bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression of cerebral small vessel disease in healthy middle‐aged adults associated with inherited risk of Alzheimer’s disease: The PREVENT‐Dementia study
Authors: Low Audrey , Su Li , Stefaniak James D , Mak Elijah , Dounavi Maria‐Eleni , Ritchie Karen , Ritchie Craig W , Markus Hugh S , O'Brien John T 
Published: December 2020

AbstractBackgroundSubclinical brain changes in Alzheimer’s disease (AD) are detectable many years before symptom onset. While cerebral small vessel disease (SVD) has been well‐established as a key pathology in AD, whether genetic predisposition to AD influences markers of SVD in midlife remains unclear. In this study, we compare the longitudinal change in SVD burden between cognitively healthy middle‐aged adults with and without genetic predisposition to AD, and their effect on cognitive decline.Method151 cognitively‐normal participants (age 52.0 ± 5.5; PREVENT‐Dementia study) underwent 3T MRI and cognitive assessment at baseline and two‐year follow‐up. Genetic predisposition to AD was assessed by family history of parental dementia (FH) and APOE4 carriership. White matter hyperintensity (WMH) volumes were segmented and manually corrected on FLAIR MRI and cerebral microbleeds (CMB) on susceptibility‐weighted imaging (Figure 1). WMH volume was adjusted for total intracranial volume and inverse‐normal transformed. SVD progression was compared between groups using ANCOVA and linear mixed modelling in R controlling for sex, age, and education.ResultCross‐sectionally, WMH and CMB did not differ by FH or APOE4 status. However, longitudinal data showed greater WMH progression in FH+ subjects (t=3.94, p<.001) and APOE4+ (t=2.09, p=.038) (Figure 2). The effect of FH on WMH progression was stronger for periventricular WMH (t=3.65, p<.001; deep WMH: t=2.13, p=.035), while APOE4+ subjects displayed greater progression of deep (t=3.30, p=.001), but not periventricular WMH (t=1.17, p=.243). CMB progression did not differ by FH or APOE4 status. Significant three‐way interaction indicated that longitudinal decline in processing speed was associated with global and deep WMH progression in FH+ but not FH‐ subjects (global: t=2.05, p=.042; deep: t=2.90, p=.004; periventricular: t=0.87, p=.384) (Figure 3), while no effect was observed regarding APOE4 carriership.ConclusionCognitively‐healthy individuals with a genetic predisposition to AD displayed greater WMH progression in midlife. WMH progression was associated with longitudinal decline in processing speed in those with FH of parental dementia, but not in those without FH. Taken together, findings suggest that WMH progression is evident decades before dementia might occur, and may be of clinical relevance in predicting cognitive decline particularly in individuals at increased inherited risk of AD.
ABCA7 PTC mutation carriers present with Alzheimer’s disease pathology and cerebral amyloid angiopathy
Authors: Hens Elisabeth , Bossaerts Liene , Sieben Anne , Bossche Tobi Van den , Engelborghs Sebastiaan , Peeters Karin , Vermeiren Yannick , De Roeck Naomi , Hanseeuw Bernard J. , Vandenberghe Rik , Deyn Peter Paul De , Cras Patrick , Martin Jean‐Jacques , Van Broeckhoven Christine 
Published: December 2020

AbstractBackgroundGenetic screening of our Belgian Alzheimer’s Disease (AD) cohort (n = 1478) observed in 69 patients, 15 different premature termination codon (PTC) mutations in the gene coding ATP‐Binding Cassette Subfamily A Member 7 (ABCA7) leading to loss of ABCA7 protein. We aimed to delineate the clinicopathological AD phenotype of the ABCA7 mutation carriers. The ABCA7 gene was initially identified as a risk gene in genome wide association studies of large AD patient cohorts.MethodsReviewing of available demographic and (n = 44) clinical data (n = 64), neuroimaging studies (n = 62), CSF analysis (n = 28) and neuropathological (n = 10) data.ResultThe 69 ABCA7 carriers had a mean onset age of 69.5 ± 9.7 years. In 68 carriers, onset age ranged from 48 to 90 years and mean disease duration was 8.1 ± 4.3 years (range 1‐18). APOE genotypes did not have a modifying effect. A positive familial disease history was noted in 75.0% of carriers. Most carriers displayed an amnestic phenotype (87.6%) without clear distinctive features in clinical examination or neuroimaging. Cerebrospinal fluid (CSF) biomarkers were available for 28 carriers, showing an AD profile in 82.1% of patients. Additional (re)analysis of CSF biomarkers is ongoing for 36 carriers, including Aβ1‐42/Aβ1‐40 ratio as an ancillary biomarker. Imaging features compatible with cerebral amyloid angiopathy (CAA) were described in 3 patients, and 2 other patients suffered from (a) lobar hemorrhage(s). Chronic microvascular damage was noticed in 78.2% of patients. Brain autopsy revealed typical AD pathology together with CAA in all 10 carriers. High levels of CAA were present in both the meningeal and capillary blood vessels, and moderate to high levels of CAA in the parenchymal blood vessels. Further, CAA was not limited to the occipital brain region, but extended to the other neocortices and even to the medial temporal region (n = 5). CAA did not correlate with the levels of AD pathology or APOE genotype.ConclusionCarriers of ABCA7 PTC mutations present with a classical AD phenotype, although with a wide onset‐age, even for carriers of the same mutation. Neuropathological examination revealed extensive levels of CAA in all 10 autopsied brains, additional to AD pathological hallmarks. These findings have important implications for future research and clinical practice.
HIV and risk of dementia in older veterans
Authors: Bobrow Kirsten , Xia Feng , Hoang Tina D , Valcour Victor , Yaffe Kristine 
Published: December 2020

AbstractBackgroundPeople living with HIV (PLWH) may be at increased risk for dementia because of increased major risk factors, chronic infection (and inflammation), and long‐term use of highly active antiretroviral therapy (HAART). Our goal was to determine whether HIV‐infection is associated with incident dementia diagnosis in older U.S. veterans accounting for important potential confounders and competing risk of death.MethodsWe included 1114 veterans, ages ≥ 55 years (mean age=62 years, SD 6), with HIV in the Veterans Health Administration health care system from 2004 to 2015, and a propensity‐matched comparison group (n= 1114) without HIV. HIV and dementia diagnoses were determined using International Classification of Diseases, Ninth Revision codes and Diagnostic Related Group codes in electronic medical records. We conducted Fine‐Gray proportional hazards models to determine whether HIV status was associated with greater risk of incident dementia and adjusting for demographics and co‐morbidities.ResultDuring follow‐up (mean=7 years, SD 4 from date of HIV diagnosis) 5% of veterans living with HIV developed dementia compared to 3% without (p=0.01). Accounting for the competing risk of death, in a model adjusted only for demographics, veterans with HIV had a 60% increased risk of dementia compared to those without HIV (adjusted hazard ratio 1.59, 95% confidence interval, CI, 1.04 ‐2.43.) In a model adjusted for age, sex, race, substance use, education and income PLWH were still 50% more likely to receive a dementia diagnosis (aHR 1.50, 95% CI 0.96‐2.35).ConclusionIn a cohort of older US veterans, we found that HIV infection increases risk of developing dementia. As the population of PLWH in the US ages, understanding general and unique dementia risk factors for this group is key to developing appropriate prevention and mitigation strategies.
Neuronal expression of a single‐chain variable fragment antibody against Aβ oligomers protects synapses and rescues memory in Alzheimer models
Authors: Selles Maria Clara , Fortuna Juliana , Cercato Magali C. , Santos Luis E , Domett Luciana , Bitencourt Andre L.B. , Souza Amanda S. , Janickova Helena , Souza Jorge M. , Alves‐Leon Soniza , Prado Vania , Prado Marco A. , Epstein Alberto , Salvetti Anna , Sebollela Adriano , Arancio Ottavio , Klein William L. , De Felice Fernanda Guarino , Jerusalinsky Diana A. , Ferreira Sergio Teixeira 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is the main cause of dementia in the elderly and is characterized by abnormal accumulation of the beta‐amyloid peptide (Aß) in the brain. Considerable evidence has shown that soluble Abeta oligomers (AßOs) are the main neurotoxins involved in synaptic dysfunction and the memory loss.MethodWe evaluated the therapeutic potential of NUsc1, a single chain variable Fragment (scFv) antibody isolated from a screen to identify scFv’s targeting AβOs. Using an adeno‐associated virus derived vector (AAV) we analyzed its protective effects both in vitro and in vivo models of AD. AAV‐NUsc1 capability to induce NUsc1 expression and secretion in humans was tested using human brain slices in culture.ResultWe here show that recombinant NUsc1, a single‐chain variable fragment (scFv) antibody that selectively targets a subset of neurotoxic AβOs, prevented AβO‐induced inhibition of long‐term potentiation in hippocampal slices, and blocked memory impairment induced by intracerebroventricular infusion of AβOs in mice. We next developed an adeno‐associated virus vector to drive neuronal expression of NUsc1 (AAV‐NUsc1) as a novel therapeutic approach for AD. Importantly, transduction by AAV‐NUsc1 induced NUsc1 expression and secretion in adult human brain slices. In primary hippocampal cultures, transduction by AAV‐NUsc1 reduced AβO binding to neurons and prevented AβO‐induced loss of dendritic spines. Remarkably, AAV‐NUsc1 prevented memory impairment caused by AβO infusion in mice and reversed memory deficits in APPswe/PS1ΔE9 AD mice.ConclusionAAV‐NUsc1 represents a potential tool for gene therapy in AD by using an AAV vector to induce in vivo sustained expression of a single chain variable fragment antibody to neutralize AβOs.
Factors related to CSF biomarkers examination in Alzheimer’s disease
Authors: Mao Chenhui , Sha Longze , Li Jie , Huang Xinying , Lei Dan , Liu Caiyan , Dong Liling , Xu Qi , Peng Bin , Cui Liying , Gao Jing 
Published: December 2020

AbstractBackgroundCerebral spinal fluid (CSF) biomarkers was important part of AT(N) framework in Alzheimer’s disease (AD) definition. Typical AD biomarkers profile was decrease of Aβ42 and elevation of t‐tau and p‐tau in CSF. However, ELISA based CSF biomarkers examination was affected by many factors, including the sampling, transportation, storage of CSF, the environment and operation process. Also, the interpretation of results was influenced by many factors.MethodAD was diagnosed based on 2011NIA‐AA guideline and other dementia was diagnosed based on DSM‐IV. Other diseases without dementia were enrolled as control. Lumber puncture was performed after informed consent. Commercial accessible ELISA kits were introduced for measurement of CSF t‐tau, p‐tau, Aβ42 respectively by INNOTEST hTAU Ag, PHOSPHO‐TAU and β‐AMYLOID (1‐42) (Fujirebio, Ghent, Belgium). CSF was sub‐packed and stored at −80℃, which was tested half a year later. Also, we used two kinds of tubes to collect CSF in the same patient, one with low protein absorption and the other one not.Result58 AD, 83 other neurodegeneration and 28 controls were included. The difference between fresh and storage for half a year was calculated. The change of Aβ42 level in the three groups was 6.2,13.9,−2.4pg/ml, t‐tau level was −184.6,−84.8,301.8 pg/ml, p‐tau level was 15.3,3.8,2.5 pg/ml. Statistically significance was found in t‐tau and p‐tau difference. 4 AD and 7 non‐AD patients were enrolled in the study comparing two kinds of tubes. The change of Aβ42 level in the two groups was 49.7,120.5pg/ml, t‐tau level was 186.3,23.9 pg/ml, p‐tau level was 5.6,−4.8 pg/ml. Changes of tau level were more obvious, although not statistically significance. However, t‐tau/ Aβ42 ratio kept stable between the two kinds of tubes.ConclusionCSF biomarkers examination was affected by collecting and storage. Tau level was significantly affected by storage, which would interfere with AD diagnosis, however, Aβ42 level was not. Low protein absorption tubes were strongly suggested when collecting CSF. Aβ42, t‐tau and p‐tau levels were all affected by absorption, while ratios were relatively stable. Ratios could reduce error of measurement to some extent. A strict standard of operation and laboratory quality control is determining factor in CSF biomarkers research.
Effect of A/T/N imaging biomarkers on impaired odor identification in Alzheimer's disease
Authors: Baek Min Seok , Cho Hanna , Lee Jae Hoon , Ryu Young Hoon , Lyoo Chul Hyoung 
Published: December 2020

AbstractBackgroundThe contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer’s disease spectrum was investigatedMethodWe analyzed data from 127 participants who completed Cross‐Cultural Smell Identification Test (CCSIT), brain magnetic resonance (MR) imaging, and 18F‐flortaucipir and 18F‐florbetaben positron emission tomography (PET) studies. We compared A/T/N neuroimaging biomarkers between normosmia and hyposmia groups, and performed correlation analysis between the biomarkers and CCSIT scores. Additionally, path analysis for odor identification ability was performed using cognitive function as a mediator.ResultIndividuals with hyposmia showed higher frequency of amyloid‐β (Aβ) positivity, and lower neuropsychological test performance than those with normosmia. After correction for covariates including total cognition scores, there was no difference in the Aβ or tau burden between the normosmia and hyposmia groups, and no correlation between CCSIT scores and Aβ or tau burden. Meanwhile, cortical volumes in the lateral and medial temporal cortices were smaller in the hyposmia group and decreased with the worsening of CCSIT scores. Path analysis showed that only neurodegeneration had a direct effect on odor identification, while Aβ and tau burden contributed to odor identification with the mediation of cognition.ConclusionIn the Alzheimer’s disease spectrum, impaired odor identification ability may be attributable to neurodegeneration rather than the direct effect of Aβ or tau burden.
A tau PET study of primary age‐related tauopathy in healthy volunteers
Authors: Shinotoh Hitoshi , Shimada Hitoshi , Tagai Kenji , Kubota Manabu , Takahata Keisuke , Sano Yasunori , Yamamoto Yasuharu , Matsuoka Kiwamu , Takado Yuhei , Nakano Yoshikazu , Hirano Shigeki , Zhang Ming‐Rong , Suhara Tetsuya , Higuchi Makoto 
Published: December 2020

AbstractBackgroundThe term “primary age‐related tauopathy” (PART) was recently introduced to describe a pathology that is commonly observed in the brain of aged individuals. Symptoms in persons with PART usually range from normal cognition to amnesia. The aim of the study is to explore the tau aggregates accumulation in the brain of healthy volunteers by PET with [18F]PM‐PBB3 ( [18F]APN‐1607).MethodFifty‐three healthy individuals (28 men and 25 women ranging in age from 23 to 79 years with a mean of 60) without any history of psychiatric and neurological diseases participated in this study. All subjects underwent neurological examination, cognitive tests, brain MRI, [11C]PiB PET (Aβ imaging), and [18F]PM‐PBB3 PET. [11C]PiB PET images (50‐70 min) was visually assessed. An automated analysis of the volumes of interest in [18F]PM‐PBB3 images (90‐110 min) was performed using the PNEURO module in the PMOD software. Standardized uptake value ratio (SUVR) values were obtained using the cerebellar cortex as a reference region. Pearson correlation analysis was performed between [18F]PM‐PBB3 SUVR and age.ResultNeurological examination revealed no significant finding except for hand tremors in one subject. Cognitive tests were normal in all subjects. Two men were Aβ positive and excluded from the following analysis. There was a positive correlation between age and tau PET signal in the parahippocampus (r = 0.30, P < 0.03), fusiform gyrus (r = 0.41, P < 0.003), and middle and inferior temporal cortex (r = 0.28, P < 0.05) of 51 subjects. No positive correlation between age and [18F]PM‐PBB3 SUVR was found in any other brain regions.ConclusionThe present result supports the concept of PART and the detectability of PART‐type tau deposits by PET with [18F]PM‐PBB3.
Compensating for choroid plexus based off‐target signal in the hippocampus using [18F]flortaucipir PET
Authors: Pawlik Daria , Leuzy Antoine , Strandberg Olof , Smith Ruben 
Published: December 2020

AbstractBackgroundThe hippocampus is an important region to study in Alzheimer’s disease (AD) since it is an early site of tau accumulation. Accurate quantification of hippocampal tau signal using the most common tau‐PET tracer 18F‐flortaucipir is complicated, however, by off‐target binding in the adjacent choroid plexus. We here present a novel method for compensating for this off‐target choroid plexus signal.MethodIt has been shown that off‐target binding in the choroid plexus is higher using 18F‐flortaucipir compared to the recently developed tau tracer 18F‐RO948. Using data from 30 patients that underwent both 18F‐flortaucipir and 18F‐RO948 PET, we created a binary hippocampal mask where 18F‐flortaucipir signal was higher than 18F‐RO948 signal (Figure 1). This mask, representing voxels affected by off‐target binding from the choroid plexus, was then applied to 18F‐flortaucipir PET‐scans from 145 patients across the AD‐spectrum. In this way the off‐target component was excluded. Results were analysed with and without partial volume error correction (PVEc/non‐PVEc).ResultsWe found that unmasked hippocampal standardized uptake value ratios (SUVR) were significantly correlated to choroid plexus SUVRs using both non‐PVEc (r = 0.28, p < 0.001) and PVEc data (r = 0.18, p < 0.05) (Figure 2a‐b). After applying the mask these correlations disappeared (Figure 2c‐d). We next tested the diagnostic accuracy in separating cognitively impaired (CI) from cognitively unimpaired (CU) subjects using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) from ROC analysis increased after masking from 0.79 (95% C.I., 0.72–0.87) to 0.84 (95% C.I., 0.77–0.91) for non‐PVEc data, and from 0.80 (95% C.I., 0.72–0.87) to 0.83 (95% C.I., 0.77–0.90) for PVEc data (Figure 3). Correlations between 18F‐flortaucipir hippocampal SUVR and MMSE improved significantly for masked vs unmasked data, both with (r = ‐0.50 vs. r = ‐0.45) and without (r = ‐0.50 vs. r = ‐0.44) PVEc. Similar results were found using the ADAS‐Cog Delayed Word Recall test.ConclusionCorrecting 18F‐flortaucipir hippocampal SUVR for spill‐in from the choroid plexus using an off‐target mask is feasible, increases the diagnostic accuracy of hippocampal SUVRs and improves correlation with cognitive measures. Importantly, the proposed mask provided better results than applying PVE correction alone.
Validation of composite proxy measures of cognitive reserve
Authors: Boyle Rory , Scarlett Siobhan , Knight Silvin P , Looze Celine , Stern Yaakov , Robertson Ian H , Anne Kenny Rose , Whelan Robert 
Published: December 2020

AbstractBackgroundCognitive reserve (CR) enables individuals to maintain cognitive function despite the presence of brain pathology or atrophy [1]. CR is typically measured via proxy variables that reflect exposure to lifetime experiences, such as education [2]. Composite measures of multiple proxies combine contributions from several experiences and display consistent positive relationships with cognitive function [3]. However, the optimal set of proxies for inclusion in composite measures remains to be determined [2]. Here, we aimed to identify a combination of proxies that best reflects the ability to maintain cognitive function despite cortical thinning.MethodAs part of a larger analysis, 277 healthy adult participants provided data for this study (mean age = 69.18, SD age = 6.66, 141 females). Global cognition was defined as average of z‐scores from the Animal Naming task, Colour Trails Test 1 and 2, Immediate and Delayed Recall. Mean cortical thickness was calculated using FreeSurfer using a previously reported method [4]. CR proxies were: educational attainment, occupational complexity, premorbid intelligence, social engagement, cognitively stimulating activity, leisure activity, and physical activity. For each composite, a three‐step hierarchical‐multiple regression was performed to predict global cognition. Independent variables in Step 1 were age, gender, cortical thickness, CR composite was added in Step 2, and an interaction term (cortical thickness*composite) was further added in Step 3. Positive associations between CR composites and global cognition – independent of age, gender and cortical thickness – were ranked on significant R‐squared change values from Step 1 to Step 2. Moderation effects were identified by significant R‐squared change values from Step 2 to Step 3.ResultMost CR composites had positive associations with global cognition, independent of age, gender, and cortical thickness (see Figure 1). A CR composite measuring cognitively stimulating activity, leisure activity, and physical activity had the biggest negative moderation effect (R2 change = 0.013, p = 0.0276) on the cortical thickness‐global cognition relationship.ConclusionA composite measure of cognitively stimulating‐, leisure‐, and physical‐activity, displays construct validity as a measure of CR in addition to a wide range of composites which display positive, independent, associations with cognitive function.