bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing structural neuroimaging biomarker changes in the canine model of Alzheimer’s disease
Authors: Noche Jessica A. , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin D. , McCarty Katie , Meacham Beverly , Smiley Jeffrey , Puskas Laszlo G. , Powell David K , Sordo Lorena , Bailey Stasia A. Bembenek , Phelan Michael J. , Norris Christopher M. , Head Elizabeth , Stark Craig E.L.
Published: December 2023

Background

The aging beagle is an exceptional model for longitudinal preclinical studies of Alzheimer’s disease due to their endogenous accumulation of beta‐amyloid plaques linked to cognitive impairment in aging, human‐like metabolisms, and ability to undergo serial neuroimaging. However, studies that use standardized analysis methods for evaluating longitudinal changes to neuroimaging biomarkers in this model are lacking. Here, neurostructural changes were characterized from longitudinal neuroimaging of middle‐aged beagles under chronic calcineurin inhibitor (CNI) treatment.

Method

T1‐weighted structural images were collected from 3T MRI at baseline and annually for 3 years from 43 middle‐aged beagles (6.47 +/‐ 1.1 years old) in an environmental enrichment paradigm under a chronic low dose of Tacrolimus (n = 15), Q134R (n = 14) or placebo (n = 14). Tissue segmentation and normalization to a group template for atlas‐based statistics were performed using Advanced Normalization Tools (ANTs) where atrophy rates were assessed from 27 bilateral cortical and subcortical regions of interest (ROIs). The auxiliary log‐Jacobian determinant images derived from non‐linear timepoint‐to‐template warps in ANTs were used to conduct whole‐brain, deformation‐based morphometry in AFNI.

Result

Among the brain structures examined with both ROI‐based and voxel‐based measures, the pregenual gyrus within the frontal lobe exhibited a distinct acceleration in atrophy. In contrast, the volume of the hippocampus was selectively preserved over the three years. Neither atrophy rate nor the preservation of hippocampal volume was modified by chronic CNI treatment.

Conclusion

Structural analysis from serial MRI in the beagle model of AD revealed that age‐related brain atrophy is accelerated within the frontal lobe, an area susceptible to early beta‐amyloid deposition in canines, and is unaltered by CNI treatment. Furthermore, the maintenance of hippocampal volume over time across all groups warrants further investigation into the effects of environmental enrichment on altering the trajectory of hippocampal structural decline. The novel application of robust longitudinal neuroimaging analysis methods in canines offers a novel framework for evaluating canine brain aging characterics and for monitoring treatment‐related structural alterations in preclinical intervention studies.
Polysomnography derived sleep metrics and cognition in the Sleep and Dementia Consortium (SDC): a study of 5 population‐based cohorts
Authors: Pase Matthew P. , Harrison Stephanie , Misialek Jeffrey , Kline Christopher , Cavuoto Marina G. , Baril Andree‐Ann , Yiallourou Stephanie , Bisson Alycia , Himali Dibya , Leng Yue , Yang Qiong , Seshadri Sudha , Beiser Alexa S. , Gottesman Rebecca F. , Redline Susan , Lopez Oscar L. , Lutsey Pamela L. , Yaffe Kristine , Stone Katie L , Purcell Shaun , Himali Jayandra J
Published: December 2023

Background

Good sleep is essential for health, yet the role of sleep in dementia risk is incompletely understood. The Sleep and Dementia Consortium (SDC) was established to study associations between polysomnography (PSG)‐derived sleep metrics and the risk of dementia and related cognitive and brain MRI endophenotypes. This study presents the associations of sleep architecture and obstructive sleep apnea (OSA) with cognitive function across participating cohorts.

Method

The SDC curates data from five population‐based cohorts with methodologically consistent, overnight, home‐based PSG and neuropsychological assessments over 5 years of follow‐up. Cohorts include the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study (MrOS), and Study of Osteoporotic Fractures (SOF). Global cognitive composite scores were derived from principal component analysis as the primary outcome. All sleep metrics were harmonized centrally and then distributed to the participating cohorts for cohort‐specific analysis using linear regression; study‐level estimates were pooled in random effects meta‐analyses. Results are adjusted for demographic variables, the time interval between the PSG and neuropsychological assessment (0‐5 years), body mass index, antidepressant use, and sedative medication use.

Result

The mean age of the cohorts ranged from 58 to 89 years (Figure 1) with a pooled sample of 5,946 participants. As shown in Figure 2, across cohorts, higher REM sleep percentage (pooled β±SE = 0.49±0.18 per % increase; p = 0.008) and Sleep Maintenance Efficiency (pooled β±SE = 0.08±0.03 per % increase; p = 0.01) were associated with better global cognition whereas OSA (Apnea‐hypopnea index [AHI] ≥ 5) was associated with worse global cognition (pooled β±SE = ‐0.06±0.02 vs. AHI<5; p = 0.03). Differences in N3 sleep were not associated with cognition.

Conclusion

Better sleep consolidation and higher REM sleep percentage were associated with better cognition whereas OSA was associated with worse cognition over 5‐years follow‐up. The role of interventions to improve sleep for maintaining cognitive function and potentially reduce dementia risk requires investigation.
Causal effects of Alzheimer’s Disease on snoring may be driven by Body Mass Index: A bidirectional Mendelian Randomization Study
Authors: Gao Yaqing , Andrews Shea J , Yaffe Kristine , Leng Yue
Published: December 2023

Background

Loud snoring is a symptom commonly associated with obesity and obstructive sleep apnea (OSA), which have both been suggested as risk factors for Alzheimer’s disease (AD). However, it remains unclear whether snoring might be causally linked to AD and if body mass index (BMI) may play a role in this relationship. Here we use bidirectional Mendelian randomization (MR) analysis to investigate the causal relationship between snoring and AD.

Method

We performed two sample MR using summary statistics for genome‐wide association studies of AD (n = 94,437; cases = 35,274) and snoring (n∼408,000; snorers∼152,000). Genetic instruments were obtained by selecting independent genome‐wide significant SNPs (p<5e‐8, r2 = 0.001, window = 10Mb) for each exposure and harmonizing their effects with each outcome. We used fixed‐effects inverse‐variance weighted (IVW) meta‐analysis as the primary method, and MR‐Egger, Weighted mode, Weighted median, radial‐MR, estimators as sensitivity analyses. LHC‐MR was used to investigate bidirectional effects accounting for potential heritable confounders. Heterogeneity was assessed using Cohcrans Q test, and pleiotropy using the MR‐Egger intercept. We used multivariable MR to estimate direct effects of AD on snoring independent from BMI.

Result

No causal effect of snoring (OR [95%CI] = 0.842 [0.391, 1.798], p = 0.653) on AD was observed. In the reverse direction, we did not observe significant effects of AD on snoring using IVW (OR [95%CI] = 0.991 [0.979, 1.002], p = 0.114) or LHC‐MR (OR [95%CI] = 1.022 [0.805, 1.298], p = 0.850). However, suggestive causal effects were observed in the MR‐Egger (OR [95%CI] = 0.974 [0.958, 0.990], p = 0.004), Weighted mode (OR [95%CI] = 0.981 [0.965, 0.997], p = 0.031), and Weighted Median (OR [95%CI] = 0.979 [0.963, 0.996], p = 0.013) analyses. There was no evidence of heterogeneity, but some evidence of pleiotropic effects (p = 0.009). Multivariable MR indicated that the effect of AD on snoring was likely driven by BMI.

Conclusion

Genetic liability to AD reduced snoring, possibly through lower BMI due to AD. Further analyses are needed to determine if OSA is causally related to AD and the role of BMI in this relationship.
Improvement of Cognitive Functions And Neurotrophic Effects through by Α5‐GABAA Receptor Positive Allosteric Modulation in Animal Models of Risk for Alzheimer’s Disease
Authors: Prevot Thomas D , Bernardo Ashley D , Marcotte Michael D , Wong Kayla D , Mian Md Yeunus , Sharmin Dishary , Mondal Prithu , Cook James M , Sibille Etienne
Published: December 2023

Background

Reduced GABA/somatostatin (SST) signaling is reported in psychiatric, stress‐related and neurodegenerative disorders. SST+ interneurons from cortical layers and the hippocampus inhibit the dendrites of excitatory neurons, largely through α5‐containing GABAA receptors (α5‐GABAAR). Recently, we showed that an α5‐positive allosteric modulator (α5‐PAM) alleviates working memory deficits and reverses neuronal atrophy in old mice. We then started to investigate the behavioral and neurotrophic effects of this α5‐PAM in animal models of aging, chronic stress, and β‐amyloid load, as risk factor for developing Alzheimer’s disease.

Method

Three studies are presented, with ∼12 mice/group, 50% female: 1) Young C57BL6 subjected to unpredictable chronic mild stress (UCMS) to induce cognitive deficits. 2) 22 month‐old C57BL6 developing an age‐related cognitive decline. 3) 5xFAD transgenic mice with progressive amyloid‐related cognitive decline. In all studies, efficacy of chronic administration of GL‐II‐73 (30mg/kg, p.o, for 4 weeks) at rescuing cognitive deficits across 3 domains was assessed. Working memory was assessed in an alternation task, spatial memory in the water maze, and cognitive flexibility in a set‐shifting assay. Brains were then stained using Golgi‐Cox technique (n = 4brain/group; 8cell/brain) for quantification of dendritic length and spine density in the prefrontal cortex and hippocampus (NeuroLucida).

Result

Chronic treatment in all models reversed cognitive deficits across domains (ps<0.01), with a strong effect on working memory. Chronic treatment also significantly reversed UCMS‐, age‐, or amyloid‐induced dendritic shrinkage and reduction of spine density at apical and basal dendrites (p<0.001 in PFC and CA1).

Conclusion

Together, results support that selective α5 targeting of GABAA receptors overcomes chronic stress‐, aging‐, or amyloid‐related cognitive deficits and detriments in neuronal morphology. This represents the first intervention targeting the GABAergic system to have a symptomatic and disease‐modifying therapeutic potential in a transdiagnostic manner. This could represent a major avenue for clinical development for patients suffering from cognitive deficits across brain disorders.
Proportion of Dementia Cases in the Oldest‐old Attributable to 8 Neuropathological Changes: The 90+ Study
Authors: Corrada María M. M. , Jiang Luohua , Sajjadi S. Ahmad , Montine Thomas J. , Bukhari Syed A. , Cholerton Brenna , Boyle Patricia A , Brookmeyer Ron , Kawas Claudia H.
Published: December 2023

Background

People aged 90 and older have the highest rates of dementia. At advanced ages, dementia is due to a variety of diseases but the relative contribution of each is unknown. We estimated the proportion of dementia cases attributable to 8 different neuropathological indices in a cohort of individuals aged 90 and older.

Methods

Participants (n = 425) are from The 90+ Autopsy Study, a community‐based longitudinal study of aging and cognition. Most participants (62.1%) were initially part of the Leisure World Cohort Study and the remaining were non‐cohort community volunteers (37.9%). The 8 neuropathologic features examined were Alzheimer’s disease neuropathologic change (ADNC), limbic predominant age‐related tdp‐43 encephalopathy (LATE‐NC), hippocampal sclerosis (HS), Lewy body disease (LBD), microvascular lesions (MVL), cerebral amyloid angiopathy (CAA), atherosclerosis, and arteriolosclerosis. We examined the association of the 8 neuropathologic features with all‐cause dementia using multivariable logistic regression adjusting for age, gender education, and cohort affiliation. We then estimated the proportion of dementia cases that could be attributed to each neuropathologic change.

Results

Participants were on average 97.6 years at time of death, most were women (68%), and about half (43%) had dementia at time of death (Table 1). ADNC, LBD, LATE‐NC, arteriolosclerosis and atherosclerosis were significantly associated with dementia, whereas HS, MVLs, and CAA trended toward a significant association with dementia (Table 2). For the individual neuropathologic features, ADNC (26%) and arteriolosclerosis (24%) had the highest and similar attributable fraction of dementia cases, followed by LATE‐NC (17%) and CAA (10%) (Figure). When combinations of neuropathologic features were considered, vascular pathologic changes had the highest attributable fraction of dementia cases (38%), non‐AD changes (LBD, LATE‐NC, HS) had an attributable fraction of 28%, and LATE‐NC and HS combined had an attributable fraction of 20% (Figure). Overall, 78% of dementia cases could be attributed to these 8 neuropathologic features.

Conclusions

Vascular pathologic changes, as a group, account for the largest fraction of dementia cases in this oldest‐old cohort. Furthermore, when considered together, non‐AD neuropathologic changes are as important contributors to dementia as ADNC. Therefore, interventions targeting a variety of diseases will be needed to significantly reduce the burden of dementia in the oldest‐old.
Screening of Mild Cognitive Impairment Subtypes Through the Training of 1D Convolutional Neural Network with QEEG Features
Authors: Ko Juhee , Choi Boeun , Park Ukeob , Baik Kyoungwon , Ye Byoung Seok , Kang Seung Wan
Published: December 2023

Background

The pre‐clinical stage of dementia, mild cognitive impairment (MCI) carries various pathological pathways and respective prognoses. The two foremost causes of MCI and dementia that have been identified through autopsy diagnoses are Amyloid plaques and Lewy body, commonly referred to as Alzheimer’s disease (AD) and Lewy body disease (LBD) respectively. Although correct identification of pathological pathways plays a crucial role in effective designing of treatment methods, MCI subtypes are underexploited in the current diagnostic paradigm due to multiple reasons, mainly cost‐effectiveness. Hence, we utilized quantitative electroencephalography (QEEG) that are cheap and convenient to record in the distinguishment of MCI subtypes.

Method

A total of 151 MCI patients’ EEG data were aggregated into 3 groups, pure AD (n = 29), pure LBD (n = 88), and mixed (n = 34). The mixed type was further subdivided into main AD (n = 31) and main LBD (n = 3) groups, in accordance with AD/LBD tendency exhibited by the patients. The clinical labelling was brought by the experienced experts of Yonsei Severance hospital, South Korea.

1D SE‐ResNet‐based classification model was established for quantitative investigation of AD and LBD propensity. The power spectrum density (PSD) in dB/Hz scale were computed from the EEG data and were used to train the model. Due to the small number of data, augmentation was applied to the training data. The final dataset was split into 8 to 1 to 1 ratio (Train n = 7092: 2274 pure AD + main AD; 3694 pure LBD + main LBD, Validation n = 14: 6 pure AD + main AD; 8 Pure LBD + main LBD, Test n = 15: 6 pure AD + main AD; 9 pure LBD + main LBD).

Result

The classification model showed validation results of 85.7% accuracy, 83.3% AD sensitivity and 87.5% LBD sensitivity. Test results were at 92.8% accuracy, 83.3% AD sensitivity and 88.9% LBD sensitivity.

Conclusion

QEEG‐based deep learning classifier developed in this study successfully distinguished the two main causes of cognitive degeneration in MCI patients. Our model can help identify subtype‐specific spectral trends, which could also make contributions in the establishment of effective treatment methods for MCI.
Application of Cognitive Enhancement Protocol Based on ICT Program to Improve Cognitive Level of Older Adults Residents in Small‐sized City Community: A Pilot Study
Authors: Yun Sohyeon , Lee Hamin , Kim Mi Kyeong , Kim Inhye , An Hyun Seo , Park Hae Yean
Published: December 2023

Background

A home‐based ICT program to elderly people aged 65 years or older to confirm the effect of the cognitive enhancement program and explore the possibility of remote rehabilitation.

Method

This study from August to October 2022, three subjects were selected and the intervention was conducted for about two months. This intervention was conducted using the Korean version of Mini‐Mental State Examination(MMSE‐K), the Korean version of Montreal Cognitive Assessment(MoCA‐K), the Computer Cognitive Senior Assessment System(CoSAS), and the two shorter form of the Center for Epidemiologic Studies Depression scale(CESD‐10‐D) to evaluated cognitive improvement before and after the program. The therapist remotely set the difficulty lever of cognitive training suitable fore the level of the subject through weekly feedback, and during the program. Interviews were conducted for additional opinions on the cognitive enhancement program.

Result

After the intervention, all subjects showed improved scores in most items of the Korean version of the Montreal Cognitive Assessment conducted before and after the intervention. In addition, among the items of CoTras, upper cognition, language ability, attention, visual perception, and memory were improved. In addition, subjective satisfaction with the cognitive improvement program was high.

Conclusion

Cognitive rehabilitation training using a home‐based ICT program not only prevented dementia but also made it habitual. Through this study, it was confirmed that remote rehabilitation for the elderly could be possible.
Deep learning based automatic detection algorithm of Frank’s sign and its application
Authors: Jo Sungman , Kim Ki Woong
Published: December 2023

Background

Frank’s sign (FS) is a diagonal crease in the ear lobe extending from the tragus across the lobule to the rear edge of the auricle. Many of previous research have studied that FS is associated with the risk of cardiovascular, cerebrovascular diseases, cognitive impairment and aging. However, existing studies have lack of work in the application of FS. Meanwhile, cutting edge deep learning segmentation techniques allow to build large‐scale trainable models that have the capacity to learn the optimal features with great speed and accuracy. This study is the first to analyze 3D Nifti FS dataset by applying a deep learning approach and developing the automatic detection algorithm of FS (ADAFS).

Method

We used 700 brain MRI dataset and manually segmented FS masks of 550 older adults with FS. 400 out of 550 datasets were used into the developing ADAFS. Rest of them and 150 older adults without FS served to validate the ADAFS. The preprocessed 3D datasets were fed into the candidate models including 3D U‐net, 3D Attention U‐net, 3D Nested U‐net, and 3D USE‐net in order to train ADAFS (figure 1). We adapted 5‐fold cross‐validation test which can estimate the general effectiveness of an algorithm on an independent dataset. Furthermore, we classified the FS‐detected mask in 4 cases; left lateral, right lateral, bi‐lateral and no FS.

Result

On development of ADAFS, Nested U‐net out of 4 different models showed the highest average dice similar coefficient (DSC; 0.714 ± 0.160) across test folds. Given validating the developed ADAFS, the multi‐label classification and segmentation results of receiver operating characteristic curve (ROC) analysis were below: accuracy = 0.907, average area under ROC curve = 0.940, and DSC = 0.736 ± 0.172.

Conclusion

ADAFS may support the faster decisions of FS presence, and considerably similar FS segmentation performance. This may serve a variety of FS shape descriptors and further study including an association of cognitive aspects and them.
Alpha Asymmetry as biomarker for Mild Cognitive Impairment
Authors: Shin Jaekang , Park Sanguk , Jeong Taegyun , Park Ukeob , Kim Daekeun , Youn Young Chul , Kang Do‐Young , Park Kyung Won , Kim Sangjin , Park Hyuntae , Lee Young‐Min , Seo Chang‐Sung , Kang Seung Wan
Published: December 2023

Background

Early screening of dementia at its pre‐clinical stage is crucial, seeing as how deteriorated cognitive functions can be recovered through appropriate medicinal practices. The pre‐clinical stage, which we refer to as mild cognitive impairment (MCI) is known to affect the alpha rhythm of the brain activity. Hence, our study aims to establish quantitative EEG (qEEG)‐based alpha asymmetry biomarker that aids the diagnoses of MCI.

Method

The qEEG dataset were composed of age‐ and sex‐ matched subjects (N = 634, 317 healthy control (HC), 317 MCI), acquired in accordance with the 10‐20 system and under resting state with their eyes being closed. Subjects were recruited by Chung‐Ang University (153 HC, 111 MCI), iMediSync(164 HC, 76 MCI), Dong‐a Medical Center(84 MCI) and Pusan Medical Center(46 MCI).

The features were classified into four types: the absolute and relative region alpha power (AAP/RAP) of six regions (Prefrontal, Frontal, Temporal, Central, Parietal, Occipital); alpha power asymmetry (APA) between regions that align in anterior‐posterior and lateral planes; occipital alpha peak frequency (OPF) that analyzes peak frequencies.

In order to highlight the alpha variability, EEG signals were bandpass filtered (6.5‐12Hz). Filtered signal at each channel was categorized into slow (6.5‐8Hz), middle (8‐10Hz) and fast alpha (10‐12Hz). The mean and standard deviation of their FFT were computed through moving time window. Henceforth, the feature set were used to train machine learning algorithms. Data were split into 8(training N = 507) to 2(test N = 127) ratio. 101 subjects were randomly selected and used as validation set. The algorithm that exhibited the best classification performance were determined through 5‐fold cross validation (CV) results.

Result

Support vector machine (SVM) showed the best 5‐fold CV results – 84.61% average accuracy, 74.02% sensitivity, 95.25% specificity, 94.15% precision and F1‐Score of 0.8273. The RAP decreased for all regions and OPF were slower in MCI group when compared to HC. APA patterns of the right intra‐hemisphere exhibited most significant differences.

Conclusion

This study illustrates the potential of APA as a biomarker for MCI. Current applications of APA are confined to emotional‐related studies, such as depressive disorder. The reported cases of MCI‐associated depression also uphold the validity of APA as a biomarker for MCI.
Comparing informant‐based measures of cognitive functioning between the US and Mexico
Authors: Cantu Phillip A , Zhang Yuan S , Saenz Joseph
Published: December 2023

Background

Informant reports are important for understanding cognitive impairment and dementia in older populations. Recently, several population‐based aging studies have included harmonized direct and informant assessments to assess the prevalence of dementia globally as part of the international Harmonized Cognitive Assessment Protocol (HCAP). However, the social and cultural contexts of nations, sociodemographic characteristics of informants, and the participant‐informant relationship may affect the accuracy of informant ratings of cognitive decline and functioning. This study examines the extent to which informant characteristics and the participant‐informant relationships are associated with informant‐reported cognitive function in the United States and Mexico.

Methods

Data are from the 2016 US Health and Retirement Study (HRS) HCAP (N = 2,918) and the Ancillary Study of Cognitive Aging in Mexico (Mex‐Cog) (N = 1,750). Informant‐reported cognitive function was measured by the informant Community Screening Instrument for Dementia (CSI‐D). Participants’ cognitive function was measured using the HCAP. We compared the characteristics of informants, informant ratings, and directly‐assessed cognitive functioning in both nations, and used regression to assess the association of informant characteristics and the participant‐informant relationship with the informant CSI‐D score.

Results

We find older Americans have worse informant‐reported cognitive functioning but higher directly‐assessed cognitive functioning than Mexicans. Nearly 80% of informants lived with the subject in Mexico, compared to less than half in the US. In both countries, older informants, children and other family members (compared to spouse) report less cognitive impairment. In Mexico, female informants reported more impairment. In the US, coresident informants reported more impairment.

Conclusion

This research shows how social environments influence informant reporting. Understanding heterogeneity in informants is vital when examining informant measures of cognitive function in cross‐countries studies.
Serum FOXO3A: A potent marker for early diagnosis of Alzheimer’s disease
Authors: Pradhan Rashmita
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. In any ageing society it’s a major health concern and a public health challenge. Diagnosis of Alzheimer’s disease (AD) is often difficult because of distinct and subjective clinical features, especially in the early stage. FOXO3a protein present in the cognitive centre of brain in inferior temporal region and parahippocampus. FOXO3a can be a potential novel target against AD.

Method

AD, Mild Cognitive impairment (MCI) and Geriatric Control (GC) were recruited after diagnosis by clinical assessment, MRI, Tau PET and FDG PET. We have quantified serum FOXO3a by surface plasmon resonance (SPR) and compare with Tau PET between of AD, MCI patients and GC.

Result

Serum FOXO3A was significantly lower in AD (1.42 ± 0.09 ng/μl) compare to MCI (1.61 ± 0.14 ng/μl) and GC (1.89 ± 0.07 ng/μl). ROC curve for FOXO3A protein level was plotted and showed a reasonably good sensitivity and specificity at the cut‐off value for detecting cognitively impaired patients (AD and MCI) in compared to control older subjects. For Tau PET in inferior temporal region, the AUC for predicting AD from GC was 0.72 and AD from MCI was 0.71.

Conclusion

Serum FOXO3A could significantly differentiate AD vs MCI, MCI vs GC and AD vs GC. It may serve as novel blood marker for early detection for AD and target for therapeutic intervention.
Childhood and life‐course socioeconomic position and cognitive function in adult population of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Filigrana Paola , Moon Jee‐Young , Gallo Linda C , Fernandez‐Rhodes Lindsay E , Perreira Krista M , Daviglus Martha L , Thyagarajan Bharat , Garcia‐Bedoya Olga L , Cai Jianwen , Lipton Richard B. , Kaplan Robert C. , González Hector M , Isasi Carmen R
Published: December 2023

Background

The Hispanic/Latino population experiences extensive socioeconomic adversity across the lifespan and is at greater risk of cognitive decline. Yet little is known about the role of life‐course socioeconomic position (SEP) and cognitive function in this population. We assessed the association between childhood SEP and cognitive function in Hispanic/Latino adults, whether this association is mediated by midlife SEP, and whether socioeconomic mobility is associated with cognitive function.

Method

We used baseline data (2008‐2011) from 9556 adults aged 45‐74 years of the Hispanic Community Health Study/Study of Latino (HCHS/SOL), a multi‐center cohort study conducted in four major U.S cities. We determined childhood SEP using parental educational attainment. Midlife SEP was determined through an index combining participants’ education and household income. We classified participants into socioeconomic mobility categories from childhood to adulthood (e.g., persisting low, upward mobility). Cognitive function was ascertained using neurocognitive tests, including the Six‐Item Screener; Brief‐Spanish English Verbal Learning Test Sum and Recall, Controlled Oral Word Association (or Word Frequency), and the Digit Symbol Substitution Test. Using confirmatory factor analysis and these tests we created a global cognition score. We also standardized z‐score of these neurocognitive measures. Survey linear regression models were performed adjusting for age, sex, Hispanic background, U.S born, smoking, depression, and cardiovascular factors. We also conducted mediation analysis to decompose the direct effect of childhood SEP on cognition and the indirect effect through midlife SEP.

Result

Childhood SEP showed a graded association with cognitive function in adulthood with a dose‐response relationship across levels of parental education (β and [95% Confidence Interval (CI)]): Elementary/middle school vs. No schooling 0.34 [0.25‐0.43]; High school (HS) vs. No schooling: 0.53 [0.42‐0.64]; and >HS vs. No schooling: 0.68 [0.57‐0.79]). High midlife SEP was also associated with greater cognitive function relative to low midlife SEP. 37% (95% CI 32%‐44%) of the association between childhood SEP and cognition was mediated through midlife SEP. Holding a high SEP over the life‐course was associated with greater cognitive performance (β: 0.90, 95% CI: 0.79‐1.00) as compared with a persisting low SEP.

Conclusion

This study provides evidence that childhood and life‐course SEP influence cognitive performance in adulthood
Association between dietary diversity and cognitive impairment in community‐dwelling older adults
Authors: Kiuchi Yuto , Tsutsumimoto Kota , Doi Takehiko , Kurita Satoshi , Nishimoto Kazuhei , Makizako Hyuma , Shimada Hiroyuki
Published: December 2023

Background

Mild cognitive impairment (MCI) is an intermediate state between normal cognitive aging and dementia, and it is a target population for interventions in dementia prevention. Dietary diversity is associated with the risk of dementia. However, the association between dietary diversity and MCI, remains unclear. The present study aimed to examine whether dietary diversity is associated with cognitive impairment, including MCI, in community‐dwelling older Japanese adults.

Method

This cross‐sectional study was conducted using data from the National Center for Geriatrics and Gerontology Study of Geriatric Syndromes. MCI and global cognitive impairment (GCI) were assessed using the Mini‐Mental State Examination and National Center for Geriatrics and Gerontology‐Functional Assessment Tool (NCGG‐FAT), which are multicomponent neurocognitive tests that include memory, attention, executive function, and processing speed. Participants with one or more cognitive decline were defined as having MCI. Dietary diversity was assessed using the diet variety score (DVS). DVS assessed the one‐week consumption frequency of ten food groups and either 0 or 1 point was allocated to each category based on the following responses: (1) “eat almost every day” (1 point), (2) “not eaten almost daily” (0 points). Older adults with a DVS of 3 or more points were defined as having high dietary diversity.

Result

Data included 8,987 older adults (mean age: 73.9 ± 5.5 years; men: 44.3%). The overall prevalence of MCI and GCI followed; 17.1% (n = 1,538) and 8.4% (n = 753), respectively. The proportion of patients with a high dietary diversity was 69.9% (n = 6,286). Multinomial logistic regression analysis revealed high dietary diversity was associated with MCI (OR 0.83, 95% CI 0.73‐0.94) and GCI (OR 0.77, 95% CI 0.65‐0.92) after adjusting for covariates.

Conclusion

This study showed that high dietary diversity was associated with a lower proportion of MCI and GCI among older adults. Ingesting a wide variety of foods contributes to the enhancement of cognitive function among older adults.
Association between physical, cognitive and social activity and incident sarcopenia among older adults with cognitive decline: A 4‐year longitudinal study
Authors: Nishimoto Kazuhei , Tsutsumimoto Kota , Doi Takehiko , Kurita Satoshi , Kiuchi Yuto , Shimada Hiroyuki
Published: December 2023

Background

Cognitive decline and sarcopenia are associated with each other among older adults. However, it is unclear that the prospective association of older adults with cognitive decline with incident sarcopenia. Therefore, the purpose of this study was to examine longitudinal association between physical, cognitive and social activities and incident sarcopenia among older adults with cognitive decline.

Method

Among older adults with cognitive decline (MMSE score range: 18 to 27) aged 65 years or older who participated in the National Center for Geriatrics and Gerontology, 1440 participants (mean age: 71.6 ± 4.9, man: 53.3%) were included after excluding those who meet the exclusion criteria. The participants were asked about the status of implementation concerning physical (PA), cognitive (CA) and social activity (SA), respectively. The participants were categorized to high/low‐PA, high/low‐CA and high/low‐SA group. Sarcopenia was defined by the European Working Group on Sarcopenia in Older People2, and participants were classified as robust or sarcopenia.

Result

During 4 years, 361 (25.1%) participants developed sarcopenia. After adjusting for covariates (age, sex, education level, medication, current smoking and alcohol), the logistic regression analysis model showed that low‐PA group (OR 1.77, 95%CI 1.23‐2.56) and low‐SA group (OR 1.40, 95%CI 1.05‐1.85) had a significantly higher risk of incident sarcopenia compared with each high group. Low‐CA group had no significant association with incident sarcopenia.

Conclusion

In older adults with cognitive decline, low physical and social activity in daily life influences the future incidence of sarcopenia. On the other hand, cognitive activity might not be effective in preventing incident sarcopenia, especially among older adults with cognitive decline.
Evaluation of BTXBrain‐Tau, an AI‐powered automated quantification software for Flortaucipir PET images
Authors: Kang Seung Kwan , Kim Daewoon , Shin Seong A , Kim Yu Kyeong , Choi Hongyoon , Lee Jae Sung
Published: December 2023

Background

Positron emission tomography (PET) has been used to visualize the distribution of brain biomarkers associated with AD. Flortaucipir (18F‐AV‐1451) is a tau‐specific PET tracer that has been used to detect tau pathology in AD. However, the accurate quantification of Flortaucipir PET images requires an accurate spatial normalization of the image data. We evaluated BTXBrain‐Tau, an AI‐based automated quantification software that does not require an MRI, on the Flortaucipir data. In comparison, performance on automatic quantification was demonstrated against conventional MRI‐based spatial normalization results.

Method

In the previous study, BTXBrain‐Tau was pretrained with approximately 1000 amyloid PET images. To fine‐tune the network, 180 Flortaucipir images were obtained from Seoul National University Hospital. Trained network was evaluated using 146 Flortaucipir images from the ADNI. Each image had been quantified using FreeSurfer at UC Berkeley, and these quantifications served as the “ground truth.” Spatial normalization was also performed using SPM12 with 3D T1 MRI to demonstrate the proposed method’s superiority. The results were compared using four Braak stage‐based composite regions of interest. Statistical analysis of the results was conducted using linear regression and intraclass correlation coefficients.

Result

The linear regression slopes for BTXBrain‐Tau were 0.95, 0.97, 1.03, and 0.95 for four regions of interest (ROIs), outperforming the results of SPM12 (0.81, 0.80, 0.81, 0.79). The R‐squared values also showed superior performance for BTXBrain‐Tau (0.94, 0.98, 0.95 and 0.98) compared to SPM12 (0.88, 0.97, 0.91 and 0.96). ICCs between the ground truth and SPM12 normalization results were 0.93, 0.96, 0.94 and 0.96 for SPM12, however, these values were improved in BTXBrain‐Tau processing (0.97, 0.99, 0.97 and 0.99).

Conclusion

The results demonstrated that BTXBrain‐Tau was able to generate spatially normalized images without the use of 3D MRI input. Statistical analysis revealed a high degree of correspondence between the FreeSurfer‐based quantification and the proposed method. Additionally, the study demonstrated the generalizability of the network by assessing its performance on different types of test data, (training on Asia, testing on Caucasian). These results suggest that BTXBrain‐Tau is a promising tool for the accurate quantification of Flortaucipir PET images, which could lead to early detection and precise staging of Alzheimer’s disease.
AlzPED: Raising the Standards for Preclinical Efficacy Testing of Candidate Therapeutics in Alzheimer’s Disease
Authors: Chakroborty Shreaya , Viswanathan Jaya , Gallofre Maria Fe Lanfranco , Martin Zane , Petanceska Suzana S , Refolo Lorenzo M
Published: December 2023

Background

Positive findings of therapeutics and interventions from studies conducted in Alzheimer’s disease (AD) animal models are often not translated to effective treatments. Assessments of these studies highlight the lack of methodological rigor and inadequate reporting practices as contributive to the preclinical to clinical translation gap in AD therapy development. AlzPED/Alzheimer’s Disease Preclinical Efficacy Database, developed by the NIA, is a searchable and publicly available knowledgebase that prioritizes and promotes the use of rigorous methodology in the planning of animal studies through its Rigor Report Card. The Rigor Report Card, through its checklist of experimental design elements, creates awareness of reporting recommendations and standards early in the research process and provides a practical and easy approach to planning a therapeutic study in animals.

Method

Using key word‐driven literature searches published studies are acquired and curated by two experts for bibliographic details, funding source, study goals and principal findings, data on relevant translational criteria like therapy type, therapeutic agent, therapeutic target, animal models, and AD‐related outcome measures, prior to publication in the database. Rigor in study design and methodology is evaluated with the Rigor Report Card.

Result

AlzPED hosts curated summaries from nearly 1300 published preclinical therapeutic studies in AD animal models, and data related to 251 therapeutic targets, 1123 therapeutic agents, 210 animal models, more than 2000 AD‐related outcome measures, and thousands of principal findings. Evaluation of Rigor Report Cards from each study demonstrates significant under‐reporting of critical elements of methodology such as power/sample size calculation, blinding, randomization, balancing for sex, animal genetic background, and inclusion/exclusion criteria, these being reported by fewer than 35% of the nearly 1300 curated studies. These serious deficiencies in reporting critical elements of methodology diminish the scientific rigor, reproducibility, and translational value of the preclinical studies.

Conclusion

Rigorous experimental design and transparent reporting are clearly essential if animal studies are to inform future research, science policies, and successful clinical trials. Adopting a standardized set of best practices like those proposed by AlzPED can improve the predictive power of preclinical studies in AD animal models and promote the effective translation of preclinical drug testing data to the clinic.
Herpes Simplex Virus Infection and in vivo Alzheimer’s Disease Pathologies
Authors: Chang Yoon Young , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Kim Min Jung , Jung Joon Hyung , Kong Nayeong , Sohn Bo Kyung , Lee Jun‐Young , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2023

Background

Interest in the role of Herpes Simplex Virus (HSV) infection in the pathogenesis of Alzheimer’s disease (AD) has increased in recent years. However, previous studies yielded inconsistent findings and no studies have yet investigated the relationship between HSV infection and in vivo AD pathologies such as beta‐amyloid (Aβ) and tau deposition in brain. We examined whether the level of serum anti‐HSV immunoglobulin G (IgG) antibodies (HSV‐IgG), an index of past infection of HSV, is associated with in vivo Aβ and tau deposition in nondemented individuals. We also investigated the modulating effect of HSV‐IgG titer on the relationship between Aβ and tau deposition.

Method

A total of 426 nondemented older individuals (55‐90 years old) were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. All participants underwent comprehensive clinical assessment, [11C]‐Pittsburgh Compound B positron emission tomography (PET), and blood sampling for measurement of serum HSV antibodies. A subset of participants (N = 129) underwent [18F] AV‐1451 PET. Individuals whose HSV‐IgG titer was lower than 25 percentile of the whole group was classified as the HSVlow group, while those with HSV‐IgG titer higher than 25 percentile were classified as the HSVhigh group.

Result

There was no significant difference in age, sex, clinical diagnosis (cognitive normal vs. mild cognitive impairment), and apolipoprotein E e4 positivity (APOE4) between the HSVlow (N = 106) and HSVhigh (N = 320) groups. In terms of AD biomarkers, neither global Aβ nor tau deposition was different between the HSVhigh and HSVlow groups, even after controlling the effect of age, sex, and APOE4. However, there was a significant HSV group x Aβ deposition interaction effect on tau deposition (p = 0.037), suggesting the level of HSV‐IgG modulates the relationship between Aβ and tau deposition. Subsequent subgroup analyses showed a significant positive association between Aβ and tau deposition only in the HSVhigh group (p < 0.001), but not in the HSVlow group.

Conclusion

Our finding suggests that past HSV infection may aggravate the influence of Aβ on tau deposition. In regard of AD prevention, the result also supports that more attention needed to be paid to controlling HSV infection.
Non‐physical Leisure Activity patterns and Cognitive Function in 4,121 Hong Kong older adults with no major neurocognitive disorders
Authors: Lam Linda Chiu Wa C.W. , Lee Allen TC , Chan Wai Chi , Wong Samuel YS , Ma Suk Ling , Lin Cuichan CW , Fung Ada WT , Yip Benjamin HK , Cheng Calvin Pak Wing , Lai Frank HY , Cheng Sheung Tak
Published: December 2023

Background

Emerging evidence supports the role of lifestyle in maintenance of cognitive function. Physical exercise, diet and sleep are found to play important roles in cognitive health at later life. In this recently completed epidemiological study in Hong Kong, we explored if non‐physical leisure activity participation also contributes to cognitive function in older adults.

Method

The Hong Kong Mental Morbidity Survey for Older People (HKMMSOP) is a commissioned study supported by the Health and Medical Research Fund of the Hong Kong SAR. From 2019 till 2022, we have successfully assessed 4,369 community dwelling older adults (60 years or over). 4,121 participants satisfied clinical Dementia Rating (CDR) of either 0 or 0.5. Assessments included Montreal cognitive assessment (MoCA), cumulative illness rating for physical disease burden, Clinical Interview Schedule – Revised (CIS‐R) for depressive and anxiety symptoms, types of physical exercise (aerobic, mind body, resistance muscle training, stretch), types of non‐physical activities (cognitive, social, spiritual, volunteering, passive solitary) activities were counted as positive if regular practice frequency were once weekly or more.

Result

Of the 4,121 participants, 3118 were cognitively healthy (CDR = 0), 1003 had mild neurocognitive disorder with CDR 0.5. The mean age and education (years) was 68.9(SD 6.9)(range 60‐98) and 9(SD 4.5) respectively. 44% were men. The mean MoCA score was 24.4 (SD 4.0). Regression analysis with MoCA score as the dependent variable showed that cognitive, volunteer and spiritual activities were significant factors (after controlling for gender, age, education, physical health burden, psychological symptoms (CIS‐R), and total number of physical exercise)(R2 = 295). In the CDR 0 group, cognitive and spiritual activities are significant factors (R2 = 0.184). In the CDR 0.5 group, cognitive and volunteer activities are significant (R2 = 0.196).

Conclusion

The HKMMSOP provides empirical evidence on the association between cognitive function and apparently pro‐mental wellbeing leisure activities. The observation that the introspective spiritual activities being significant factor in healthy, and external volunteering activities being significant in mild cognitively impaired group should invite further replication and exploration on the associated mechanisms.
Memory interference in APPswe/PS1dE9 mice: Role of astrocytic β‐adrenoreceptors
Authors: Choudhury Rupsa Roy , Kushwaha Srishti , Karunakaran Smitha
Published: December 2023

Background

Previous studies have reported that long‐term β‐adrenoceptor (β‐AR) agonist, isoproterenol hydrochloride (IPE), treatment brings about beneficial effects in an induced model of Alzheimer’s disease (AD) by neutralizing microglial inflammatory morphology against soluble amyloid β oligomers (PMID: 30093491). However, we do not have a clear understanding of how such treatment impacts astrocyte morphology, and whether that afford beneficial effects. Introducing a proactive memory interference step to the classical novel object recognition (NOR) paradigm impairs long‐term memory formation in 2‐month‐old familial model of AD ‐ APPswe/PS1dE9 (APP/PS1) mice. Long‐term IPE treatment rescued long‐term memory. In this study we attempt to understand the impact of long‐term IPE treatment on astrocyte morphology, and how they bring about the reversal in cognitive deficits.

Method

(1) Mice were taken through a proactive interference step in which they were exposed to objects of varied shape, size and colour before taking them through NOR paradigm. (2) Mice were treated with β‐AR agonist IPE at P26 (0.05g/litre) in drinking water for 21 days till P47. (3) They were sacrificed at 2‐months of age by transcardial perfusion and 100µm coronal sections of hippocampus were stained with astrocytic markers GFAP and S100β by immunohistochemistry. The number and morphology of astrocytes were analysed using ImageJ, SMorph (PMID: 34137444) and Imaris software.

Result

Our observations suggest that NOR memory is intact in 2‐month‐old APP/PS1. However, introducing an object‐based short‐term interference before NOR leads to recognition memory deficits in APP/PS1 but not in wild‐type mice. Treatment with IPE restored long‐term memory of APP/PS1 mice to normal levels, thereby protecting them from the effects of interference during the NOR task. Our preliminary findings indicate that IPE impacts the morphology of astrocytes and thus contribute to the reversal of recognition deficits in APP/PS1 at 2 months of age.

Conclusion

β‐AR activation can bring about morphological changes in astrocytes that in turn can modulate memory representations.