bluuebunny/crossref_metadata_2025_split huggingface dataset:
The possible role of Optical Coherence Tomography (OCT) and OCT‐Angiography (OCTA) as new non‐invasive biomarkers of prodromal Alzheimer’s disease
Authors: Biscetti Leonardo , Luchetti Elisa , Menduno Paola Santina , Lupidi Marco , Eusebi Paolo , Chipi Elena , Lisetti Viviana , Cataldi Samuela , Cagini Carlo , Parnetti Lucilla 
Published: December 2020

AbstractBackgroundSeveral papers support the existence of a possible link between reduced retinal thickness and Alzheimer’s disease (AD) [1]. Other explorative studies based on retinal oximetry and Doppler flowmetry suggest an alteration of retinal perfusion in AD [2, 3]. Nowadays, retina layers and retinal perfusion can be studied by means of non invasive techniques, ie, Optical Coherence Tomography (OCT) and OCT‐Angiography (OCT‐A). So far, data on OCT‐A in AD patients are scarce, conflicting [4‐5] and refer mostly to the dementia phase. Here, we have compared the retinal thickness and the perfusion index, measured by means of OCT and OCT‐A, in patients with mild cognitive impairment showing a CSF profile compatible with AD (MCI‐AD), and age‐matched cognitively healthy controls.MethodWe enrolled 37 subjects, 24 MCI‐AD patients, and 13 sex and age‐matched cognitively healthy subjects as control group. The mean age was 69.8 in MCI‐AD and 73.6 in controls. The MCI‐AD patients underwent neurological evaluation, neuropsychological assessment and lumbar puncture: in all these patients, the CSF profile, based on t‐tau, p‐tau, Aβ42 and Aβ42/40, was compatible with AD. OCT and OCT‐A have been used for evaluating retinal nerve fiber layer, ganglion cell layer and other retinal thicknesses and retinal and choroidal capillary plexuses. ANCOVA was used for comparing OCT measurements after adjustment for age, diabetes and hypertension.ResultA significant reduction of superficial capillary plexus (10.10±0.81 vs. 10.79±0.67, p=0.012), deep capillary plexus (72.80±3.31 vs. 75.78±3.71, p=0.012) and intermediate capillary plexus (75.57±2.85 vs. 78.03±2.84, p=0.015) was found in MCI‐AD patients compared to controls. Conversely, the fractal dimension (FD) was increased in MCI‐AD with respect to control (1.51±0.02 vs. 1.50±0.01, p=0.044); CSF Abeta42/Tau ratio correlated negatively with FD (r=‐0.51, p=0.010).ConclusionA reduction of retinal perfusion as opposed to an increased fractal dimension in MCI‐AD patients vs controls has been found. The latter finding could be due to a compensative mechanism. These data could support the role of OCT‐A as possible biomarker of prodromal AD. Further larger prospective studies are needed in order to confirm this hypothesis.
Urokinase plasminogen activator (uPA) as a novel biomarker for cerebral amyloid angiopathy
Authors: Vervuurt Marc , de Kort Anna M. , Schreuder Floris HBM , Klijn Catharina J.M. , Kuiperij H. Bea , Verbeek Marcel M. 
Published: December 2020

AbstractBackgroundCurrent diagnostic criteria for cerebral amyloid angiopathy (CAA) are predominantly based on radiological identification of evidence of CAA (micro‐ or macrobleeds). These criteria present only end‐stage manifestations of the disease, however. The development of transgenic rat models for CAA, carrying the E693Q/D694N mutations in APP (rTg‐DI rats), has the potential of discovery of novel biomarkers for CAA. Shotgun proteomics analysis of rTg‐DI tissue, compared to wild‐type rats has yielded elevated levels of urokinase plasminogen activator (uPA) in CAA. uPA is a serine protease active in the conversion of plasminogen to plasmin, a fibrinolytic factor. We investigated the potential of uPA in a pilot biomarker discovery study for the diagnosis of CAA by analyzing uPA concentrations in cerebrospinal fluid (CSF) of patients with CAA compared to control patients.MethodCSF was obtained from patients with possible or probable CAA (according to the current diagnostic imaging tool, the Boston Criteria) (n=28), and control subjects (n=42). uPA levels in CSF were determined using a uPA Quantikine ELISA (R&D Systems, Minneapolis, USA). Total protein levels were assayed using a Pierce® BCA Protein Assay (Thermo Fisher, Waltham, USA). Associations of uPA with known concentrations of other neurological markers, including aβ peptides and tau proteins were also analysed.ResultThe concentration of uPA was significantly increased in the CSF of CAA patients compared to controls (303 ± 23.2 vs. 227 ± 12.5 pg/mL; p=0.001). CSF uPA levels (very) weakly correlated with age at lumbar puncture (rSP=0.33, p=0.005) and total protein content (rSP=0.24, p=0.042). uPA levels in controls were correlated in a weak‐to‐moderate extent with Aβ‐38, 40, 42, and total‐ and phosphorylated tau protein (rSP=0.46, 0.63, 0.47, 0.53 and 0.41 respectively, p<0.02), whereas this correlation was practically absent in the CAA group.ConclusionComparison of CSF levels of uPA shows a significant elevation in CAA patients compared against controls. CAA patients show lower levels of correlation of uPA with circulating aβ peptides and tau protein variants as compared to controls. This reinforces the potential of uPA as an effective biomarker in the diagnosis of CAA patients and incentivizes further research into this biomarker.
Is kidney disease associated with both Alzheimer’s disease and vascular dementia?
Authors: Basit Saima , Damholt Mette Brimnes , Wohlfahrt Jan , Boyd Heather A 
Published: December 2020

AbstractBackgroundPrevious studies have found associations between renal dysfunction and cognitive impairment. Associations between kidney disease and dementia are less well‐established and the available evidence for associations with dementia subtypes is conflicting.MethodOur study cohort included 4,320,824 individuals ≥40 years of age and living in Denmark at some point during 1996‐2017. Of these, 123,269 persons developed dementia during 60,043,110 person‐years of follow‐up (median follow‐up time, 14.8 years). We compared the risks of dementia in persons with and without a history of kidney disease using Cox regression with age as underlying time scale. All analyses were adjusted for sex, birth year, cardiovascular disease, autoimmune diseases, diabetes and hypertension.ResultCompared with persons without kidney disease, persons with any kidney disease had a higher risk of dementia overall (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.19‐1.25) and of early‐onset (<65 years) dementia in particular (HR 1.66, 95% CI 1.50‐1.85). Stronger associations were observed for acute kidney disease (dementia overall: HR 1.45, 95% CI 1.38‐1.52; early‐onset dementia: HR 2.12, 95% CI 1.70‐2.63; late‐onset dementia: HR 1.44, 95% CI 1.36‐1.52) than for chronic kidney disease (dementia overall: HR 1.15, 95% CI 1.10‐1.20; early‐onset dementia: HR 1.49, 95% CI 1.24‐1.78; late‐onset dementia(≥65 years): HR 1.15, 95% CI 1.11‐1.19). Persons with kidney disease had increased risks of vascular dementia (HR 1.43, 95% CI 1.33‐1.54) and other/unspecified dementia (HR 1.30, 95% CI 1.26‐1.34); in contrast, kidney disease was not associated with the risk of Alzheimer’s disease (HR 0.98, 95% CI 0.94‐1.03). The magnitude of the association with vascular dementia overall was similar for acute kidney disease (HR 1.57, 95% CI 1.33‐1.86) and chronic kidney disease (HR 1.44, 95% CI 1.28‐1.63). However, acute kidney disease was very strongly associated with the risk of early‐onset vascular dementia (HR 3.09, 95% CI 1.65‐5.81).ConclusionKidney disease, especially acute kidney disease, was associated with increased risks of dementia, early‐onset dementia in particular. Kidney disease was associated with increased risks of vascular dementia but not of Alzheimer’s disease.
Characterisation of Alzheimer’s disease patients with agitation and their antipsychotic use: A study using the UK Clinical Practice Research Datalink
Authors: Baker Ross A , Lind Stefan , Qizilbash Nawab , Johnson Michelle , Collings Shuk‐Li , Bøg Martin , Tran Cam Thanh , Jørgensen Kristian Tore 
Published: December 2020

AbstractBackgroundThere are few data on patients with agitation in Alzheimer’s disease (AD) and their use of antipsychotics (APs). This study characterised patients with agitation in AD (AAD) in terms of falls, and disease duration and examined their AP use compared to AD patients with other neuropsychiatric symptoms (NPS) and no NPS.MethodsData from the UK Clinical Practice Research Datalink were analysed in two ways. Cross‐sectionally to characterise patients with AAD, other NPS and no NPS on 01/07/2016, using chi‐square and ANOVA for differences in proportions and means between groups, respectively. Retrospectively between 01/01/2015 and 31/12/2017 to compare AP use between AD patients with agitation, other NPS and no NPS using a Cox proportional hazards model adjusted for covariates.ResultsAt 01/07/2016, there were 10,573 AD patients with a mean age of 83 years. Patients with AAD (n=605) had longer mean duration of disease (4.3 years) versus patients with other NPS (n=5102, 2.8 years) and no NPS (n=4772, 2.5 years) (p<0.001); more falls (53%) versus patients with other NPS (47%) and no NPS (33%) (p<0.001); were more likely to be prescribed atypical APs within last 60 days (24%) versus patients with other NPS (7%) and no NPS (4%) (p<0.001); and were more likely to have ever been prescribed benzodiazepine (64%) versus patients with other NPS (52%) and no NPS (24%) (p<0.001). During the 3‐year follow‐up, there were 24,464 AD patients with median follow‐up of 1.1 years. The proportion of patients with an AP prescription during follow‐up was: 38% (AAD, n=2432), 20% (other NPS, n=13,076) and 12% (no NPS, n=11,816). Compared to patients with no NPS, the adjusted hazard ratio for AP use was 3.45 (95% CI 2.86‐4.17) for patients with AAD and 1.31 (95% CI 1.19‐1.44) for patients with other NPS.ConclusionPatients with AAD are a particularly difficult to manage group. More patients with AAD had experienced falls and had a longer duration of AD than patients with other or no NPS. At the same time AP use was more than 3‐fold higher in patients with AAD than in patients without NPS.
Pronounced regional spectral, connectivity and network changes reflect visual deficits in posterior cortical atrophy: An EEG study on PCA
Authors: Briels Casper T. , Eertink J.J. , Stam Cornelis J. , van Der Flier Wiesje , Scheltens Philip , Gouw Alida A. 
Published: December 2020

AbstractBackgroundElectroencephalography (EEG) has shown differences in spectral, functional connectivity and network measures between typical Alzheimer’s disease (AD) and controls. Subjects with posterior cortical atrophy (PCA) show more severe visuospatial and perceptual deficits compared to typical AD. The aim of this study was to investigate whether functional alterations measured by EEG can help understand the mechanisms that explain the clinical heterogeneity.Methods21‐channel EEG recordings of 29 PCA subjects, with positive biomarkers for amyloid pathology, were compared with 29 typical AD subjects and 29 controls with subjective cognitive decline matched for age, gender and disease duration (respectively 41%/38%/45% male, age:63±5/63±5/63±5yr, median MMSE:19/18/28). Relative band power, alpha band functional connectivity (defined by volume conduction corrected amplitude envelope correlation) and network characteristics of the minimum spanning tree(MST) were assessed at global and electrode levels. Differences between diagnostic groups were analysed with pairwise permutation testing. Correlations between electrode level peak frequency with visual (dotcounting and fragmented letters) and memory (Rey Auditory Verbal Learning Test) tasks were assessed within the PCA group.ResultsPCA and AD subjects had a lower global relative alpha and beta and higher theta power compared to controls (p<0.05). PCA subjects had higher global relative delta and lower alpha power compared to AD subjects (p<0.05), driven by a decrease in the dominant posterior frequency (Figure 1). Global functional connectivity was decreased in both PCA and AD compared to controls (both p<0.001). The MST showed an increased network diameter, a decreased posterior and an increased frontal degree in PCA compared to controls (Figure 2). In PCA, decreased right posterior peak frequency correlated with worse performance on visual tasks (Dotcounting: r=0.50, p=0.012; fragmented letters: r=0.51, p=0.008) but not with the memory task (Figure 3).ConclusionThe clinical differences between PCA and typical AD subjects corresponded with a more severe slowing of oscillatory activity in the posterior regions in PCA subjects. The network of PCA subjects showed a less efficient topology and a shift in hubness from posterior to frontal channels. This indicates that in PCA, regional synaptic dysfunction might interplay with previously reported atrophy and tau accumulation in the networks responsible for visual processing.
Pilot study: Stress‐induced noradrenergic activity as potential indicator for practice effects — Association between acute stress, noradrenaline response and practice effects
Authors: Pagen Linda H.G. , Smeets Tom , Müller‐Ehrenberg Lisa , Yassa Michael A. , Verhey Frans R.J. , Jacobs Heidi I.L. 
Published: December 2020

AbstractBackgroundStress has both enhancing and impairing influences on memory performance. Interestingly, aging has been associated with changes in the stress system as well as a decline in memory performance. Reductions in memory practice effects have gained interest as a risk factor for future cognitive decline, yet research on how stress influences practice effects in older individuals is scarce. Considering the age‐related changes in the stress systems, it is conceivable that exposure to stressors may facilitate the identification of individuals with an absence or attenuation of practice effects.MethodA total of thirty healthy individuals aged 40‐70 years old were subjected to a pattern separation memory task with and without an acute cognitive stressor before encoding. Several salivary alpha amylase (SAA) samples were obtained at different time points as a proxy of noradrenaline activity. Using the change scores on the memory task, we divided participants in learners (exhibiting practice effects) and non‐learners (Figure 1A). Spearman correlation coefficients were calculated to examine the relation between practice effects and SAA levels. Subsequently, an age by SAA interaction on practice scores was explored with a linear model for SAA levels at all time points.ResultIn the entire group, higher baseline SAA levels correlated to worse practice effects (r
s= ‐0.46, p=0.02) while controlling for age. The non‐learners showed significantly higher SAA scores at all time points compared to learners (table 1). The learners demonstrated a significant interaction between age and SAA levels after encoding (b=0.02, t=4.35,p=0.0019) on pattern separation difference scores controlled for SAA baseline levels (Figure 1B). No such interaction was observed for non‐learners (b=0.0009, t=0.56, p=0.6; Figure 1C).ConclusionThese results show that elevated baseline noradrenaline activation is associated with the absence of practice effects. Additionally, in learners practice effects were observed in middle‐aged individuals with relatively lower levels of noradrenergic activity. These findings suggest that noradrenergic system activation may be a promising indicator of imminent cognitive decline. Future research is needed to understand variability in noradrenaline activation and practice effects over the adult age span.
Life expectancy with and without dementia after diagnosis of mild cognitive impairment: A population‐based study
Authors: Mooldijk Sanne S , Yaqub Amber , Wolters Frank J , Licher Silvan , Koudstaal Peter J , Ikram M Kamran , Ikram M Arfan 
Published: December 2020

AbstractBackgroundReliable prognosis of mild cognitive impairment (MCI) in terms of life expectancy (LE) with and without dementia is important to inform patients and their relatives, as well as health policy makers, but data from unselected older populations are scarce.MethodBetween 2002 and 2015, all participants aged 60‐105 years of the population‐based Rotterdam Study were assessed for the presence of MCI and were followed subsequently for the onset of dementia or death. MCI was defined as subjective cognitive complaints with objective cognitive impairment in the absence of dementia. We constructed multistate life‐tables for the transitions from MCI to dementia, MCI or dementia to death, and determined age‐specific LE with and without dementia by gender, APOE‐ε4 carrier status, and educational attainment.ResultOf 648 individuals with MCI (median age at entry 71.7 years (interquartile range 65.0‐78.1); 53.9% women), during 4423.4 person‐years of follow‐up, 136 developed dementia and 293 died. Overall LE in women ranged from 23.4y [90% confidence interval (CI) 21.6‐25.5] at age 60 to 4.4y [3.1‐6.2] at age 90, and in men from 19.3y [17.5‐21.7] at age 60 to 3.3y [2.2‐5.2] at age 90. Women were at higher risk of conversion to dementia (HR 1.20; 95% CI 0.85‐1.71), and consequently lived more years with dementia than men (from age 60: 3.7y [2.7‐5.2] vs. 2.0y [1.4‐3.0]; from age 90: 1.9y [1.0‐3.6] vs. 1.0y [0.5‐2.5]). APOE‐ε4 carriers were at higher risk of conversion to dementia as well as death, such that their expected life years with dementia were similar to non‐carriers (2.9y [2.0‐4.4] for carriers vs. 2.8y [2.0‐4.1] for non‐carriers). Higher education conferred a benefit in overall life expectancy compared to further and lower education, but these additional years were lived predominantly with dementia (at age 60: 4.9y [3.7‐6.6] vs. 2.9y [2.2‐4.1] and 2.0y [1.5‐2.9]).ConclusionWomen with MCI live longer than men, both with and without dementia. To provide accurate information to patients and policy makers, acknowledged prognostic factors like APOE‐ε4 carrier status and educational attainment should be interpreted against the backdrop of remaining life expectancy.
Association of periodontitis and cognitive impairment: A systematic review and meta‐analysis
Authors: Asher Sam , Stephen Ruth , Suominen Anna Liisa , Mäntylä Päivi , Solomon Alina 
Published: December 2020

AbstractBackgroundEmerging evidence suggests link between poor periodontal status and cognitive impairment. This review systematically assessed longitudinal evidence on the association of periodontitis and tooth loss with cognition.MethodsComprehensive literature search for studies examining effect of periodontitis on cognition was conducted on two electronic databases, Medline and Scopus. Longitudinal studies having periodontitis or its surrogate measure (tooth loss) as exposure and cognition as outcome were included. Meta‐analysis was conducted on RevMAN‐5 software. Primary random effects model analyzing the effect of periodontitis (all measures) on cognition was generated. Secondary analyses included models based on periodontal specific measures 1 and tooth loss. Quality assessment of included studies was conducted.ResultsOut of 97 studies, 16 were included in the systematic review. Meta‐analysis included 9 studies. In preliminary results, primary model showed significant association between periodontitis and cognitive impairment (OR=1.22, 95%CI:1.01–1.49, p=0.04). In secondary analyses, neither periodontitis (based on specific measures) nor tooth loss was associated with cognitive impairment. However, further stratification of tooth loss found significant association between partial tooth loss and cognitive impairment (OR=1.53, 95%CI:1.03–2.29, p=0.04). The overall quality of evidence was low.ConclusionPeriodontitis appears to contribute to overall risk of cognitive impairment. This association may be driven by specific aspects of periodontitis such as severity, chronicity and corresponding tooth count. However, firm conclusions cannot be drawn due to overall low quality of evidence and lack of coherent methodology among studies (e.g. variability across periodontal and cognitive assessments). Well‐designed longitudinal studies with larger sample size and including comprehensive and standardized assessment of both periodontal and cognitive status are warranted.
Phenotypic heterogeneity of the rare R377W PSEN1 mutation: Late‐onset presentation with mixed Alzheimer’s and frontotemporal dementia features
Authors: Scarioni Marta , Arighi Andrea , Fenoglio Chiara , Serpente Maria , Rotondo Emanuela , Pietroboni Anna , Fumagalli Giorgio G. , Carandini Tiziana , Scarpini Elio , Galimberti Daniela 
Published: December 2020

AbstractBackgroundAutosomal dominant mutations in the PSEN1 gene have been associated with the earliest Alzheimer’s disease onset and a typical amnestic syndrome of the hippocampal type, although behavioural and psychiatric presentations have also been reported. The R377W PSEN1 mutation has only been found in two patients until now. Here, we want to describe an unusual presentation of the rare R377W PSEN1 mutation in an Italian patient with a late age of onset, and to provide for the first time antemortem pathological evidence for this mutation.MethodA 71‐years old female patient with progressive cognitive decline in the past three years underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid‐PET and extensive genetic screening with a next generation sequencing technique.ResultThe diagnostic work‐up revealed mixed frontotemporal dementia and typical Alzheimer’s disease features on neuropsychological tests, MRI and FDG‐PET. Amyloid‐PET detected amyloid deposition in the frontal areas as well as in the parietal lobes and the precunei. The genetic screening unraveled the presence of the rare R377W mutation in the PSEN1 gene.ConclusionExtensive genetic screening is advisable also for late onset presentations of Alzheimer’s disease, especially in the presence of a positive family history.