bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement bias in depression assessment according to brain amyloid burden, cognitive function, and sex in the A4 study
Authors: Thompson Louisa I. , Jones Richard N. 
Published: December 2020

AbstractBackgroundWe sought to identify measurement bias (differential item functioning, DIF) in the Geriatric Depression Scale (15 item version) attributable to cerebral amyloid level (Aβ) among cognitively normal older adults. Specifically, we were interested in determining if endorsement of self‐reported memory problems on the GDS‐15 differed by Aβ level. We hypothesized that persons with high Aβ would have a greater probability of endorsing memory problems than those with low Aβ, consistent with the literature showing that subjective cognitive decline in older adults is associated with increased AD risk. We also examined DIF attributable to level of cognitive functioning and sex as positive controls that may account for differences in self‐reported depression.MethodAnalyses were conducted using the pre‐randomization database of the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study (N=3,961). We used the MIMIC (multiple indicators, multiple causes) approach to detect DIF. The MIMIC approach is consistent with item response theory, and allows for the detection of uniform DIF for predictors that are either discretely observed (sex) or continuously observed (Aβ level, cognitive function).ResultWe found DIF with respect to Aβ level, sex, and cognitive functioning. Most DIF detected was of a trivial effect size with some showing small‐to‐moderate effect sizes. Mild DIF, attributable to Aβ level, was shown for the GDS memory item in the hypothesized direction: after adjustment for depressive symptom severity (overall GDS symptoms), persons with high Aβ had a greater probability of endorsing memory problems than those with low Aβ (effect size = 0.22, p <.001). Interestingly, DIF for 2 items assessing hopelessness were also observed according to high Aβ versus low Aβ. Despite these findings we determined that there was negligible impact of DIF attributable to Aβ level on overall depressive symptom level.ConclusionParticipant responses on items of the GDS‐15 are sensitive to Aβ burden, sex, and level of cognitive functioning over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects are of small magnitude and do not appreciably impact the validity of inferences based on the GDS‐15.
In vivo assessment of the noradrenergic nucleus locus coeruleus in Alzheimer’s disease and other types of dementia
Authors: Giorgi Filippo Sean , Galgani Alessandro , Lombardo Francesco , Palermo Giovanni , Hana Hlavata , Daniele Della Latta , Ghicopulos Irene , Martini Nicola , Baldacci Filippo , Coi Alessio , Tognoni Gloria , Siciliano Gabriele , Ceravolo Roberto , Pavese Nicola , Fornai Francesco , Bonuccelli Ubaldo 
Published: December 2020

AbstractBackgroundThe Locus Coeruleus (LC) is the main noradrenergic nucleus of the brain. Pathological analysis in humans have shown that LC is degenerated in Alzheimer’s disease (AD), and that its impairment might start years before the occurrence of cognitive impairment. Several experimental studies in animal models even suggested a pathogenetic role of an early LC degeneration in AD pathogenesis. LC neuromelanin‐containing neurons can be assessed by using MRI scan, in T1‐weighted sequences. In this study, we assessed in vivo the integrity of LC by 3T MRI in patients with dementia due to AD (ADD) and in MCI subjects, comparing them with patients with Fronto‐temporal dementia (FTD), with patients with Lewy Body Dementia (LBD)/ Parkinson’s Disease Dementia (PDD) and with healthy controls (HC).Method234 subjects (HC=60; MCI=80; ADD=40; FTD=18; LBD/PDD=36) were submitted to a 3 Tesla brain MRI (Signa‐GEH), including neuromelanin (NM)‐sensitive FSE T1‐weighted sequences for LC study. The sequences were then evaluated using a semi‐automatic software by blinded operators. An indirect measures of LC volume, based on the number of Voxels selected, is expressed by the parameter VOX. All subjects underwent detailed clinical and neuropsychological assessment.ResultVOX was significantly lower in ADD compared to HC, while no differences were observed between HC and FTD. The lowest values of were observed in LBD/PDD and Early Onset AD (EOAD) patients. MCI subjects showed an LC signal lower than HC, although not statistically significant. Patients with confirmed AD pathology presented lower values of VOX than HC, and their cognitive performances correlated with the degree of LC signal reduction.ConclusionWe observed in vivo a marked alteration of LC signal in AD patients, compared to healthy controls, in line with the hypothesis of LC involvement in AD pathogenesis; the severe alteration found in EOAD, further supports this association. As expected from neuropathological and NM‐MRI studies, also PDD/LBD showed LC alterations, while FTD did not. In MCI a trend was observed, even if not significant: a longitudinal study is required to evaluate potential association with ADD conversion rate. Funding sponsor: Ministero della Salute PE‐2013‐02359574 (P.I.: FSG).
Increased connectivity in several bilateral frontal and fronto‐parietal networks predicts depressive symptoms in mid‐ to late‐life diabetics
Authors: Salardini Arash , Shen Xilin , Hashemi‐Aghdam Arsalan , Laltoo Emily , Savoia Sarah , Tokoglu Fuyuze , Constable Todd 
Published: December 2020

AbstractBackgroundDepressive symptoms may be a feature of vascular cognitive impairment secondary to diabetes. There is significant biotypic diversity amongst individuals with depressive symptoms depending on the causes and symptoms. In this study we determined the brain networks which are best correlated with depressive traits in our cohort of diabetic individuals.Method49 diabetic patients were recruited and underwent comprehensive neuropsychological testing as well as MRI imaging including structural MRI and rs‐fMRI. A linear regression model was built on a general functional connectivity matrix, derived from the rs‐fMRI data, to predict depression symptoms as measured by Beck’s Depression Inventory (BDI). The leave‐one‐out cross validation method was used to test the model.ResultsCPM was applied to imaging from 49 individuals aged 55‐90 (Mean 69, SD 8) with a diagnosis of diabetes (Mean HbA1c = 6.88, SD 1) with Fazekas scores of 0‐3 (mean 1.04, SD 0.78). BDI scores ranged 0‐20 (mean 6.12, SD 4.63) while MOCA scores spanned 13‐30 (mean 25.14, SD 3.51). A positive predictive model was discovered (R2 =0.3514, p=0.0143) which contained increased connectivity in several frontal and frontoparietal networks. Specifically, stronger connections between bilateral ventromedial prefrontal cortices and dorsal prefrontal cortices (L > R) appeared to predict higher BDI scores. No statistically significant negative predictive model (where weaker connections predicted higher BDI scores) were found.ConclusionIn this study we use connectome‐based predictive modelling (CPM) to find connections which may predict the presence of depressive symptoms in diabetic individuals. Unlike most connectome‐based techniques which determine connections which have an association with behavioral measures, CPM finds networks which likely predict behavioral scores. Our findings are consistent with what we know about the neural correlates of depression but represent the first hypothesis‐free connectivity study of depressive symptoms in mid to late‐life diabetes.
Mean arterial pressure during cerebral perfusion MRI: An arterial spin‐labeling study in younger and older adults
Authors: Sible Isabel J. , Yew Belinda , Dutt Shubir , Li Yanrong , Ho Jean K. , Jang Jung Yun , Blanken Anna E. , Gaubert Aimee , Marshall Anisa J. , Kapoor Arunima , Shao Xingfeng , Wang Danny J.J. , Nation Daniel A. 
Published: December 2020

AbstractBackgroundHigh blood pressure (BP) and low cerebral blood flow (CBF) have been independently related to Alzheimer’s disease (AD) pathophysiology. Increased cerebrovascular resistance index (CVRi), the ratio of mean arterial pressure (MAP) to CBF, has also been linked to AD risk in older adults. Autoregulatory mechanisms maintain steady perfusion across a range of MAP values through changes in cerebrovascular resistance in healthy individuals. Age‐dependent cerebrovascular stiffening can disrupt cerebrovascular resistance, leaving the brain vulnerable to hypoperfusion with increased MAP. No studies have evaluated MAP during perfusion MRI to further evaluate whether high BP may be related to lower CBF, and whether this relationship is age‐dependent. We studied MAP during perfusion MRI in a sample of younger and older adults using an MRI‐compatible device to continuously monitor MAP.MethodCommunity‐dwelling older adults (n=21; age 56‐87) free of dementia or stroke, and healthy younger adults (n=16; age 18‐34) underwent resting pseudo‐continuous arterial spin‐labelling (pCASL)‐MRI to quantify CBF during simultaneous in‐scanner, continuous MAP monitoring. Average MAP and CBF were calculated over the 5 minute scan. Multiple linear regression examined the relationship between MAP and CBF for younger and older adults, controlling for age and sex.ResultOlder adults with higher MAP during perfusion MRI exhibited significantly lower CBF levels (R2
= .49, β = ‐.23, p = .02). MAP showed no significant relationship with CBF in younger adults.ConclusionThis is the first study to evaluate MAP during perfusion MRI. Findings indicate that higher MAP is correlated with lower CBF in real time in older adults only. We hypothesize that higher MAP may cause decreased CBF through chronic increases in cerebrovascular resistance. Our approach utilizes pCASL‐MRI, capturing CBF to capillaries and smaller arterioles that are susceptible to age‐related microvascular injury. It remains unclear whether the relationship between MAP and microvascular perfusion plays a role in the increased dementia risk associated with high CVRi, but increased CVRi and decreased CBF are associated with dementia. Future work will explore the role of BP during perfusion MRI and whether it may contribute to diagnosis, prognosis or treatment decision‐making to help prevent dementia.
The effect of vitamins on cognitive function in middle‐aged and older adults without dementia
Authors: Suh Seung Wan , Kim Hye Sung , Han Ji Hyun , Bae Jong Bin , Oh Dae Jong , Han Ji Won , Kim Ki Woong 
Published: December 2020

AbstractBackgroundEvidence suggests that vitamins might have a beneficial effect for cognition. The current systematic review aims to investigate the effect of B vitamins, antioxidant vitamins, and vitamin D on cognitive function in the non‐demented middle‐aged or older people.MethodRandomized, or quasi‐randomized clinical trials comparing vitamin supplementation with a control group were included in the standard inverse‐variance random‐effects meta‐analyses. We searched PubMed/MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Library databases for articles until November 2019, and used Risk of Bias tool to evaluate methodological quality of them.ResultA total of twenty‐three studies for B vitamins (n = 22 – 1,053), five studies for antioxidant vitamins (n = 185 – 5,226), and six studies for vitamin D (n = 55 – 4,122) were included in the meta‐analyses. We found that B vitamins had a beneficial effect on global cognitive function (Standardized mean difference [SMD] ‐0.23, 95% CI ‐0.35 to ‐0.10) which effect remained significant over 3‐11 months (SMD ‐0.80, 95% CI ‐1.03 to ‐0.56) and 12 or more months (SMD ‐0.12, 95% CI ‐0.22 to ‐0.01) of supplementation, for those from North America / Europe / Australia (SMD ‐0.07, 95% CI ‐0.11 to ‐0.03), and for those with mild cognitive impairment (SMD ‐0.51, 95% CI ‐0.81 to ‐0.22). B vitamins also showed a significant benefit on episodic memory (SMD ‐0.23, 95% CI ‐0.35 to ‐0.10). Antioxidant and vitamin D revealed no significant benefit on cognitive function compared to control groups.ConclusionOur findings indicated that B vitamins might have a therapeutic effect on global cognitive function and episodic memory domain. More life‐span studies are warranted to identify the most effective timing and duration of the vitamin supplementation.
Habitual consumption of fruit, folic acid and cobalamin as risk/protection factors for the incidence of dementia: Data from the "InveCe.Ab" study
Authors: Davin Annalisa , Ceretti Arcangelo , Mimmi Maria Chiara , Cereda Cristina , Guaita Antonio 
Published: December 2020

AbstractBackgroundThe role of diet as a modifiable factor that may affect the incidence of dementia is currently under investigation. The diet effect could be mediated by blood level of Folic Acid and Cobalamin, whose low levels are recognized as risk factors for dementia. The aim of this work is to evaluate the effects of habitual fruit intake, Cobalamin and Folic Acid on the cumulative incidence of dementia over a period of 4 years in elderly people free of basal dementia.MethodThe subjects were 1321 people born between 1935‐39, enrolled in 2010 by the "InveCe.Ab" study (ClinicalTrials.gov ID: NCT01345110). The cohort was re‐evaluated in 2014 and the onset of dementia was ascertained. The association between fruit consumption and metabolic parameters with dementia at baseline was analyzed with t‐test for quantitative variables and with Pearson chi‐square for qualitative variables. The risk/protection effect of habitual fruit consumption and metabolic mediators on the onset of dementia after 4 years was evaluated by multiple logistic regression.Result988 subjects were included in the analysis, The new cases of dementia between 2010 and 2014 were 50. The high habitual fruit consumption was inversely associated with dementia incidence (p = 0.007) and also directly associated with higher levels of Folic Acid (p < 0.005). Women had higher levels of Folic Acid and Cobalamin (p < 0.001) and a tendency towards higher fruit consumption (p = 0.06). The logistic model using Folic Acid, Cobalamin, and sex as covariates, shows that the usual consumption of fruit reduces the 4‐year risk of developing dementia, (OR: 0.421; 95% CI: 0.213‐ 0.831) with a significant interaction between fruit consumption and Folate (OR: 0.771; 95% CI. 0.607‐0.980). Furthermore a higher level of Cobalamin results protective versus dementia.ConclusionOur data show that in a population of 70‐75 years the cumulative incidence of dementia is significantly reduced by habitual fruit consumption independently of the plasma levels of Cobalamin. Folate could be the metabolic mediator of this protection.
A synthetic control arm from observational data to estimate the background incidence rate of an adverse event in patients with Alzheimer’s disease matched to a clinical trial population
Authors: Blondeau Kathleen , Schneider Andres , Ngwa Innocent 
Published: December 2020

AbstractBackgroundIdentifying a potential safety issue in Alzheimer’s disease (AD) clinical trials is challenging due to the blinded nature of the studies and the number of adverse events (AEs) that occur in this patient population independent of the investigational treatment. An accurate estimate of the incidence rate of an AE in nontreated individuals with AD may help to identify unexpected safety findings.MethodThe objective of this retrospective case‐control study was to generate a synthetic control arm from observational data to estimate the background incidence rate of one AE (pneumonia) in individuals with AD. We used high‐dimensional propensity scoring to match individuals aged 50 to 89 years with AD with to controls from 01/01/2014 to 31/12/2018 in PharMetrics, a US claims database. The inclusion and exclusion criteria were matched to a Phase III clinical trial in AD evaluating crenezumab. Additional inclusion criteria included at least two diagnoses of AD using ICD‐9/ICD‐10 in 90 days and ≥90 days of continuous enrollment prior to the index date. The main outcome was the 5‐year incidence rate of pneumonia in patients with AD. A zero‐inflated Poisson model was designed to predict the expected count of pneumonia as a function of AD diagnosis, propensity score, patient age at index date, sex, disease history, and comorbidity using the Charlson Comorbidity Index.ResultsIn our preliminary analyses, 31,107 individuals with AD were identified from the database; 19,457 (63%) were female; mean age was 75.7 (SD, 8.3) years. Within 5 years of the reported date of AD diagnosis, 4,692 patients were diagnosed with pneumonia. The incidence rate (95% CI) of pneumonia in individuals with AD was 113.07 (109.84‐116.31) per 1,000 patient‐years. Increasing age (incident rate ratio [IRR], 1.06), being male (IRR, 1.5), and patient comorbidities (IRR, 1.25) were associated with an increased risk of pneumonia in individuals with AD.ConclusionA synthetic control arm from observational data may help to estimate the background incidence rate of one AE, pneumonia, in individuals with AD and can help to identify a potential safety issue in a blinded clinical trial.
A prospective long‐term study of TDP‐43 pathology in Alzheimer’s disease aggression
Authors: Vik‐Mo Audun Osland , Hortobagyi Tibor , Módis László , Aarsland Dag 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) in dementia is a major challenge for the health‐care system with a lack of effective treatment strategies. Especially agitation and aggression are pivotal as they represent a large part of the health and social care costs of dementia. But the mechanisms of agitation and aggression are still largely unknown. Comorbid TDP‐43 pathology is common in AD, and here we wanted to explore the association of TDP‐43 pathology and agitation and other NPS in Alzheimer’s disease (AD) and Lewy body dementia (LBD).MethodFrom a cohort of 223 patients with dementia who were followed annually for up to 12 years with the Neuropsychiatric Inventory to assess agitation, aggression and psychotic symptoms, post‐mortem standardized semi‐quantitative assessments of TDP‐43 were performed in 47 patients.ResultIn AD (n = 31) patients with aggression had more severe TDP‐43 pathology than those without aggression (p < 0.05). In LBD (n = 16) no significant associations between pathological scores and aggression or psychotic symptoms were found.ConclusionTDP‐43 may be a possible mechanism behind aggression in AD and its relation to neuropsychiatric symptom in AD needs further investigation. The description of Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) as a separate disease entity highlights the importance of limbic TDP‐43‐pathology in dementia, and TDP‐43 is a potential drug‐target. Cannabidiol (CBD) has shown effect on TDP‐43 pathways, and preliminary studies have suggested that cannabinoids may improve pain related to neuropathy, spasticity, and psychotic symptoms, which are all associated with aggression in dementia. We are planning Cannabidiol in Alzheimer’s disease Aggression (CanADA); a randomized control trial from 3 centers in Norway.
Measurement of CSF core AD biomarkers for routine clinical diagnosis: Do fresh vs frozen samples differ?
Authors: Bellomo Giovanni , Cataldi Samuela , Paciotti Silvia , Parnetti Lucilla 
Published: December 2020

AbstractBackgroundCerebrospinal fluid amyloid‐beta (Aβ) 1‐42/1‐40 ratio, threonine‐181‐phosphorylated‐tau (p‐tau) and total‐tau (t‐tau) represent core AD biomarkers. The wide availability of automated platforms has represented a high achievement for reducing the pre‐analytical variability of these determinations in routine clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approx. 30 min. So far, reference values are represented by measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF differ from those obtained in frozen samples. This issue could be crucial in routine diagnostic work.MethodThirty‐seven consecutive CSF samples have been analyzed immediately after lumbar puncture and after one‐month deep freezing (‐80°C). As automated platform we used LUMIPULSE G600‐II. The fresh aliquot has been analyzed in its storage tube.ResultAs shown in Table 1, in fresh samples an increase of Aβ1‐40, Aβ1‐42 and t‐tau was observed as compared to frozen samples. Aβ1‐42/Aβ1‐40 ratio and p‐tau – ie, the mandatory parameters for diagnosis of Alzheimer disease ‐ showed no variations. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis (Jack et al., 2018), no changes in classification were observed when comparing results obtained in fresh vs frozen samples.ConclusionNo differences in Aβ1‐42/Aβ40 ratio, p‐tau and t‐tau were observed in fresh vs frozen samples. According to these data, it seems not necessary to define new cut‐offs for fresh samples. Nevertheless, further larger and multi‐center investigations are needed to confirm these data.
Predicting development of AD clinical symptoms and their progression through a collection of novel plasma Aβ immunoassays
Authors: Liu Lei , Stern Andrew , Dang Yifan , Ostaszewski Beth , Chhatwal Jasmeer P. , Selkoe Dennis J 
Published: December 2020

AbstractBackgroundFor many years, fluid biomarkers for amyloid β‐protein were described exclusively for Aβ42 and Aβ40, with Aβ40 being the major secreted form and Aβ42 being the predominant component of amyloid‐plaques in AD brain. However, the C‐termini of these two Aβ peptides and the N‐terminus of the AICD are not aligned. It is now clear that secreted Aβ peptides are produced along two proteolytic pathways by γ‐secretase: Aβ49→46→43→40→37 and Aβ48→45→ 42→39/38. We now asked whether a more comprehensive analysis of Aβ peptides in plasma and CSF will help understand and predict brain amyloid pathology and its consequences.MethodWe designed novel immunoassays to detect essentially all the secreted forms of Aβ (Aβ x‐37, 38, 39, 40, 42 and 43), initially on the MesoScale‐Discovery platform (sensitive enough for human CSF samples). To measure same analytes in plasma, we built ultrasensitive immunoassays on the Quanterix SP‐X planar platform with 10‐20 folds enhanced sensitivity. We term Aβ37‐39 short and 40‐43 long Aβs.ResultWe quantified 6 Aβ‐variants in 79 CSF samples from Mayo‐Clinic divided into three diagnostic groups: cognitively normal (CN), mild cognitive impairment (MCI) and Alzheimer's disease (AD). In contrast to Aβ42/40, the short/long Aβ ratios in CSF distinguished CN from AD & MCI more effectively, with AUC (ROC‐analysis) of 0.9609 for Aβ37/42 in distinguishing CN and AD, while AUC is 0.8623 for Aβ42/40. Moreover, both 37/42 and 38/43 correlated significantly with the MMSE scores of these subjects. Next, we tested 88 plasma samples from same cohort, the Aβx‐37/1‐42 ratio in plasma clearly distinguished AD and CN (AUC of 0.8572), while the traditional Aβ1‐42 analyte could not. Currently, we are testing the Aβ37/42 and other ratios in a longitudinal Harvard‐Aging‐Brain‐Study (HABS) cohort.ConclusionCompared to the classic Aβ42/40 ratio in CSF or the Aβ1‐42 absolute level in plasma, a comprehensive analysis of Aβ peptides in plasma and CSF yields better Aβ biomarkers to distinguish CN and AD. Moreover, both 37/42 and 38/43 ratios in CSF correlated significantly with MMSE scores. Importantly, we are assessing whether plasma Aβ37/42 correlates most tightly with the development of AD clinical symptoms and their progression, using longitudinal aging cohorts.