bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioeconomic status mediating sex and racial differences using the AT(N) framework
Authors: Wisch Julie , Hudson Darrell , Coble Dean W , Xiong Chengjie , Babulal Ganesh M , Gordon Brian A , Flores Shaney E , Dincer Aylin , Benzinger Tammie LS , Morris John C , Ances Beau
Published: December 2020

Background

Previous research suggests that women and African Americans are potentially at greater risk for developing Alzheimer disease (AD). Genetic, social, environmental, and cardiovascular factors may increase the risk of AD. (1) Assess neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential sex and racial differences. (2) Consider mediating effects of socioeconomic status (SES) and cardiovascular risk factors on observed sex and race differences.

Method

Imaging measures of AT(N) (amyloid and tau positron emission tomography (PET) structural magnetic resonance imaging, and resting state functional connectivity (rs‐fc)) were collected from African American (n=169) and Caucasian (n=935) participants. Cardiovascular (white matter hyperintensities on MRI, blood pressure, and body mass index) and area‐based socioeconomic status (SES) were assessed as possible mediating factors in a multiple mediation analysis. This analysis assumed nonlinear relationships between the mediation effects and allowed for all four mediators to be considered simultaneously.

Result

Compared to Caucasian participants, African American participants had lower amyloid PET burden but greater neurodegeneration, as measured by decreased cortical volumes and decreased AD global rs‐fc signature. African American participants were substantially more likely to be female (64%) compared to Caucasian participants (55% female). Female participants had greater tau burden and decreased AD cortical signature volume; but no significant race by sex interactions were observed. African Americans had lower area‐based SES and higher blood pressure, BMI, and white matter hyperintensity volumes. These proposed mediators significantly influenced associations between race and cortical amyloid PET accumulation, AD cortical signature volume, and AD global rs‐fc signature. Area‐level SES in particular was a significant mediating factor, and BMI had a significant effect on amyloid burden.

Conclusion

Observed racial differences in AD are not primarily due to immutable, genetic differences, but rather modifiable factors fueled by differences in social contexts and resources, particularly area‐level SES. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies.
Multi‐channel IIT and Rush University Aging (MIITRA) Atlas: Development and evaluation of multimodal templates of the older adult brain
Authors: Wu Yingjuan , Ridwan Abdur Raquib , Qi Xiaoxiao , Zhang Shengwei , Bennett David A , Arfanakis Konstantinos
Published: December 2020

Background

Recent years have seen an increasing demand for multimodal MRI templates of the older adult brain. As part of the Multi‐channel IIT and Rush university Aging (MIITRA) atlas, this work aimed to develop high quality multi‐modal T1‐weighted (T1w) and diffusion tensor imaging (DTI) templates of the older adult brain. This was accomplished through a proposed iterative multimodal template construction strategy.

Method

Template construction: T1w and DTI data on 202 non‐demented older adults (50% male,65.2‐94.9 yrs) from Rush MAP were used. DTI data were aligned to the raw T1w images. In the proposed approach, each iteration includes two steps(Fig.1). In step1, a temporary T1w template is generated and the resulting transformations are also applied to the DTI data. In step2, a temporary DTI template is generated and the resulting transformations are also applied to the T1w data. The template quality at each iteration was assessed through the spatial matching of deformed data. The T1w and DTI template spatial matching was assessed by the overlap between the white matter tissue probability map and the FA map. Comparison to other templates: For the evaluation, T1w and DTI data on 202 non‐demented older adults from ADNI3 were used. The new MIITRA templates generated through the proposed approach were compared with study‐specific template(constructed using evaluation data) and other standardized templates including older adults in terms of inter‐subject spatial normalization accuracy and inter‐modality spatial matching when used as reference for normalization of evaluation data.

Results

Figure 2 demonstrates that the spatial normalization of the T1w and DTI data used to construct the templates improves(p<10‐10) and the spatial matching between the T1w and DTI templates also improves(p<10‐10), suggesting better quality of the templates with more iterations. Figure 4 to 6 show that the new MIITRA templates allow higher spatial normalization accuracy of data from older adults compared to other available templates(p<10‐10).

Conclusion

This work proposed a new multimodal templates construction approach and generated new MIITRA T1w and DTI templates of the older adult brain in the same space, which allow better spatial normalization of T1w and DTI data from older adults compared to other available templates.
Brain transcriptomes and plasma proteins reveal upregulation of a proinflammatory signature in APOE e4 carriers
Authors: Das Sudeshna , Serrano‐Pozo Alberto , Li Zhaozhi , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E , Hyman Bradley T.
Published: December 2020

Background

APOE e4 —the main genetic risk factor for Alzheimer’s disease (AD)—is associated with an increased Aβ plaque burden. Aβ plaques are surrounded by activated microglia, but whether APOE influences microglial responses to plaques in human brains has not yet been extensively studied. In this study, we investigated whether APOE alleles are associated with differences in microglial gene expression—either in concert with, or independent of, AD neuropathological changes—and with plasma protein levels.

Method

We analyzed brain transcriptomics data from the Mount Sinai Brain Bank (MSBB) and the Rush Religious Orders Study and Memory and Aging Project (ROSMAP). We performed integrative analysis to evaluate microglia gene expression across all APOE alleles: e4+ (e3/e4, e4/e4), e2+ (e2/e2, e2/e3) and e3/e3 (reference), adjusting for Braak neurofibrillary tangle (NFT) stage and CERAD neuritic plaque (NP) score. Additionally, we investigated the effect of the e4 allele on the plasma levels of 400 proteins in 34 cognitively normal subjects, measured using the OlinkTMProximity Extension Assay (PEA) panels.

Result

More than a third of the microglial genes were significantly upregulated in e4+ individuals controlling for CERAD NP score. Sensitivity analysis using Braak NFT stage yielded similar results. These genes included complement factors (C3, PLAU, PLAUR), Toll‐like receptor (TLR2, TLR5, TLR7, SPP1), and chemokines (CCL2,CCR5, CCR10). Of note, ∼20% of these genes were significantly increased even in cognitively normal e4+ subjects with low AD neuropathological changes at autopsy (none or sparse NP and Braak NFT stage 0‐II), suggesting e4 is associated with an enhanced baseline inflammatory pattern. A similar pro‐inflammatory profile was also observed in the plasma of cognitively normal e4+ carriers.

Conclusion

Our brain transcriptomic analyses and multiplexed quantification of plasma proteins indicate that carrying the APOE e4 allele is associated with a pro‐inflammatory program compared to the APOE e3/e3 reference group. This differential effect of the APOE e4 allele was observed in brains of individuals with low AD neuropathological changes at autopsy, suggesting that it is not just mediated through its effects on amyloid plaques. Thus, APOE e4 may prime microglia toward a pro‐inflammatory phenotype before plaques and tangles develop.
Characterizing MRI biomarkers for early prediction of amnestic mild cognitive impairment among the community‐dwelling Chinese
Authors: Yue Ling , Pan Yongsheng , Wang Tao , Liu Mingxia , Shen Dinggang , Xiao Shifu
Published: December 2020

Background

Identifying subjects at the preclinical amnestic mild cognitive impairment (pre‐MCI), is fundamental for early intervention of Alzheimer's disease. Extensive studies have shown that structural magnetic resonance imaging (MRI) provides objective biomarkers for automated diagnosis of Alzheimer’s disease and its prodromal stage (i.e., aMCI). This study aims to investigate a deep‐learning‐based framework for predicting the progression from normal control (NC) to MCI, by characterizing imaging biomarkers in structural MRI data.

Method

Motivated by previous disease diagnosis systems with MRI, we create a unique deep‐learning framework for pre‐MCI conversion prediction, by evaluating the discriminative capability of single region‐of‐interest (ROI) or multiple ROIs in the brain. Our framework includes 2 steps: 1) a single‐ROI‐based network (SRNet) for locating the informative regions in the brain, and 2) a multi‐ROI‐based network (MRNet) for pre‐MCI conversion prediction (see Fig 1). We use 845 subjects with baseline MRI in ADNI‐1 to train SRNet and MRNet. To balance the sample size in each category, we use both AD and progressive MCI (within 3 years) patients as positive samples, while NC and stable MCI (within 3 years) samples as negative samples. We then apply the model trained on ADNI‐1 to our private dataset from the Chinese Longitudinal Aging Study (CLAS). The dataset of CLAS included 109 subjects with a baseline NC diagnosis and a 7‐year follow‐up diagnosis. Among these subjects, 40 NC are absolutely converted to aMCI within 7 years (pNC) and 69 NC remain cognitively normal (sNC).

Result

We illustrate the predicted scores of all testing subjects derived by our method, where the subjects are roughly sorted by their stages. We further compared these two groups by logistic analysis while controlled for age, gender, education level, depression symptoms, anxiety symptom, physical disease and baseline cognitive score, pNC individuals remained significant higher predicted score than sNC (see table 1).

Conclusion

This study develops an ROI‐based deep‐learning framework to predict the progression from cognitive normal to aMCI. Experimental results suggest that our method can discriminate the cognitive normal individuals who would be diagnosed with MCI 7 years later, which is helpful for early diagnosis.
Implementation of an interprofessional approach to assessment and care planning in ambulatory older adults with cognitive impairment
Authors: Osbaugh Nicole A , Pearson Scott M , Fixen Danielle R , Hartley Kirbie , Parnes Bennett L , Linnebur Sunny A
Published: December 2020

Background

Medicare‐reimbursed assessment and care planning for cognitive impairment and associated functional decline requires a comprehensive approach that may be challenging for medical practices to implement. An interprofessional team approach to this service utilizes unique strengths of team members to optimize care.

Methods

The University of Colorado Health Seniors Clinic developed an interprofessional “Memory Clinic,” in May 2017 to meet these needs. The team includes geriatricians, clinical pharmacists, a social worker, and medical assistants who are part of the larger Seniors Clinic team. Patients referred to the “clinic” are scheduled for a 40‐minute appointment with a geriatrician for medical, cognitive and functional assessment; receive a pharmacist‐provided cognition‐focused medication, lab, and recreational drug review; and visit with the social worker for functional and caregiver support and resources. Medical assistants assess vital signs and perform depression screening prior to the physician appointment. Medicare Part B is billed for the visit using CPT code 99483.

Results

A review of the electronic medical record identified 112 patients referred to the “clinic” through early December 2019. The mean patient age was 82 years (range 71‐96 years) and all patients received a pharmacist review. 94 (84%) were seen by a geriatrician, and 51 (46%) met separately with a social worker. The majority of patients evaluated by the geriatrician were assessed with the MOCA test (86%, mean score 17.9/30) and the FAST (95%, most common stages 2 and 4). Almost two‐thirds of patients had documented advance directives and a majority had caregivers present at the visit (72%). The pharmacist review identified a mean 2.4 medications per patient that could contribute to cognitive impairment and additional laboratory assessment needed in approximately 50% of patients. FDA‐approved pharmacologic treatments for dementia were prescribed in 17 (15%) patients. A small number of patients stated they regularly ingested marijuana (n=3), applied it topically (n=2), or drank alcohol excessively (n=11).

Conclusions

An interprofessional team‐based approach to cognitive impairment screening and care planning was successfully implemented in a University‐based ambulatory geriatrics clinic. Evaluated patients were found to most often be mildly impaired and have several medications that could be impacting their cognition.
Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy
Authors: van Veluw Susanne J. , Charidimou Andreas , Frosch Matthew P. , Greenberg Steven M
Published: December 2020

Background

Cortical superficial siderosis (cSS) is an established hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA) and emerging as a strong independent risk factor for future lobar intracerebral hemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cSS remain elusive.

Method

Fourteen autopsy cases with CAA (mean age at death 73 years, 9 males) and three controls (mean age at death 91 years, 1 male) were included. Intact formalin‐fixed cerebral hemispheres were scanned on a 3 tesla MRI scanner. cSS was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, eleven representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI‐defined cSS. In addition, samples were taken from pre‐defined standard areas of the brain, blinded to MRI findings. Serial sections were stained for H&E and Perls’ Prussian blue, and immunohistochemistry was performed against Aβ and GFAP.

Result

cSS was present on ex vivo MRI in 8/14 cases and 0/3 controls. Histopathologically, cSS corresponded to Iron‐positive hemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels (Figure 1). Increased severity of cSS was associated with upregulation of reactive astrocytes. Next, cSS and CAA pathology were assessed on a total of 65 sections from MRI‐targeted and untargeted samples. Moderate‐to‐severe cSS was associated with concentric splitting (an advanced form of CAA‐related vascular damage) of the walls of leptomeningeal vessels (p<0.0001), but reduced CAA severity in cortical vessels (p=0.048). Moderate‐to‐severe cSS was associated with the presence of microinfarcts (p=0.025), though not microbleeds (p=0.973).

Conclusion

cSS on MRI corresponds to Iron‐positive depositions in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. cSS appears to be the result predominantly of advanced CAA of the leptomeningeal vessels and may trigger secondary ischemic injury in affected areas.
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

Background

Subclinical 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.

Method

151 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.

Result

Cross‐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.

Conclusion

Cognitively‐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

Background

Genetic 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.

Methods

Reviewing of available demographic and (n = 44) clinical data (n = 64), neuroimaging studies (n = 62), CSF analysis (n = 28) and neuropathological (n = 10) data.

Result

The 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.

Conclusion

Carriers 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

Background

People 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.

Methods

We 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.

Result

During 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).

Conclusion

In 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

Background

Alzheimer'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.

Method

We 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.

Result

We 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.

Conclusion

AAV‐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

Background

Cerebral 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.

Method

AD 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.

Result

58 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.

Conclusion

CSF 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

Background

The contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer’s disease spectrum was investigated

Method

We 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.

Result

Individuals 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.

Conclusion

In 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

Background

The 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).

Method

Fifty‐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.

Result

Neurological 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.

Conclusion

The 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

Background

The 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.

Method

It 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).

Results

We 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.

Conclusion

Correcting 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

Background

Cognitive 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.

Method

As 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.

Result

Most 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.

Conclusion

A 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.
Long‐term adiposity is associated with poorer cognitive performance in middle‐aged adults at high risk of Alzheimer’s disease
Authors: West Rebecca , Ravona‐Springer Ramit , Sharvit‐Ginon Inbal , Golan Sapir , Heymann Anthony , Beeri Michal Schnaider
Published: December 2020

Background

The impact of adiposity on cognition in older adults is well‐established. Alzheimer’s disease (AD) neuropathology begins accumulating years prior to symptoms; investigation of potential AD risk factors, such as adiposity, in middle‐aged adults may illuminate novel pathways underlying the earliest stages of cognitive decline. We examined the relationship of body mass index (BMI), and long‐term trajectories of BMI, with cognitive functioning in middle‐aged adults, participants of the Israel Registry of Alzheimer’s Prevention (IRAP Study), all members of the Israeli HMO‐ Maccabi Health Services, who are exquisitely well‐characterized for cardiovascular risk factors.

Methods

IRAP follows middle‐aged offspring of AD patients (FH+; N=379) and offspring of non‐demented parents (FH‐; N=89). We examined relationships of BMI with global cognition and specific cognitive domains (executive functions, episodic memory, language, working memory). Linear regressions adjusting for age, sex, education, total cholesterol, systolic and diastolic blood pressure, glucose, creatinine, and diabetes status assessed associations of BMI (mean of all BMI measures in Maccabi for each participant) with cognition. Additionally, ANCOVAs were used to examine the association of long‐term trajectories of BMI (“normal, N=239; “overweight,” N= 115; and “obese, N=21” identified using SAS macro PROC TRJ), with cognition.

Results

Higher BMI was significantly associated with lower executive functions (p=.015), episodic memory (p=.032), and global cognition (p=.032), but not language (p= .729) or working memory (p=.391). Significant differences in cognition were identified for the BMI long‐term trajectories for executive functions (normal BMI=.12, overweight M=‐.24, obese M=‐.32, p=.007) episodic memory (.07, ‐.10, ‐.66, p=.021) and global cognition (normal M=.08, overweight M=‐.10, obese M=‐.40, p=.036), but not language (p=.181) or working memory (p=.855). Controlling for FH status did not alter these results.

Conclusion

Higher BMI was associated with lower executive functions, episodic memory, and global cognition in cognitively normal middle‐aged adults. This result is reinforced by the finding that long‐term trajectories of BMI (∼20 years of BMI measurements) were associated with these same cognitive functions; participants with long‐term normal BMI had the highest levels of cognition while those with long‐term obesity had the lowest. Adiposity may have a detrimental impact on the brain already in middle‐aged cognitively normal adults.
An 8‐year comparison of dementia prevalence in Korea: Results from the nationwide survey on dementia epidemiology of Korea, 2008 and 2016
Authors: Kim Ki Woong , Suh Seung Wan , Kim You Joung
Published: December 2020

Background

In many high‐income countries, the prevalence of dementia had been reduced over the past one or two decades. We investigated whether the prevalence of dementia had changed over the past 8 years in Korea.

Method

We had conducted the Nationwide Survey on Dementia Epidemiology of Korea (NaSDEK) in 2008 and 2016 on the Koreans aged 65 years or older who were randomly sampled from 15 administrative districts across the nation. We employed a two‐stage design; a screening phase using MMSE and a diagnostic phase using the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet. We used inverse probability weighting methods to estimate dementia prevalence adjusting for the sampling fraction and the response rate at each phase.

Result

In the NaSDEK 2008, 8,199 were sampled, and 6,141 and 1,673 participated in the screening and diagnostic phases, respectively. In the NaSDEK 2016, 5,056 were sampled, and 3,703 and 551 participated in the screening and diagnostic phases, respectively. According to the NaSDEK 2008, the prevalence of dementia in 2017 was estimated to be 13.7% (967,828). However, the NaSDEK 2016 revealed that the prevalence of dementia in 2017 would be 10.5%, (741,977), which was reduced than expected by the NaSDEK 2008 (OR 0.739, 95% CI 0.737‐0.742, p <.001).

Conclusion

A cohort effect of dementia prevalence was also found in Korea, with earlier‐born individuals having a higher risk of prevalent dementia than their later‐born counterparts.
Multi‐faceted brain changes associated with proximity to dementia onset: The PREVENT‐Dementia study
Authors: Mak Elijah , Dounavi Maria‐Eleni , Low Audrey , McKiernan Elizabeth , Carter Stephen F , Newton Coco , Williams Guy B , Ritchie Karen , Wells Katie , Sahin Zeynep , Terrera Graciela Muniz , Carriere Isabelle , Ritchie Craig W , Su Li , O'Brien John T
Published: December 2020

Background

First‐degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Identifying preclinical brain changes would facilitate both early quantifiable longitudinal disease monitoring and interventional trials. However, the literature of imaging changes in FH+ remains highly controversial. We aim to investigate “estimated years to onset of dementia” (EYOD) as a surrogate marker of preclinical progression and assessed whether FH+ approaching the parental age of dementia onset would express more severe patterns of longitudinal brain changes.

Method

89 FH+ persons underwent serial 3T‐MRI with T1‐MPRAGE, DWI and ASL (mean interval: 2 years). The longitudinal Freesurfer pipeline was used to segment hippocampal subfields and early‐AD regions. Partial‐volume corrected ASL data and DWI data were processed with FSL‐BASIL4 and DTI‐TK5. Small vessel disease was indexed with white matter hyperintensities (WMHs) (Figure 1). We applied linear mixed effects models to predict MRI changes relative to EYOD, accounting for age, gender, education and time from baseline. Secondary analyses examined the interaction of APOE‐ε4+ on proximity‐related brain changes.

Result

A shorter EYOD was associated with progressive decrease in FA, increase in MD/RD and atrophy of the fusiform gyrus over time (Figure 2). Interaction analyses revealed that APOE‐ε4+ carriers showed significant longitudinal atrophy of the hippocampal subfields with shorter EYOD. In contrast, cortical perfusion increased before plateauing ∼10 years before estimated onset. There were no associations of EYOD with mean cortical thickness or WMHs (See Figure 3 for a summary of main findings).

Conclusion

Our findings represent the first extensive characterisation of longitudinal brain changes associated with proximity to dementia in FH+. Individuals who are approaching their parental age of dementia onset may be showing incipient brain abnormalities, particularly amongst APOE‐ε4 carriers. The specificity our findings in early‐AD regions also confer support to biological validity of EYOD as a stage marker of preclinical progression. Further ongoing clinical follow‐up of our sample would provide critical validation of these findings.
Combination of cognitive training and assessment using mobile games with elderly participants
Authors: Bonnechère Bruno , Van Hove Olivier , Samadoulougou Sékou , Klass Malgorzata , Kirakoya‐Samadoulougou Fati , Sahakian Barbara
Published: December 2020

Background

The decline of cognitive function and psychomotor slowing are two important issues related to aging. Numerous apps and games have been recently developed to challenge the brain with fun and motivating cognitive exercises. Previous studies suggest that these types of games are correlated with cognitive scales in the elderly with and without cognitive impairment. However, little is currently known about the potential of these types of interventions to impact cognitive performance positively, especially with healthy elderly. Therefore the objective of this study was to determine if it is possible to analyze changes in the scores of Cognitive Mobile Games (CMG) over a period of training to learn about the level of score improvement that participants of different ages can reach, as a proxy of cognitive performance.

Methods

Scores from 12,000 subjects aged above 60 years old using 5 commercial CMG were retrospectively analysed over a period of 100 training sessions. Results of the first session were compared using one‐way ANOVA and mixed models were used to subsequently investigate the progression of scores over the period of training for the different age groups.

Results

Statistically significant differences were found between the age groups and the initial scores of all the games. We observed that CMG scores increased for all participants, suggesting that all participants improved their cognitive performance. The rate of the score increase is strongly influenced by the age of the participants. There are significant interactions between the age of the participants and the session to predict the evolution of the scores.

Conclusion

The current study provides two interesting insights: 1) users who train with the games improve regardless of age, suggesting that even older adults can improve their cognitive performance using new technology. 2) The presented method is a new and innovative way to assess cognitive function since older people perform less well on these types of games combined with previous findings, as expected. This kind of assessment could be used to monitor cognitive function during long term follow‐up and help early detection of cognitive decline and dementia.