0.189, p<0.05) but not with MMSE (p>0.05). CSF TREM‐1 levels were increased in AD compared to DLB (1.4‐fold, p=0.016) and controls (1.5‐fold, p=0.003, figure 1B) and correlated with all three AD CSF biomarkers (t‐Tau: ρ =0.472, p=0.001; p‐Tau: ρ=0.414, p=0.001; Aβ42: ρ=‐0.267, p=0.018) but not with MMSE (p>0.05). A panel combining MIF, t‐Tau and p‐Tau differentiated AD from DLB with high accuracy (AUC=0.941 (95%CI: 0.892‐0.989, 88% sensitivity, 89% specificity, figure 2).ConclusionInflammatory‐related proteins MIF and TREM‐1 are increased in AD. We here validated previous proteomics findings in an independent cohort using a technology that is used as a first preparatory step towards clinical implementation. This data highlights the importance of biomarkers reflecting different pathological processes as these proteins could be used to provide insight into an ongoing neuroinflammatory response.
Men and women show partly distinct effects of physical activity on markers of brain integrity
Authors: Gonneaud Julie , Moreau Ilana , Felisatti Francesca , Arenaza‐Urquijo Eider M , Ourry Valentin , Touron Edelweiss , De la Sayette Vincent , Vivien Denis , Chetelat Gaël ,   the Medit‐Ageing Research Group
Published: December 2021

AbstractBackgroundPhysical inactivity in older adults has been linked to an increased risk of dementia. On the other hand, increasing evidence indicates that sex is likely to influence Alzheimer’s disease (AD) pathophysiology, leading to a differential susceptibility to the disease in women versus men. We propose to investigate the interplay between sex and physical activity on brain integrity.MethodWe included baseline data of 134 cognitively unimpaired older adults (>65 years old, 82 women; Table) from the Age‐Well randomized control trial. They underwent multimodal neuroimaging, including structural MRI, FDG‐ and AV45‐PET, providing measures of grey matter volume (GMv), glucose metabolism, perfusion and Aβ burden. The Modifiable Activity Questionnaire was used to measure leisure time physical activity over the last 12 months. We assessed 1) the effect of sex on the amount of physical activity reported, 2) the main effects of sex and physical activity on each neuroimaging measure and 3) the interaction between sex and physical activity on the same variables. All analyses were controlled for age, education and APOE4 status.ResultThere was no sex differences in physical activity levels. GMv and brain perfusion in frontal medial regions were associated with both sex and physical activity, such that volume and perfusion were higher in women than in men and increased as a function of physical activity, without significant interaction between both terms. In contrast, there was an interaction between sex and physical activity on precuneus and posterior cingulate cortex perfusion and, at a trend level, on Aβ deposition (Figure). More specifically, the effect of physical activity on perfusion was stronger in women (higher activity being associated with higher perfusion), while its effect on amyloid burden was stronger in men (higher activity being associated with lower amyloid burden).ConclusionOur results suggest that physical activity has both sex‐dependent and sex‐independent effects on markers of brain integrity. Interestingly, the interaction between physical activity and biological sex suggests the existence of different reserve mechanisms in men and women, which might in turn influence their risk of AD.
A HABLE study of the relationship of blood‐based biomarkers of AD and cognition functioning in the cognitively normal: The impact of ethnicity
Authors: Hall James R. , Petersen Melissa , Johnson Leigh Ann , O'Bryant Sid 
Published: December 2021

AbstractBackgroundBlood‐based biomarkers of amyloid accumulation (Abeta40, Abeta 42), markers of neurodegeneration (NfL) and markers of neuronal injury (Tau) have all been proposed as biomarkers of early brain changes linked to the development of cognitive impairment and Alzheimer’s disease. The impact of ethnic differences on this relationship has received little attention. The current study examined the relationship of these blood‐based biomarkers to performance on cognitive tests in cognitively normal older Mexican Americans (MA) and Non‐Hispanic Whites (NHW) to assess the impact of ethnicity.MethodCognitively normal participants were drawn from a community‐based, longitudinal study of cognitive aging in MAs. 647 MAs (447 females, 200 males) and 644 NHWs (372 females, 272 males) were administered a neuropsychological battery to assess current level of cognitive functioning. Levels of plasma total tau, Abeta 40, Abeta 42and NfL were assayed via Single Molecule Array (Simoa) technology. Data were analyzed using t tests and linear regression.ResultMAs were significantly younger and had significantly fewer years of education than NHWs. MAs had higher levels of Abeta 40, Abeta 42 and NfL and lower levels of total tau. Regression analyses by ethnicity controlling for age and education revealed no significant relationship between any of the markers and any of the cognitive tests for MAs. Regression analyses for NHWs showed significant relationships between measures of memory, language, processing speed and Abeta 40; executive functions and NfL and attention and tau and Abeta 42.ConclusionThe results of the current research support the importance of assessing ethnic differences in the relationship of these biomarkers to cognitive functioning. It is likely that other biomarkers may be better predictors of cognitive functioning and cognitive decline for MAs. Further investigation of the nature of the relationship of specific biomarkers to specific cognitive functions in cognitively normal NHWs including neuroimaging is warranted.
WW‐FINGERS‐SARS‐CoV2 in Finland: Changes in lifestyle and risk factors for cognitive impairment during the pandemic in the FINGER study
Authors: Ngandu Tiia , Lehtisalo Jenni , Mangialasche Francesca , Hemiö Katri , Solomon Alina , Kivipelto Miia 
Published: December 2021

AbstractBackgroundRestrictions enforced in many counties during the COVID‐19 pandemic may have both short‐ and long‐term effects on the risk factors relevant for cognitive impairment and dementia. The COVID‐19 pandemic occurred during the post‐intervention follow‐up phase of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) postponing the planned follow‐up visits of the participants. We investigated how the first phase of the COVID‐19 pandemic affected lifestyles and other risk factors among the FINGER participants using a postal survey.MethodA survey was sent in June 2020 to 859 eligible FINGER participants. The survey was developed to assess the effects of the COVID‐19 pandemic and related infection‐control measures on lifestyles, daily life, commitment to distancing measures, access to healthcare and social services, and changes in cognitive and social activities, as well as emotional health and wellbeing.ResultA total of 735 participants responded to the survey (85% of the eligible participants). They were on average 78 years old at the time of the survey. Majority of the participants adopted some distancing practices during the first months of the pandemic. Older participants were more likely to practice total isolation than younger ones. Pandemic‐related changes were reported in social engagement, including less contact with friends and family, and less frequent participation in cultural events or associations, but on the other hand the frequency of remote contacts with others was increased. About a third of the participants reported that their physical activity was reduced, and this was more common among those who had been less active earlier. Pandemic‐related changes in lifestyle and activities were more evident among those living alone.ConclusionFinnish older persons were mainly reporting that they coped in the pandemic situation quite well. Older participants seemed to be more susceptible to negative changes. Also persons with less physical activity previously were likely to reduce their activities even more. This may have long‐term consequences on the cognitive health of older adults, and it may also impact the longer‐term effects of the FINGER intervention.
Oxidative stress mediates the effect of apathy on executive function in those at risk of vascular cognitive impairment
Authors: Lanctôt Krista L. 
Published: December 2021

AbstractBackgroundPeople with coronary artery disease (CAD) are at a high risk of developing mild vascular cognitive impairment and those with cognitive decline have been shown to have higher ratios of late to early lipid peroxidation markers indicating oxidative stress. Neuropsychiatric symptoms can precede biomarker abnormalities e.g., depressive symptoms. Apathy has previously been linked to cognitive impairment, particularly executive dysfunction, but the physiological pathways underlying this relationship have not been investigated. This study investigated whether oxidative stress mediates a relationship between apathy and executive function in CAD.MethodParticipants with CAD were identified from a Cardiac Rehabilitation Program at the time of intake. The Apathy Evaluation Scale (AES) was used to measure apathy and executive function (EF) was measured via FAS test for phonemic fluency, animal naming test for semantic fluency and trails making test B. Markers of late (8‐isoprostane, 8‐ISO) and early (lipid hydroperoxides, LPH) lipid peroxidation/oxidative stress were measured in the serum. Mediation effects were tested using the PROCESS macro (version 3.4) for SPSS. A bias corrected inferential bootstrapping method with 10,000 permutations was used to obtain a 95% confidence interval (CI) for the indirect effect.ResultAmong patients with CAD (n=214, 20% women, mean±SD age= 63.2±7.5 years, years of education [YOE]= 15.8±3.4, AES score= 28.2±8.7, composite z score for EF= ‐0.18±0.71), the ratio of 8‐ISO to LPH mediated the relationship between apathy and EF in a model controlling for age, sex and YOE. The standardized regression coefficients between apathy and ratio of 8‐ISO to LPH (0.4961, p=0.02) and that between the ratio of 8‐ISO to LPH and EF (‐0.0053, p=0.005) were both statistically significant. Bootstrapping produced a statistically significant unstandardized indirect effect (‐0.0027 95% CI: ‐0.0087, ‐0.0007).ConclusionThe results suggest that oxidative stress, specifically late markers of lipid peroxidation, plays a role in facilitating the relationship between apathy and executive dysfunction in those with CAD. As apathy is a strong predictor of conversion from cognitively normal to mild cognitive impairment, understanding mediators may suggest treatment targets.
Is it a new phenotype? Right temporal variant frontotemporal dementia
Authors: Erkoyun Hulya Ulugut , Pijnenburg Yolande A.L. 
Published: December 2021

AbstractBackgroundFrontotemporal dementia (FTD) is heterogeneous and presents with behavioral or language symptoms with frontal and/or temporal atrophy. A variant presenting with anomia and word comprehension deficits, is termed semantic dementia (SD) and is associated with predominant left anterior temporal atrophy. Although the clinical presentation is different on the right side, no unique syndrome to identify right temporal variant FTD (rtvFTD) has been established.MethodsWe retrospectively collected 70 rtvFTD patients from our cohort based on their initial MRI and identified the clinical characteristics based on the case notes and compared them with those reported in Alzheimer’s disease (n=70), behavioral FTD (n=70), and SD (n=70). In a subset of cases we reported the genetic (n=6) and pathological (n=5) features along with a review of cases in the literature (n=49).ResultsBased on our single‐center study, rtvFTD presented a unique combination of cognitive (face recognition and memory impairments), behavioral/psychiatric (disinhibition, apathy, depression, and bizarre preoccupations), and language problems (word‐finding difficulties and anomia). It's genetic/pathological background was heterogeneous, in contrast to SD. The most common genetic mutation was MAPT, followed by GRN and TARDBP. The most common pathological diagnoses were FTLD‐TDP type C and FTLD‐tau, followed by FTLD‐TDP type A and B. Moreover, pyramidal degeneration was observed as a co‐pathology.ConclusionThe definition of a syndrome associated with right temporal atrophy could promote its recognition as a variant of FTD, which is crucial for individual patient management. A multicenter study will shed light on the many unanswered questions about this equivocal syndrome.
Mild behavioral impairment is associated with amyloid, tau and neurodegeneration in mild cognitive impairment
Authors: Ismail Zahinoor , Chen Hung‐Yu , Gill Sascha , Naude James , Smith Eric E. 
Published: December 2021

AbstractBackgroundMild behavioural impairment (MBI) is a dementia at‐risk syndrome using later‐life neuropsychiatric symptoms (NPS) to determine risk. For some, MBI may be a non‐cognitive marker of neurodegeneration. A hallmark criterion of MBI is symptom persistence. We examined associations between NPS and Alzheimer’s disease (AD) proteins for amyloid, tau, and neurodegeneration in participants with mild cognitive impairment (MCI), comparing groups with persistent, transient, and no NPS.MethodADNI participant data was used for this study including Neuropsychiatric Inventory (NPI) scores for baseline and one‐year visits and CSF measures for β‐amyloid (Aβ42), phospho‐tau (p‐tau), and total tau (t‐tau). MBI status was derived from the NPI using a published algorithm. For each visit MBI+ was defined as an MBI score >0 and MBI‐ as MBI=0. Participants with MBI+ at both baseline and 1‐year visits were classified as having persistent NPS (i.e., MBI). An MBI+ score at only one visit was considered as transient NPS not consistent with MBI, and two consecutive MBI‐ visits were classified as no NPS. CSF protein values were log transformed due to skewness. Linear regressions were fitted to assess the association between NPS status and CSF biomarkers (Aβ42, p‐tau, t‐tau, and the derived measures p‐tau/Aβ42 and t‐tau/Aβ42), controlling for age, sex, education, and mini‐mental state examination.ResultThe sample of 480 participants had a mean age of 72.6 (SD 7.6); 195 (40.6%) were female. Compared to participants with no NPS, persistent NPS (i.e., MBI) was associated with lower CSF Aβ42 levels (p=0.02), higher CSF p‐tau (p=0.01) and t‐tau levels (p=0.026), and higher p‐tau/Aβ42 (p=0.002) and t‐tau/Aβ42 ratios (p=0.003) in adjusted models. Transient symptoms had CSF measures that did not differ from the no NPS group (Table 1).ConclusionIn older adults with MCI, MBI was associated with abnormal CSF biomarkers of amyloid, tau and neurodegeneration. In this sample, MBI served as a marker to capture a group with greater AD neuropathological burden, extending the literature linking MBI with higher risk for AD. The findings emphasize the importance of appropriately ascertained NPS, in this case with respect to symptom persistence, in dementia detection and prognostication.
Comparing the clinical utility and diagnostic performance of cerebrospinal fluid P‐tau181, P‐tau217 and P‐tau231 assays
Authors: Leuzy Antoine , Janelidze Shorena , Mattsson‐Carlgren Niklas , Palmqvist Sebastian , Jacobs Dirk , Cicognola Claudia , Stomrud Erik , Vanmechelen Eugeen , Dage Jeffrey L , Hansson Oskar 
Published: December 2021

AbstractBackgroundSeveral studies indicate that increases in cerebrospinal fluid (CSF) phosphorylated tau (P‐tau) in Alzheimer’s disease (AD) occur in response to very early amyloid‐β (Aβ) pathology and precede widespread tau aggregation. Thus far, however, there are no studies comparing different P‐tau isoforms—i.e., tau phosphorylated at threonine‐181 (P‐tau181), 217 (P‐tau217) and 213 (P‐tau231) levels—in relation to Aβ and Tau PET across the symptomatic stages of AD, nor data directly comparing their diagnostic performance for separating AD dementia from non‐AD neurodegenerative disorders and for identifying abnormal Aβ and Tau PET status. We herein aimed to address these questions using cross‐sectional data from the Swedish BioFINDER‐2 study.MethodWe included cross‐sectional data for 629 participants (cognitively unimpaired, amyloid‐β (Aβ)‐positive mild cognitive impairment, Alzheimer’s disease (AD) dementia and non‐AD disorders). In addition to comparing P‐tau181 and P‐tau217 measured using assays with the same capture antibodies from Eli Lilly (P‐tau181Lilly and P‐tau217Lilly; Meso Scale Discovery platform) with P‐tau231 from ADx NeuroSciences (P‐tau231ADx; sandwich ELISA), we also compared P‐tau181Lilly with P‐tau181 measurements from two commonly used assays (Innotest [P‐tau181Innotest; sandwich ELISA] and Elecsys [P‐tau181Elecsys; fully automated electrochemiluminescence immunoassay]). Aβ and Tau PET were performed using [18F]flutemetamol and [18F]RO948.The discriminative performance of CSF P‐tau measures was assessed using the area under the receiver operating characteristic curve (AUC).ResultThough all P‐tau variants increased across the AD continuum, P‐tau217Lilly showed the greatest dynamic range (13‐fold‐increase vs 1.9‐5.4‐fold‐increase for other P‐tau variants for AD dementia vs non‐AD) (Figure 1). P‐tau217Lillyshowed stronger correlations with Aβ‐ and tau‐PET (P<0.0001) (Figure 2). P‐tau217Lilly exhibited higher accuracy than other P‐tau variants for separating AD dementia from non‐AD (AUC, 0.991vs 0.906‐0.982, P<0.0001) and for identifying Aβ‐PET positivity (AUC, 0.951 vs 0.816‐0.924, P<0.0001) and tau‐PET positivity (AUC, 0.957 vs 0.836‐0.938, P<0.0001) (Figure 3). Finally, P‐tau181Lilly generally performed better than the other P‐tau181 assays, (e.g., AD dementia vs non‐AD, AUC, 0.976 vs 0.923, P<0.0001).ConclusionCSF P‐tau217Lilly seem to be more useful than other included P‐tau assays in the diagnostic work‐up of AD and for tracking disease progression. Varied results across P‐tau181 assays also highlights the importance of anti‐tau antibodies for biomarker performance.
Memory concerns and cognitive decline in a multi‐ethnic cohort of oldest‐old individuals: The LifeAfter90 study
Authors: Corrada Maria M. , Gilsanz Paola , Kawas Claudia H. , DeCarli Charles S. , Vieira Katharine E. , Hayes‐Larson Eleanor , Farias Sarah Tomaszewski , Mayeda Elizabeth Rose , Mungas Dan M. , Glymour M. Maria , Whitmer Rachel A. 
Published: December 2021

AbstractBackgroundSubjective memory concerns are relatively easy to assess and are useful if they can identify people with cognitive deficits or can predict cognitive decline. In a multiethnic cohort of oldest‐old individuals, we studied whether baseline cognitive performance and cognitive decline differ between individuals who report memory concerns and those who do not.Method
LifeAfter90 participants are long‐time members of the Kaiser Permanente Northern California Health Care System without a dementia diagnosis in their medical record at recruitment. Evaluations are every six months and include the Spanish and English Neuropsychological Assessment Scales (SENAS), which assesses episodic memory, semantic memory, and executive function domains. At baseline, participants answered the question ‘Are you concerned that you have a memory or other thinking problem?’ Using linear mixed models with random intercepts, we estimated the baseline and longitudinal association of memory concerns with each SENAS domain. The models used years since baseline as the time variable, and adjusted for baseline age, sex, race/ethnicity, education, and practice effects. Potential differences in cognitive decline by presence or absence of memory concerns were assessed with an interaction term (memory concerns*time).ResultAt baseline, the 665 participants were on average 92.8 years of age, 62% were women, 34% were college graduates, 69% were racial/ethnic minorities, and 40% reported memory concerns (Table 1). The average follow‐up was 0.9 years (range: 0‐1.9). Memory concerns were associated with worse baseline performance in episodic memory (ß=‐0.21) and executive function (ß=‐0.12) but not semantic memory (ß=‐0.01) (Figure & Table 2). Although cognitive scores decreased over time for semantic memory (ß=‐0.31) and executive function (ß=‐0.10), the decline did not differ between people with and without memory concerns (Figure & Table 2).ConclusionIn this multi‐ethnic oldest‐old cohort, individuals with memory concerns have worse baseline cognitive performance in executive function and episodic memory, but their rate of decline is similar to individuals without memory concerns. Although memory concerns appear to identify individuals with objective cognitive impairment, it does not identify those who may decline faster. With additional follow‐up, we will continue to explore the utility of memory concerns in predicting future cognitive performance.