bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using imputation to harmonize longitudinal measures of cognition across two large cohorts: AIBL and ADNI
Authors: Shishegar Rosita , Cox Timothy , Rolls David , Dore Vincent , Lamb Fiona , Robertson Joanne S , Laws Simon M , Porter Tenielle , Maruff Paul T , Savage Greg , Rowe Christopher C , Masters Colin L , Weiner Michael W. , Villemagne Victor LL , Burnham Samantha C ,   the Alzheimer’s Disease Neuroimaging Initiative,   the AIBL research Group
Published: December 2020

AbstractBackgroundTo ensure the generalisability of findings and consider more nuanced hypotheses, larger sample sizes are required. Combining data from different but similar study cohorts is one solution. However, the disparity of these datasets, e.g. using differing tests to assess specific cognitive domains, makes this a non‐trivial task. Here, we propose a harmonisation solution using imputation strategies1,2 for cognitive memory performance in AIBL3 and ADNI4.MethodAIBL participants (N=1813 [1180 NC, 297 MCI and 328 AD; aged 72.52±7.72; 777 males]) and ADNI participants (N=1945 [756 NC, 820 MCI, 369 AD; aged 73.92±7.23; 1028 males]) were included in this study. Scores for tests administered in one cohort but not the other were imputed in the cohort for which they were missing (with the RAVLT5 being used in ADNI and the CVLT‐II6 in AIBL). Non‐parametric multivariate imputation using random forests (missForest)7 was employed to impute the ‘missing’ data and test scores across both cohorts from the full neuropsychological testing batteries, and age, gender, years of education and APOE‐ɛ48 status were used to inform the models. The discriminatory power of the actual and imputed scores to differentiate between NC, MCI & AD was assessed. To further validate the method, data for Logical Memory II (LMII; administered in both cohorts) was simulated as missing in each cohort, respectively, and the correlation between the actual and imputed LMII test scores was assessed.ResultSimilarly, high levels of significant discrimination (p<.001) between clinical classifications were observed for the actual and the imputed scores of the CVLT‐II and RAVLT (Figure 1). Comparing the imputed LMII test scores which were simulated as missing to the actual LMII scores resulted in correlation coefficients of ≥90%.ConclusionThe need to combine large datasets will increase as we aim to improve the generalisability of findings and test more complex hypotheses. The results here suggest it is possible to use data imputation, capitalising on underlying structures and relationships, to impute specific tests scores in a cohort for which that test what not administered. In turn, providing a practical solution for data harmonization across large, cross‐sectional and longitudinal datasets. References: 1doi:10.1038/srep21689.2doi:10.1002/sim.5894.3doi:10.1017/S1041610209009405.4doi:10.1212/WNL.0b013e3181cb3e25. 5doi:10.1002/1097‐4679(199311)49:6<883::AID‐JCLP2270490616>3.0.CO;2‐66doi:10.1076/clin.14.4.526.7204. 7doi:10.1093/bioinformatics/btr597.8doi:10.1212/wnl.43.8.1467.
Evolution of the core clinical features of dementia with Lewy bodies
Authors: Choudhury Parichita , Radford Jonathan Graff , Wurtz Lincoln , Aakre Jeremiah A. , Brushaber Danielle , Jones David T. , Knopman David S. , Kantarci Kejal , Savica Rodolfo , Graff‐Radford Neill R. , Drubach Daniel A. , Fields Julie A. , Machulda Mary M. , Pedraza Otto , Forsberg Leah K. , Allen Laura A. , Miyagawa Toji , St. Louis Erik K. , Silber Michael H. , Kremers Walter K. , Petersen Ronald C. , Boeve Bradley F. , Ferman Tanis J. 
Published: December 2020

AbstractBackgroundDementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia but the evolution of the core clinical features of DLB has not been clearly defined. The objective of this study was to identify the temporal relationship between each core feature from the estimated onset of cognitive symptoms.MethodParticipants include 485 patients with probable DLB who were evaluated at the Mayo Clinic Alzheimer Disease Research Center with neurologic and neurocognitive assessment. Each core clinical feature was compared using Kaplan‐Meier (KM) curves with the sentinel event representing age at which each core feature developed, or time from estimated cognitive onset.ResultThe sample was disproportionately male (76%). Patients were followed longitudinally, with 84% followed until death. Mean MMSE at the last evaluation was 18.3 ± 7.8. KM curves for age of onset and cumulative incidence for DLB core features as time from cognitive onset are provided. REM‐sleep behavior disorder (RBD) developed earliest and in 77% of our sample with a median KM survival estimate of 69 years (95% CI: 67.6–70.8). RBD was present in greater than 50% of patients at cognitive symptom onset. The median KM survival estimate for cognitive symptom onset was 70.2 years (95% CI: 69.3‐71.0). Parkinsonism developed in 89% with a median KM survival estimate of 73.7 years (95% CI: 72.7‐74.7). 76% had fluctuations with a similar median KM survival estimate of 74.6 years (95% CI: 73.7‐75.8). Visual hallucinations (VH) were present in 70% emerging at a median KM survival estimate of 80.2 years (95% CI: 79.5‐ 81.3). Cumulative incidence estimates for median time from cognitive onset to parkinsonism, fluctuations and VH were 2 years (95% CI: 2.0‐2.5), 2.3 years (95% CI: 2.0‐3.2) and 4.3 years (95% CI: 4.0‐4.8 years), respectively.ConclusionIn this DLB cohort, RBD was most likely to precede cognitive onset. The evolution of the other core features after cognitive onset was parkinsonism and fluctuations and then VH. While VH occur about 4 years after cognitive symptom onset, parkinsonism and fluctuations occur within the first 2 years.
Reduced density of noradrenergic fibers without prominent neuron loss or tau pathology in the locus coeruleus in APP knock‐in mouse models of Aβ amyloidosis
Authors: Iijima Koichi M. , Sakakibara Yasufumi , Ibaraki Kyoko , Takei Kimi , Saito Takashi , Saido Takaomi C. , Sekiya Michiko 
Published: December 2020

AbstractBackgroundLocus coeruleus (LC) is a nucleus containing the cell bodies of noradrenergic neurons in the brain, and is one of the earliest regions affected by Alzheimer’s disease (AD). Norepinephrine (NE) is critical for cognitive functions as well as anti‐inflammatory and neuroprotective properties, both of which are implicated in AD. LC neurons are among the first to display tau pathology and that significant loss of forebrain noradrenergic projections is evident at prodromal stage of AD, suggesting that abnormality in LC‐NE system initiates the disease pathogenesis. However, mechanisms underlying neurodegeneration in LC‐NE system remain elusive. We have previously reported that AppNL‐G‐F/NL‐G‐F
mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits and severe neuroinflammation accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how LC‐NE system is altered in AppNL‐G‐F/NL‐G‐F
mice.MethodTo ask whether AppNL‐G‐F/NL‐G‐F
mice exhibit noradrenergic degeneration, we compared the density of norepinephrine transporter (NET)‐positive fibers in the cortex and hippocampus as well as the number of dopamine β‐hydroxylase (DBH)‐positive neurons in the LC between AppNL‐G‐F/NL‐G‐F
and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the LC‐NE system in these mice.ResultHistochemical analyses revealed that 24‐month‐old AppNL‐G‐F/NL‐G‐F
mice exhibited significant decreases in the density of NET‐positive fibers in the prefrontal and entorhinal cortices and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice. In contrast, AppNL‐G‐F/NL‐G‐F
mice did not display loss of DBH‐positive neurons in the LC even at 24 months of age. Furthermore, AppNL‐G‐F/NL‐G‐F
mice did not develop prominent tau pathology either in the nerve terminals or in the cell bodies of LC neurons.ConclusionThis study demonstrates that Aβ pathology is sufficient to reduce the density of noradrenergic fibers independent of neuron loss and tau pathology in the LC. These results also suggest that age‐dependent accumulation of Aβ in the cortex or tau in the LC may additively and independently damage LC neurons from the nerve terminals or from the cell bodies, respectively.
Prioritizing potential diagnostic biomarkers of Alzheimer’s disease by investigating gene expression data: A network‐based approach
Authors: Chand Yamini , Sao Prachi , Singh Shivani , Chandra Niharika , Das Surojeet , Singh Sachidanand 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive neurodegenerative disorder. The identification of differentially expressed genes (DEGs) across affected brain regions can provide new insights into the mechanisms of AD.MethodOur study aims to identify potential biomarkers of AD across brain regions using gene expression and network‐based approaches. The gene expression data were downloaded from Gene Expression Omnibus (GEO) for the series GSE5281. The series comprises expression data from 6 brain regions Entorhinal Cortex (EC), Hippocampus (HIP), Middle temporal gyrus (MTG), Posterior cingulate cortex (PC), Superior frontal gyrus (SFG) and visual cortex (VCX). Differentially expressed genes (DEGs) were identified using GeneSpring GX 12.6.1 software. A protein‐protein interaction network (PPIN) was constructed from high throughput experiments using Biosogenet. A subnetwork comprising common DEGs and their first neighbors was extracted from the complex PPIN, and the network centralities, including degree and betweenness, were calculated using NetworkAnalyzer plugin in Cytoscape 3.7.1.ResultOur results identified 4748 non‐redundant DEGs, of which 1493 and 3255 constitute the up and down‐regulated genes, respectively. A total of 124 common DEGs were identified across more than four brain regions. The subnetwork comprised 5723 and 140625 nodes and edges, respectively. Topological analysis of the subnetwork identified 474/148 Hub/Bottleneck genes and 146 Hub‐Bottleneck genes. Two HB genes EGFR and FYN and two H genes NOTCH2NL and SRRM2 were identified as up‐regulated across four brain regions. Six HB genes CUL3, COPS5, HSP90AB1, YWHAZ, YWHAB, and CDC42, and two H genes SNCA, TUBA4A were identified down‐regulated across five brain regions. Furthermore, four HB genes UBC, CUL1, C1QBP, and UBQLN1 and 10 H genes TUBB, GAPDH, SSX2IP, AP2M1, PSMA1, SKP1, TERF2IP, ATP5A1, CCT7, and NDUFA4 are found to be down‐regulated across four brain‐region. Of these, SNCA, GAPDH, UBQLN1 were known to be associated with AD.ConclusionThe identification of AD biomarkers across different brain regions integrating differential gene expression study and network‐based approach may provide new insights into the mechanisms of AD.
The association between aldehyde dehydrogenase gene (ALDH2) polymorphism and cognitive impairment among Chinese oldest old
Authors: Jin Xurui , Long Tingxi , Chen Huashuai , Zeng Yi , Yan Lijing 
Published: December 2020

AbstractBackgroundAldehyde dehydrogenase 2 (ALDH2) is one of the aldehyde dehydrogenase isoforms responding for 3,4‐dihydroxyphenylglycolaldehyde metabolism and a common mutation in ALDH2 (rs671 AG or AA) causes the activity of ALDH2 to be reduced which was associated with Asian flush and series of cancers. Recent study suggested that carrying rs671 A allele and high intaking of alcohol will jointly increase the risk of Alzheimer disease in mice. Accordingly, we investigated the association between the ALDH2 RS671 genotype and cognitive impairment among Chinese oldest old.MethodWe used a genetic sub‐study of the Chinese Longitudinal Healthy Longevity Survey including 1949 participant aged over 90 years old. Mini‐Mental State Examination (MMSE) score was used to ascertain cognitive impairment at baseline, defined as MMSE score less than 18 out of 30. RS671 genotype was further categorized as non‐carrier (GG) and carriers (AG or AA). Multivariable logistics regression models were applied to examine the association between RS671 genotype and cognitive impairment.ResultAmong the participants, 76.2% were women and 36.0% were RS671 carriers, with a mean age of 100.7 (SD 3.29) years. The mean MMSE score was 16.4 (SD: 10.6) and 49.3% of the participants had cognitive impairment. Carrying RS671 mutation was associated with 26.1% higher odds (95% CI: 0.7%‐58.0%) of cognitive impairment. Significant interaction between RS671 genotype and fruit consumption (P=0.045) was observed. Carrying RS671 mutation was significantly associated with higher odds of cognitive impairment among those with low fruits consumption (OR=1.58, 95% CI 1.01‐2.51), but the significance was not significant in the group with high fruits consumption.ConclusionIn the Chinese oldest old, carrying ALDH2 RS671 mutation was associated with higher odds of cognitive impairment, and the association between RS671 genotype and cognitive impairment is more pronounced in those with low fruit consumption. No interaction between alcohol consumption and RS671 genotype was observed.
Alterations in the bone microarchitecture in Psen1 L166P KI mice depicting pathogenesis of Alzheimer’s disease
Authors: Suryadevara Vidyani , Krehbiel Connor J , Monte Willis S 
Published: December 2020

AbstractBackgroundAn accelerated bone loss (osteoporosis) has also been reported in the early stages of Alzheimer’s disease, as seen by the reduction in bone mineral density in these patients, compared to healthy individuals. In the present study, we investigated knock‐in mice with a Psen1 mutation(L166P) and a human APP Tg+(Psen1 L166P KI). These mice develop brain amyloid pathology by six months of age, evidenced by amyloid deposition in the cerebral cortex; the role of PSEN1 L166P on bone has not previously been reported.MethodPsen1 L166P KI and strain‐matched wildtype control mice were analyzed by Dual Energy X‐ray Absorptiometry(DEXA) to determine whole‐body mineral density and bone mineral content in vivo over time. The left femur and L5 vertebra were isolated and analyzed by micro‐CT(SkyScan 1172) to quantify cortical and trabecular microarchitecture.ResultDEXA analysis of Psen1 L166P KI mice identified a reduction in whole‐body mineral density and bone mineral content in females(p<0.05), but not male, mice compared to age‐ and gender‐matched wildtype control mice at 12 months of age. Cortical bone loss identified by micro‐CT analysis of the femur included a significant reduction in total cross‐sectional area, cortical area, cortical thickness, periosteal thickness, and minimum moment of inertia(p<0.05). Trabecular bone loss identified in female PSen1 KI femurs was evidenced by a reduction in trabecular thickness(p<0.05). In contrast, male PSEN1KI femurs had significantly reduced bone volume fraction, tissue mineral density, and trabecular number compared to male wildtype mice.ConclusionFemale Psen1 L166P KI mice exhibit a loss in the trabecular and cortical structure in a sex‐dependent manner. These findings indicate that a Psen1 L166P mutation may alter bone morphology via direct crosstalk with the brain (possibly through Aβ deposition) or by endogenous PSEN1 in bone cells. Furthermore, recent studies have reported that Psen1 deletion results in skeletal abnormalities, consistent with PSEN1’s role in bone cells. These studies suggest a concurrence of amyloid pathology and changes in bone metabolism that may parallel the accelerated bone loss reported in human AD. They also indicate that the bone pathology in AD may be a biomarker to consider in the early detection and progression of AD patients.
APOE ε4 genotype, lifestyle profiles, and cognitive function among Chinese oldest old
Authors: Jin Xurui , He Wanying , Gong Enying , Yin Ruoyu , Ji John Sihan , Li Yaxi , Chen Huashuai , Zeng Yi , Yan Lijing 
Published: December 2020

AbstractBackground
APOE ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease. While its interaction with lifestyle profile on cognition has been controversial and a recent study indicated that healthy lifestyle profiles only showed its benefits among APOE ε4 non‐carriers among those elderly aged over 65 years old. Accordingly, we examined the association between the APOE genotype and cognitive impairment and its interaction with lifestyle profiles among Chinese oldest old (aged over 80 years old).Method
APOE ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease. While its interaction with lifestyle profile on cognition has been controversial and a recent study indicated that healthy lifestyle profiles only showed its benefits among APOE ε4 non‐carriers among those elderly aged over 65 years old. Accordingly, we examined the association between the APOE genotype and cognitive impairment and its interaction with lifestyle profiles among Chinese oldest old (aged over 80 years old).ResultAmong the 6,160 participants, 57.6% were women and 17.5% were APOE ε4 carriers, with a mean age of 90.1 (SD 7.2) years. The mean MMSE score was 23.3 (SD: 0.4) and 18.2% of the participants had cognitive impairment at baseline. Carrying APOE e4 allele was associated with 22% higher odds (95% CI: 1.02‐1.46) of cognitive impairment. Compared with those with unhealthy lifestyle score, participants with healthy lifestyle score were associated with a 38% (95% CI: 23% ‐ 50%) lower odds of cognitive impairment. No significant interaction between APOE genotype and lifestyle profiles was observed. The association between lifestyle profiles and cognitive function did not vary by APOE genotype.Conclusion
APOE genotype and lifestyle profiles were associated with cognitive function among Chinese oldest old, respectively and healthier lifestyle is associated with lower odds of cognitive impairment regardless of APOE genotype.
Anticholinergic burden among participants in Alzheimer’s clinical trials
Authors: Kennedy Richard E. , Fowler Mackenzie E. , Cutter Gary R. , Schneider Lon 
Published: December 2020

AbstractBackgroundMedications with anticholinergic properties are known to adversely affect cognition with acute administration, and have been associated with increased dementia incidence. Such drugs are taken by a substantial number of older adults despite guidelines recommending that their use be avoided in this population. The extent to which participants in AD clinical trials use medications with anticholinergic properties, and their effect on trial outcomes, is currently unknown.MethodsWe used a metadatabase of 18 ADCS studies and ADNI to examine total anticholinergic burden. We included 15 studies for a total of 4,002 subjects with AD. We calculated the total anticholinergic burden for each participant using the Anticholinergic Burden Scale.4 For the 10 studies with longitudinal data on the ADAS‐cog, we estimated the annual rate of decline using linear mixed effects models with adjustment for age and education, and compared rates of decline using random effects meta‐analysis.ResultsAcross the 15 studies, the mean total ACB score was 1.63 (SD 2.13). Approximately 25% of participants had a clinically relevant anticholinergic burden, defined as a total ACB score 3. Meta‐analysis showed the rate of decline for participants with total ACB 3 was 1.2 points/year greater than the rate for participants with total ACB < 3 (Figure).ConclusionsUse of medications with anticholinergic properties is common among participants in AD clinical trials. High levels of anticholinergic burden are associated with greater rates of cognitive decline, and may offset benefits of cholinesterase inhibitors or experimental interventions. Reducing unnecessary use of medications with anticholinergic properties among AD trial participants is needed, and trials should consider stratifying by anticholinergic burden to reduce potential confounding in analyses.
LDL cholesterol may have protective properties for brain health in older age: Do we need to re‐think current guidelines?
Authors: Kuszewski Julia C , Zaw Jay Jay Thaung , Wong Rachel HX , Howe Peter RC 
Published: December 2020

AbstractBackgroundElevated low‐density lipoprotein (LDL) cholesterol is a major contributor to cardiovascular diseases (CVD), which are associated with accelerated cognitive decline. However, recent studies suggest LDL cholesterol to be protective against cognitive decline in the very elderly (>85 years). We investigated associations between serum LDL cholesterol, cerebrovascular function and cognition in community‐dwelling adults aged 50‐80 years, testing for differences between mid‐life (50‐64 years) and older age (65‐80 years).MethodOur cross‐sectional analysis used baseline assessments from 236 older adults (78% female, age: 65±0.5 years, BMI: 28.2±0.3 kg/m2, LDL: 3.7±0.1 mmol/L) participating in two intervention trials investigating effects of vasoactive nutrients on cognition, cerebrovascular function and cardiometabolic biomarkers. None were taking statin medication. Assessments included a battery of 10 neuropsychological tests, transcranial Doppler ultrasound to measure cerebral blood flow velocity (BFV) and cerebrovascular resistance index (CVRi), clinic blood pressure and a fasted venous blood sample to measure serum cholesterol.ResultLDL cholesterol correlated with Framingham CVD risk in mid‐life (R=0.360, P<0.001), but not in older adults (R=‐0.124, P=0.174). In adults aged >65 years (n=122), higher LDL cholesterol correlated with higher mean BFV (R=0.255, P=0.009), lower CVRi (R=‐0.266, P=0.006) and higher overall cognitive performance (R=0.228, P=0.011). The latter two were inversely correlated (R=‐0.154, P=0.024, age adjusted).ConclusionLDL cholesterol appears to have a positive association with cerebrovascular and cognitive functions in advanced age; hence, pharmacologically reducing LDL cholesterol to <2mmol/L as currently recommended might not be beneficial for this age group. Further research is warranted to establish optimal LDL cholesterol levels in the elderly.