bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND‐China): an Update 2018‐2021
Authors: Wang Yongxiang , Tang Shi , Hou Tingting , Cong Lin , Du Yifeng , Qiu Chengxuan
Published: December 2022

Background

Around one‐third of people with dementia worldwide might be attributable to seven modifiable risk factors, implying that interventions to control these risk factors may delay the onset of dementia. Therefore, we initiated the multimodal interventions to delay dementia and disability in rural China (MIND‐China) in 2018 and updated the main progresses of the project in 2018‐2021.

Methods

MIND‐China is designed as a community‐based 2‐year cluster‐randomized, controlled, multimodal intervention study, which targets people who are aged 60‐79 years and living in the rural communities of Yanlou Town, western Shandong Province, China. Following the baseline examination in 2018, 52 villages in Yanlou Town are randomly (cluster‐randomization) divided into three groups: control group (regular primary health care service), vascular intervention group, and multimodal intervention group. The vascular intervention includes healthy lifestyle guidelines and the national guidelines‐based medical treatment of major cardiometabolic risk factors. The multimodal intervention group receives, in addition to the interventions planned for vascular intervention, group physical exercise, personalized leisure activities, and cognitive training.

Results

In March‐September 2018, 5,765 participants underwent the core module assessments via face‐to‐face interviews, clinical examinations, neuropsychological testings, and laboratory tests (74.9% of all eligible residents). The mean age was 70.9 years (SD 5.9), 57.2% were women, 40.6% were illiterate, and 88.3% were farmers. Specific modules of examination were performed for subsamples (e.g., brain MRI scans, genetic and blood biomarkers, physical function, sleep quality, audiometric testing, and OCT examination). In May‐September 2019, the pilot study was completed to test the feasibility of the intervention programs and the implementation procedure in 7 villages (2 villages in control group, 3 villages in vascular intervention group, and 2 villages in multimodal intervention group). Recruitment of participants for interventions started in October 2019. In July‐November 2021, we conducted the 1‐year follow‐up assessments of participants in the interventions.

Conclusion

By the end of 2021, MIND‐China had completed baseline screening assessment, recruitment of intervention participants, and the first follow‐up assessments following the initiation of interventions. MIND‐China demonstrates the feasibility of implementing the multimodal interventions in rural communities. COVID‐19 has minimal impact so far on the project.
Genetic risk for attention‐deficit/hyperactivity disorder is associated with amyloid‐dependent cognitive decline in older adults
Authors: Leffa Douglas Teixeira , Ferrari‐Souza João Pedro , Bellaver Bruna , Ferreira Pamela C.L. , Tissot Cécile , Brum Wagner S. , Caye Arthur , Lord Jodie , Proitsi Petroula , Tudorascu Dana L , Lopez Oscar L. , Villemagne Victor L , Cohen Ann D , Klunk William E , Rosa‐Neto Pedro , Zimmer Eduardo R. , Karikari Thomas K , Rohde Luis Augusto , Pascoal Tharick A
Published: December 2022

Background

Recent epidemiological studies using population‐based registers showed that patients with Attention‐Deficit/Hyperactivity Disorder (ADHD) are more likely to be diagnosed with mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting a higher risk for cognitive impairment in older age. Here, we aimed to assess whether genetic liability for ADHD, as measured by a validated polygenic risk score (ADHD‐PRS), is associated with cognitive decline in cognitively unimpaired (CU) subjects and whether these effects vary according to baseline amyloid‐β (Aβ) burden.

Method

We studied 212 CU participants (116 women [54.7%], mean [SD] age of 73.1 [5.9]) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Subjects had available baseline Aβ burden (measured by [18F]Florbetapir Aβ‐PET) and genetic information, as well as a minimum of 2 cognitive assessments (Preclinical Alzheimer Cognitive Composite [PACC] and MMSE) in a 6‐year period. Aβ positivity was defined using a previously published cutoff of global [18F]Florbetapir PET SUVR > 1.11. We calculated ADHD‐PRS using data from the latest genome‐wide association study on ADHD, with a p‐value threshold of 1. Statistical analyses were performed using linear mixed‐effects models adjusted for age, sex, APOE ε4 status, and the first seven principal components to adjust for population stratification.

Result

ADHD‐PRS was normally distributed and was not associated with age, sex, or APOE ε4 status (Figure 1). We observed a significant ADHD‐PRS by time interaction (β=‐.03, 95% CI ‐.05 to ‐.01, p‐value=.001 for PACC, β=‐.04, 95% CI ‐.07 to ‐.009, p‐value=.01 for MMSE) on cognitive performance, indicating that higher ADHD‐PRS is associated with decreased cognitive function over time (Figure 2). Additionally, we observed a significant interaction between ADHD‐PRS, time, and baseline Aβ burden (β=‐.05, 95% CI ‐.10 to ‐.008, p‐value=.02 for PACC, β=‐.08, 95% CI ‐.15 to ‐.01, p‐value=.02 for MMSE), suggesting that higher ADHD‐PRS is associated with longitudinal cognitive decline only in Aβ‐positive individuals (Figure 3).

Conclusion

Our findings indicate that higher genetic liability for ADHD is associated with cognitive decline in Aβ‐positive older adults without cognitive impairment. These findings support the hypothesis that higher rates of MCI and AD in patients with ADHD may result from decreased resilience to Aβ pathology.
Influence of Sex Hormones in a Mouse Model of Multi Etiology Dementia
Authors: Abi‐Ghanem Charly , Kelly Richard D , Salinero Abigail E , Kyaw Nyi‐Rein , Wang Matthew , Riccio David , Gannon Olivia J , Mansour Febronia , Kordit David , Sura Avi , Zuloaga Kristen L
Published: December 2022

Background

Up to 80% of Alzheimer’s Disease (AD) patients suffer from concurrent vascular contributions to cognitive impairment and dementia (VCID) resulting in multi‐etiology dementia. VCID (the 2nd leading cause of dementia) is more common in men throughout most of the lifespan. while the majority (approximately 2/3) of Alzheimer’s Disease (AD) patients are women. Ageing is a main dementia risk factor which may act through the depletion of sex hormones. Both testosterone, in men, and estrogen, in women, have been shown to be neuroprotective. In this study we examine the effect of gonadal hormones on cognitive changes in a mouse model of multi etiology dementia using the AppNL‐F/NL‐F knock‐in Alzheimer’s disease mouse model that does not overexpress amyloid precursor protein.

Methods

5‐6 months old App
NL‐F/NL‐F mice were subjected to gonadectomy or sham surgery and left to recover for 3 weeks to clear any endogenous gonadal hormones. Multi‐etiology dementia was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion). Control animals (App
NL‐F/NL‐F without hypoperfusion; AD only model) received a sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and then brains and serum were collected.

Results

Cognitive impairment differences between groups were investigated using several behavioral tests: anxiety‐like behavior and activity levels using an open field testing, episodic‐like memory using a novel object recognition test, spatial learning and memory via Barnes maze testing and activities of daily living using a nest building test. Our next step is to evaluate the underlying pathology in the brain that could mediate cognitive deficits (i.e. amyloid pathology, white matter damage and neuroinflammation).

Conclusions

We hope that this work will highlight the importance of modeling endocrine aging in animal models of dementia and will contribute to further understanding of sex differences and sex specific risk factors for dementia.
An amyloid‐cognition composite score for estimating time‐consistent biomarker trajectories across the Alzheimer’s continuum
Authors: Raket Lars Lau , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Hansson Oskar
Published: December 2022

Background

While the temporal dynamics of biomarkers in Alzheimer’s disease (AD) have been studied in much detail, the lack of established methods for accurately staging pre‐dementia individuals in a time‐consistent manner has resulted in uncertain trajectories and lack of accurate estimates on the temporal relations between biomarkers and clinical milestones.

Methods

A novel latent‐time disease progression model was developed to estimate a multivariate time‐consistent trajectory describing the typical timeline of clinical scales (CDR‐SB, ADAS‐cog, MMSE) and amyloid PET along the AD continuum based on data from amyloid‐negative (A‐) cognitively unimpaired (CU) and the full cognitive spectrum of A+. For each subject, the model predicted amyloid‐cognition (AC) scores that represented the progression along the estimated timeline. Correlation to unseen variables was used to validate the AC score construct. AC scores were then used as a natural timescale for comparing a range of biomarker trajectories.

Results

Using 1424 individuals (6236 visits, 4581 follow‐up years) from the Alzheimer’s Disease Neuroimaging Initiative, we estimated a timeline of Alzheimer’s disease that spanned almost 20 years from the earliest stages of CU amyloid PET positivity (AC score 0) to severe dementia (Figure 1).

The predicted subject‐level AC scores had the best cross‐domain correlation among all compared staging methods (Table 1).

CSF biomarkers (Aβ1‐42/p‐tau181) showed the earliest changes, followed by amyloid PET, plasma p‐tau181 and finally tau PET (Figure 2). In terms of abnormality relative to A‐ CU, CSF Aβ1‐42 reached a population‐level mean value above the A‐ CU 95%‐percentile 1.5 years before amyloid PET. Tau PET reached this level 8 years after amyloid PET (Figure 3). In early pre‐clinical stages, CSF Aβ1‐42 was the biomarker that was most sensitive to change. In the later pre‐clinical and early symptomatic stages amyloid PET was most sensitive followed by tau PET in prodromal stage, and measures of cognition and function in the dementia stage (Figure 4).

Conclusion

This analysis supports the AC score as a data‐driven approach for studying biomarker trajectories across the Alzheimer’s continuum. The analysis highlighted the value in using different biomarkers to detect subject‐level changes across disease stages. Replication analyses in the BioFINDER study are ongoing.
Plasma levels of exosome‐bound Aβs accurately identify Alzheimer’s disease patients
Authors: Park Min Cheol , Kim Hye‐Ri , Kang JiYoon , Kim SangYun , Heo Youhee
Published: December 2022

Background

Blood‐based diagnosis of Alzheimer's disease may be the most efficient, non‐invasive, and cost‐saving method. However, in contrast to CSF, the performance of plasma Aβ42/40 ratio is still arguable in AD diagnosis. Recently, exosome‐based biomarkers have been found that is more reliable biomarker especially in blood‐based AD diagnosis. Here, we assessed the performance of plasma levels of exosome‐bound Aβs.

Method

We quantified plasma levels of exosome‐bound Aβs with a high‐sensitive ABSOL HS system, which is based on PIFA (Photooxidation‐Induced Fluorescence Amplification) technique to detect very small amount (sub pg/mL) of biomarkers (FIG.1). The ABSOL HS system fully‐automated the entire ELISA steps and PIFA measurement using a disposable strip‐well cartridge and tip within 30 minutes. To assess the feasibility of plasma levels of exosome‐bound Aβs, 61 Alzheimer’s disease patients and 60 normal controls were enrolled in this study.

Result

AD group had lower level (3.447 ± 2.114 pg/mL) of exosome‐bound Aβs than NC group (10.153 ± 6.616 pg/mL). The plasma levels of exosome‐bound Aβs identified Alzheimer’s disease with an area under the ROC curve (AUC) of 0.9124 at a cutoff of 5.564 pg/mL, which was equivalent to 81.97% of sensitivity and 81.67% of selectivity (FIG 2, FIG 3).

Conclusion

The plasma levels of exosome‐bound Aβs showed similar tendency with plasma Aβ42/40 ratio, but the diagnosis accuracy is higher with AUC of 0.9124 than the plasma Aβ42/40 ratio (AUC about 0.8). In this study, the plasma levels of exosome‐bound Aβs accurately identified Alzheimer’s disease patients, which means the exosomal Aβs could serve as a more reliable biomarker to diagnosis Alzheimer’s disease.
Identifying heritable brain networks that may confer cognitive reserve to Alzheimer's disease
Authors: Murdy Thomas J , Dunn Amy R , Telpoukhovskaia Maria , Zhang Shanrong , Febo Marcelo , Kaczorowski Catherine C.
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disease that affects 50 million people worldwide (Breijyeh & Karaman, 2020). Among individuals with AD, cognitive dysfunction varies, giving rise to the hypothesis that neural function and anatomical substrates provide “cognitive reserve” against AD. This idea inspired the brain reserve hypothesis, which states that structural features of the brain may protect against AD‐related cognitive decline (Stern, 2012). One potential source of brain reserve is neural microanatomy, which varies across individuals (Wang et al., 2020) and may then explain the differential cognitive outcomes in AD associated with cognitive reserve.

Method

We utilized a population of genetically distinct AD mice produced by crossing the 5XFAD model of AD to five mouse strains (C57BL/6J, DBA/2J, FVB/NJ, CAST/EiJ, and WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI), a collection of techniques that characterizes brain microstructure (Campbell & Pike, 2019), to probe variation of neural microanatomy in 430 regions of interest (ROIs). At 5 months of age, when cognitive decline is expected (Oakley et al., 2006; Devi & Ohno, 2010), these mice underwent contextual fear conditioning (CFC) and contextual fear memory (CFM) paradigms. Hierarchical clustering was performed on the correlations between dMRI measurements in each brain region influenced by strain and CFC and CFM performance.

Result

362 ROIs had dMRI metrics with significant effects of sex, strain, and/or 5XFAD genotype. Of these ROIs, 348 had a significant effect of strain, 68 had a significant effect of sex, and 30 or fewer had a significant effect of genotype or any variable interactions. We identified one network of ROIs in which nearly all dMRI parameters correlated positively and strongly to CFC performance and two networks whose dMRI measures correlated strongly to CFM performance, although the directionality of these correlations varied within these two networks.

Conclusion

Our work identifies three neural networks that are influenced by strain and correlate strongly to CFC and CFM performance. Further analyses should explore genetic factors influencing these networks and the structural and functional connectivity of brain regions in these networks.
Synaptic loss in behavioural variant of frontotemporal dementia:an in vivo [11C]UCB‐J PET study
Authors: Malpetti Maura , Jones P Simon , Cope Thomas E , Holland Negin , Naessens Michelle , Rouse Matthew A , Savulich George , Fryer Tim D , Hong Young T , Milicevic‐Sephton Selena , Aigbirhio Franklin I , O'Brien John T , Rowe James B
Published: December 2022

Background

Post‐mortem clinical studies and animal models described severe synaptic loss as an early feature of neurodegenerative disease, including frontotemporal dementia. Recently, PET radiotracers that bind to synaptic vesicle glycoprotein 2A have been developed and proven to enable in vivo quantification of synaptic loss in people with neurodegenerative diseases. This study used [11C]UCB‐J PET to quantify synaptic loss in people with behavioural variant frontotemporal dementia (bvFTD).

Method

We recruited 10 people with a clinical diagnosis of bvFTD and 24 age‐ and sex‐matched healthy controls. Participants underwent dynamic [11C]UCB‐J PET‐MR, and a neuropsychological assessment, including the Addenbrooke's cognitive examination (ACE‐R) as a global measure of cognitive performance, and the INECO frontal screening. Synaptic density was estimated using [11C]UCB‐J non‐displaceable binding potential (BPND) at voxel level and in whole‐brain regions of interest. General linear models were used to compare [11C]UCB‐J binding voxel‐wise between groups, and correlate synaptic density with cognitive performance in bvFTD cohort. These analyses were also performed using regional [11C]UCB‐J binding potentials, with and without partial‐volume correction. Regional correlations were performed with both frequentist and Bayesian approaches.

Result

People with bvFTD showed severe synaptic loss compared to controls at individual level and as a group. [11C]UCB‐J binding was significantly reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insula cortex and medial temporal lobe (5.1 ≤ t ≤ 9.3, p < 0.05 FWE at voxel level, Figure 1A). Results from ROI‐based analyses mirrored the voxel‐wise results, with and without partial‐volume correction. Synaptic loss in the left frontal and cingulate regions significantly correlated with cognitive impairments as assessed with ACE‐R and INECO (r > 0.8, p<0.001 at voxel level, p<0.05 FWE at cluster level, Figure 1B). Correlations were confirmed by regional‐based analyses, with both frequentist and Bayesian approaches (Figure 1C).

Conclusion

Different analytic approaches converged showing a significant and widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to disease severity. [11C]UCB‐J PET could therefore be a useful supporting tool for translational studies and experimental medicines strategies for new disease‐modifying treatments in this condition.
Pharmacological preconditioning with mitochondrial dynamic modulators exerted neuroprotection against cardiac ischemia‐reperfusion injury in obese rats via suppressing microglial inflammation
Authors: Maneechote Chayadom , Arunsak Busarin , Nawara Wichwara , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2022

Background

Obesity is widely acknowledged as a major risk factor for brain and heart complications. Brain inflammation and microglial activation can be induced by either cardiac ischemia/reperfusion (I/R) injury or obese condition. While mitochondrial fission inhibitor (Mdivi‐1) and fusion promoter (M1) have already been reported as potential cardioprotective therapies, their protective effects in the brain suffered from cardiac I/R injury under obese condition have not been investigated.

Method

Thirty male Wistar rats were fed with a high‐fat diet (HFD) for 12 weeks to induce obese‐insulin resistance, and then were randomly divided into the sham (HFS, n=6) and the cardiac I/R (n=24) groups. Cardiac I/R rats were intravenously injected with either vehicle (HFV, n=6), Mdivi‐1 (HFMD, n=6), M1 (HFM1, n=6), or Mdivi‐1+M1 (HFMD+M1, n=6) 15 min prior to a 30‐min ischemia by left anterior descending coronary artery ligation, followed by 120‐min reperfusion. At the end of the protocol, the brain was rapidly removed to determine the protein expression of brain inflammation, microglial markers, and brain pathological conditions.

Result

Cardiac I/R markedly induced brain pathology via increasing inflammation, microglial activation, and brain pathologies, as shown by increased levels of tumor necrosis factor alpha (TNF‐α), ionized calcium binding adaptor molecule 1 (IBA1), and beta‐amyloid (Aβ) per amyloid‐beta precursor protein (APP) ratio in the HFV group, compared with those of HFS group (p<0.05, Figure 1). In HFD‐fed rats with cardiac I/R injury, either Mdivi‐1, M1, or combined therapies provided neuroprotection by restoring TNF‐α, IBA1, and Aβ/APP protein levels (p<0.05, Figure 1), as well as improved left ventricular ejection fraction [58±5% HFMD; 53±3% HFM1; 55±6% HFMD+M1 vs 42±2% HFV].

Conclusion

Rebalancing brain mitochondrial dynamics rescued brain inflammation and brain pathologies induced by cardiac I/R injury of obese rats. These findings suggest that the modulators of mitochondrial dynamics may act as a novel therapeutic approach for combating brain damage caused by cardiac I/R in an obese subject.
The impact of COVID‐19 lockdown on cognitive decline over time
Authors: Bakker Els D. , van Maurik Ingrid S. , van der Pas Stéphanie L. , Gillissen Freek , Bouwman Femke H. , Scheltens Philip , van der Flier Wiesje M.
Published: December 2022

Background

During the COVID‐19 pandemic, memory clinic patients reported worries for faster cognitive decline as a consequence of lockdown measures, e.g. loss of structure and feelings of loneliness and depression. We aimed to investigate the impact of the COVID‐19 lockdown on cognitive decline over time in a mixed memory clinic population, compared to historical controls.

Method

We included patients who visited Alzheimer Center Amsterdam six months to a week before the first COVID‐19 lockdown in the Netherlands (mid‐March 2020), and a second visit one year later, after this lockdown period (n = 114; 67±7 years old; 30% female; Mini‐Mental State Examination (MMSE): 25±3; diagnosis: n = 55 dementia, n = 32 mild cognitive impairment, n = 18 subjective cognitive decline, n = 9 postponed diagnosis). We selected historical controls with a visit in 2016 or 2017 and a second visit one year later (n = 641). Historical controls were matched 1:1 to patients during COVID‐19 lockdown by optimal Mahalanobis distance matching based on age, sex, diagnosis, MMSE, type of visit (baseline/follow‐up) and time between the first and second visit. Matching was successful and led to balanced groups (both n = 114) on all matching variables (table 1). We used linear mixed models with terms for time, group (i.e. lockdown patients vs. historical controls) and the interaction between time and group. Outcome measures were MMSE, Trail Making Test part A and B, Rey‐Auditory Verbal Learning Test (RAVLT) immediate and delayed recall and category fluency.

Result

As expected, there was no effect of group on baseline test performance for any of the tests. We found significant interactions between time and group for RAVLT immediate recall [B(SE) = ‐2.74(1.07), p = 0.011] and delayed recall [B(SE) = ‐1.07(0.34), p = 0.002], indicating steeper cognitive decline during lockdown. In non‐matched historical controls, we found similar results; significant interactions between group and time for RAVLT immediate recall [B(SE) = ‐3.34(0.80), p<0.001] and delayed recall [B(SE) = ‐0.94(0.23), p<0.001], and additionally steeper decline on category fluency [B(SE) = ‐1.42(0.51), p = 0.005].

Conclusion

Memory clinic patients during COVID‐19 lockdown show steeper decline in memory than matched historical controls, providing evidence that lockdown regulations contributed to faster cognitive decline.
Factors associated with risk of transition to high likelihood of dementia profile in population‐based surveys of aging: a longitudinal analysis
Authors: Gharbi‐Meliani Amin , Josse Julie , Husson François , Vandendriessche Henri , Bayen Eleonore , Yaffe Kristine , Bachoud‐Levi Anne‐Catherine , de Langavant Laurent Cleret
Published: December 2022

Background

Dementia (Major Neurocognitive Disorder) is associated with acquired cognitive impairment and functional decline in daily life. Several population‐based surveys of aging similar to the American Health and Retirement Study exist worldwide. In these studies, cognitive performance and functional status are available, but not the diagnosis of dementia. We previously identified participants with high likelihood of dementia using cross‐sectional data from these studies and unsupervised machine‐learning (Cleret de Langavant et al., 2018; 2020). Here, we propose an application of this method by assessing simultaneously six waves, i.e., minimum 11‐year follow‐up for each participant, in order to study factors associated with risk of transition toward dementia.

Method

We used a modified version of a previously developed unsupervised machine‐learning algorithm in the Survey of Health, Ageing and Retirement in Europe (SHARE). We restrained the analysis to participants with available data at each wave (N = 5,536, 9 countries). Cognitive tests and autonomy variables were used to discriminate three groups: one healthy ageing group (Healthy), one characterised by mobility but no functional impairment (Mobility), and one with probable dementia (Dementia). We examined the role of several factors in transitioning from one group to another one using multi‐state models with age as time‐scale.

Results

Hazard ratios (HR) examination confirmed that higher education lowers the risk of transition to mobility impairment and to dementia (HRhealthy→mobility = 0.46 [0.42 ‐ 0.50], HRmobility→dementia = 0.44 [0.32 ‐ 0.62], and HRhealthy→dementia = 0.58 [0.36 ‐ 0.92]). Similarly, obesity, stroke, hypertension, and poor hearing were significant risk factors. Isolation and depression were found to increase the risk of transition from Mobility to Dementia group (HRmobility→dementia = 2.97 [2.08 ‐ 4.24] & HRmobility→dementia = 2.23 [1.86 ‐ 2.67], respectively) and from Healthy to Dementia group (HRhealthy→dementia = 5.56 [2.39 ‐ 12.94]) & HRhealthy→dementia = 1.98 [1.33 ‐ 2.95], respectively). Results for smoking and alcohol were inconclusive.

Conclusion

While obesity, stroke, hypertension, poor hearing, depression and isolation were associated with an increased risk of transition to the Dementia group, high educational attainment was protective.
Brain‐wide spatial analysis reveals cell‐type‐specific genetic modifiers of Alzheimer’s disease progression
Authors: Gurdon Brianna , Hadad Niran , Telpoukhovskaia Maria , Yates Sharon , Puchades Maja Amedjkouh , Bjaalie Jan , Kaczorowski Catherine C.
Published: December 2022

Background

There is significant variation in the age at onset and severity of cognitive decline among those with Alzheimer’s disease (AD). Despite strong genetic links to AD loci, the specific variants, target genes and cell types that drive AD‐related deterioration remain elusive. Recent advances in brain‐wide cell type and pathology quantification across our AD mouse genetic reference panel provide new opportunities to identify genetic factors that act in a cell‐type‐specific fashion to modify disease progression in response to causal AD mutations; linking, for the first time, genetics to regional cell composition to characterize susceptibility versus resilience to AD.

Method

Immunohistochemistry was completed to evaluate neurodegeneration(NeuN), gliosis(Iba1&GFAP), and amyloid pathology(AB1‐42) in 250 mice from the AD‐BXD genetic reference panel. Using the QUINT workflow, hemibrain slices were systematically segmented and registered to the Allen Brain Atlas to gain a global perspective of percent cell/pathology coverage. The heritability of individual cell composition was calculated and quantitative trait loci(QTL) mapping was completed.

Result

Compositional differences between the strains, particularly the BXD founder strains, became apparent when evaluating neurodegeneration and microglial proliferation. Despite comparable levels of amyloid, cortical and hippocampal NeuN and Iba1 coverage significantly varied among strains; however, this variation did not explain individual differences in short and long‐term memory capacity. Genetic mapping of individual cell composition traits identified a significant QTL associated with cortical neuron load (h = 0.6) on chromosome 17. Lrfn2 was identified as a gene of interest as it was differentially expressed between mice that had the BB vs BD genotype at the most significant variant location under the peak.

Conclusion

This method of combining omics and imaging data to link changes in gene expression, cell composition, and behavior allows for the assessment of disease subtypes with the potential to aid the development of precision medicine solutions to AD. Specifically, changes in cell coverage can be associated with differences in gene expression among the AD‐BXD population to detect genes associated with regional cell composition. These candidates will be validated by creating cell‐type‐specific knock‐in or knock‐out models and measuring cognitive functioning to determine the effect of these genes on memory performance.
Perivascular SPP1 modulates microglia‐synapse engulfment in Alzheimer’s disease models.
Authors: Hong Soyon
Published: December 2022

Background

Microglia and other resident macrophages in the central nervous system (CNS) exhibit heterogeneous phenotypes dependent on spatiotemporal context, allowing them to fulfil various functions in health and disease. Emerging data suggest that microglia mediate synaptic loss in Alzheimer’s disease (AD) (Bartels et al., Science 2020), yet we know little about the underlying mechanisms and potential subsets or cell states involved.

Method

We performed single‐molecule fluorescent hybridisation (smFISH) using RNAScope, immunohistochemistry, super‐resolution microscopy, ultrastructural microscopy (CLEM), flow cytometry, and a newly generated SPP1‐reporter mouse to identify cellular source of SPP1 in the hippocampus of mice. We assessed SPP1 mRNA and protein, as well as synapse and complement pathology in hAPP‐NL‐F knock‐in mice. We validated localisation of SPP1 in AD human patient brains. To assess functional effects of SPP1 in the hippocampus, we performed intracerebroventricular injections of oligomeric Abeta in wild‐type (WT) vs. SPP1 KO mice.

Result

Here we report SPP1/Osteopontin, a glycoprotein involved in phagocytosis, is upregulated in a region‐specific manner in the hippocampus of AD mouse and human brains. There is a brain‐region specific upregulation of SPP1 mRNA and protein in hippocampus of AD models, coinciding at a time point of complement deposition and when synapses are vulnerable to microglial engulfment. Interestingly, we found that SPP1 is produced not by microglia but by a type of CNS‐resident macrophages that line the perivascular space, i.e., the perivascular macrophages (PVM), which is then secreted to alter microglial engulfment state. In Spp1‐knockout mice, Aβ oligomers are unable to induce synapse loss as compared to wild‐type controls. Furthermore, microglia fail to upregulate phagocytic markers as well as C1q.

Conclusion

Our data suggest SPP1 and PVM as mediators of synapse engulfment in pre‐plaque AD mouse models
A Novel In Vivo‐Active Small Molecule Inducer of Progranulin for the Treatment of Frontotemporal Dementia
Authors: Blain Jean‐François , Chen Angela Y.P. , Brand Morgan A. , Lanter James C. , Holler Christopher J. , Brendel Jerusha K. , Koenig Gerhard , Burnett Duane A. , Hurst Raymond S.
Published: December 2022

Background

Heterozygous mutations in GRN that lead to haploinsufficiency of the progranulin (PGRN) protein cause the fatal neurodegenerative disease frontotemporal dementia (FTD‐GRN). Complete loss of PGRN, on the other hand, leads to an early onset lysosomal storage disorder, indicating a critical role for PGRN in the lysosome. Although its exact function is unknown, PGRN is both secreted and trafficked to the lysosome where it is processed into granulins. Lysosomal granulins are reported to modulate the activity of lysosomal enzymes. Currently there are no treatments for FTD‐GRN but restoring PGRN to normal levels is a promising therapeutic strategy.

Methods

We performed a small molecule screen in BV‐2 cells and identified novel compounds that increase progranulin secretion. Some of these molecules were further characterized in vivo to help determine an exposure‐response relationship.

Results

Through structure activity relationship optimization, we improved the potency of compounds at increasing PGRN secretion from >2 mM down to <1 nM. Importantly, we found that lysosomal granulins are increased following compound treatment and that this effect is sustained beyond the secreted PGRN increase. Using an optimized brain‐penetrant compound with good pharmacokinetic properties, we established an exposure‐response relationship for PGRN changes in the CSF of non‐human primates, demonstrating an excellent in vitro‐in vivo correlation. Finally, we report that multi‐day dosing produced a sustained increase in PGRN in CSF over the course of the treatment period.

Conclusion

Overall, these data support further development of our novel small molecules for the treatment of FTD‐GRN.
White matter connectivity networks predict early dementia conversion in Parkinson’s disease
Authors: Chung Seok Jong , Kim Yaeji , Jung Jin Ho , Lee Hye Sun , Ye Byoung Seok , Sohn Young H , Jeong Yong , Lee Phil Hyu
Published: December 2022

Background

Several clinical and neuroimaging biomarkers have been proposed to identify individuals at high risk for dementia conversion in Parkinson’s disease (PD). This study aimed to explore whether white matter (WM) connectivity disruption can predict the dementia conversion in patients with newly diagnosed PD with mild cognitive impairment (PD‐MCI).

Method

Neuroimaging analyses of WM structural connectivity were performed in 75 patients with drug‐naïve PD‐MCI who underwent serial cognitive assessments during the follow‐up period (>5 years). The patients were classified into either the PD with dementia (PDD) high‐risk group (PDD‐H, n = 38) or low‐risk group (PDD‐L, n = 37), depending on whether they converted to dementia within 5 years of PD diagnosis. We conducted degree‐based statistics (DBS) analyses based on a graph‐theoretical concept to identify the subnetworks whose WM connectivity was disrupted in the PDD‐H group compared with the PDD‐L group. We also performed partial correlation analyses to investigate whether the network connectivity strength was correlated with either the cognitive composite scores or the estimated risk score for PDD conversion within 5 years.

Result

The PDD‐H group showed poorer cognitive performance on frontal/executive, visual memory/visuospatial, and attention/working memory/language function than the PDD‐L group at baseline assessment, even though there was no difference in parkinsonian motor deficits severity, disease duration, and years of education. The PDD‐H group exhibited more severely disrupted WM connectivity in both frontal and posterior cortical regions with eight hub nodes in the DBS analysis. The strength of structural connectivity within the identified subnetworks was correlated with the composite scores of the frontal/executive function domain (γ = 0.393, p = 0.010) and the risk score of PDD conversion within 5 years (γ = ‐0.480, p = 0.001).

Conclusion

The present study demonstrated that disrupted WM connectivity in frontal and posterior cortical regions, which was correlated with frontal/executive dysfunction, could be used as a marker for early dementia conversion in patients with PD‐MCI.
Pathological Validation of RORB and CDH9 as Selectively Vulnerable Neurons in Alzheimer’s Disease
Authors: Nasar Rakin T , Pereira Felipe Luiz , Li Song Hua , Miramontes Silvia , Kampmann Martin , Leng Kun , Seeley William W. , Spina Salvatore , Miller Bruce L. , Grinberg Lea Tenenholz
Published: December 2022

Background

: The excitatory neurons of the entorhinal cortex are extremely vulnerable to Alzheimer’s disease (AD). Recently, we demonstrated that among those neurons, expressing high levels of RORB, are more vulnerable than other neighboring excitatory neuronal subpopulations. Our single nucleus RNA sequencing of 10 EC at progressive stages of AD neurofibrillary pathology also suggested that CDH9+ excitatory neurons from the EC can also be early vulnerable to AD. Here, we used quantitative neuropathological methods in cases across AD progression to interrogate whether CDH9+ neurons are early vulnerable to AD.

Method

We used quantitative histopathological assessment using multiplex immunofluorescence to quantify the number of NeuN+, T231+, CDH9+, and RORB+ cells in 18 cases across Braak stages 0‐V1. All cases were 8μm thick, formalin‐fixed and paraffin embedded coronal sections of EC. Slides stained with hematoxylin and eosin were used to delineate the EC boundaries and identifying clusters of stellate cells in layer II. Neuronal quantification of EC external layers was done using an in‐house automated cell counting tool with manual quality control and using the ImageJ cell counter plugin.

Result

The number of neurons (NeuN+) decreased along the Braak stages II‐VI (p<0.01) (Fig. 1A), whereas the proportion of ptau+ (T231) neurons increased stages II‐VI (p<0.001) (Fig. 1B). CDH9+ neurons had a significantly higher proportion of T231 colocalization in Braak stages II‐IV (p<0.01) and IV‐VI (p<0.05) compared to 0‐II (Fig. 1G). We observed a trend on neuronal loss, but it did not reach statistical significance (Fig. 1C, E). Similar results were observed to the RORB+ neuronal population (Fig. 1 D, F H).

Conclusion

CDH9+ and RORB+ cells are more likely to accumulate tau compared to non‐CDH9+ and non‐RORB+ cells. RORB+ and CDH+ cells are more likely to accumulate tau in Braak stages II‐IV, but the relationship is not linear, and the accumulation plateaus in the Braak stages IV‐VI. The trend of CDH9+ and RORB+ cell loss did not reach statistical significance, suggesting this pilot study is still underpowered. The results confirm that CDH9+ and RORB+ cells are selectively vulnerable to tau pathology.
Retrospective MRI‐based tracking of hippocampal sclerosis
Authors: Ortega‐Cruz Diana , Uceda‐Heras Alicia , Zhang Linda , Iglesias Juan Eugenio , Rabano Alberto , Strange Bryan A
Published: December 2022

Background

The hippocampus plays a crucial role in memory encoding and retrieval and is highly vulnerable to age‐related pathologic alterations. Hippocampal sclerosis (HS) is a prominent histologic finding in dementia patients which results in worsening of cognitive symptoms but has been so far understudied. Contrary to HS developed in epilepsy, HS of aging specially affects individuals over 85 years old. It is defined by severe neuronal loss and gliosis in CA1 and subiculum areas, which is disproportionate to the expected damage from other pathologies that commonly coexist with HS, such as AD and TDP‐43 pathology.

Method

We studied a cohort of dementia patients who underwent follow‐up at the CIEN Foundation (Madrid, Spain) and selected 45 subjects with in vivo MRI and post‐mortem pathological diagnosis. In this neuropathological evaluation, the presence of gliosis without neuronal loss in relevant areas of the hippocampus has been considered a precursor stage of HS, as suggested by previous studies (Hokkannen et al., Brain Pathol 2018). Based on this criterium, a staging system (0‐IV) for HS has been proposed including precursor stages as part of the pathology spectrum. We have explored relations between this staging system and pre‐mortem anatomical differences via analysis of MRI scans. Specifically, we used SPM software to perform voxel‐based morphometry and FreeSurfer to obtain segmentations of hippocampal subfields.

Result

We found that the extent of HS measured with this staging system is associated with a bilateral reduction in grey matter density in the hippocampus detectable in vivo. These effects are obtained after controlling for other neuropathologies, indicating an independent contribution of HS to atrophy. Additionally, a reduction in volume is observed at most severe stages of HS in all subfields of the hippocampal cortex, rather than exclusively in CA1 and subiculum. We also found volume differences notable at more than 5 years before death via longitudinal analysis of earlier MRI timepoints.

Conclusion

Our results validate this staging system as an accurate description of HS progression and provide hints towards a clinical diagnosis of HS of aging supported by MRI.
Genetically predicted Telomere Length and its relationship with Alzheimer’s disease and Life Expectancy
Authors: Rodríguez‐Fernández Blanca , Gispert Juan Domingo , Guigó Roderic , Navarro Arcadi , Vilor‐Tejedor Natalia , Crous‐Bou Marta
Published: December 2022

Background

Telomere length (TL) is a well‐known hallmark of biological aging, being telomere shortening associated with overall mortality and increased rates of age‐related diseases, such as Alzheimer’s disease (AD). However, observational studies are limited to conclude whether TL is causally associated with those outcomes or with related underlying pathological processes. This study aimed to evaluate whether TL may play a causal role in life expectancy and the risk of neurodegenerative diseases through Mendelian Randomization (MR) analyses.

Method

Summary level genetic data were extracted from the most recent genome‐wide association studies for TL (N = 78,592), AD (N = 455,258), Parkinson’s disease (N = 482,730), Frontotemporal dementia (N = 4,131), Amyotrophic lateral sclerosis (N = 36,052), progressive supranuclear palsy (N = 12,308) and life expectancy (N = 75,244). Inverse‐variance weighted (IVW), maximum likelihood, weighted median and weighted mode methods were used to estimate the causal effect of genetically predicted longer TL on the outcomes of the study. Cochran Q statistic, MR‐PRESSO and MR‐Egger intercept‐test were used as ad hoc sensitivity analysis for evaluating the robustness of significant results. Effect sizes were reported as Odds Ratio (OR) and 95% confidence intervals (CI) for all the pathologies and the estimated coefficient (βIVW
) and standard error (SE) for life expectancy. Multiple comparison corrections were performed through False Discovery Rate (FDR).

Result

Genetically predicted longer TL was associated with a lower risk of AD (ORIVW: 0.964; 95% CI: 0.936‐0.992; FDR corrected p‐value = 0.039) [Figure 1]. Longer TL was significantly associated with increased life expectancy (βIVW
: 0.011; SE: 0.004; FDR corrected p‐value = 0.039) [Figure 2]. The maximum likelihood, weighted median and weighted mode engendered similar patterns of effects. Sensitivity analyses supported the consistency of our results [Table 1]. No other statistically significant causal relationships were observed with other neurodegenerative diseases.

Conclusion

Our results showed that genetically predicted longer TL might increase life expectancy and play a protective effect on AD. This suggests that the involvement of different biological aging mechanisms (through TL biology) might differ between life expectancy, AD and other neurodegenerative diseases. Further observational studies are needed to confirm these results.
Executive Functions and Episodic Memory are Associated with Extracellular White Matter Microstructure in Early Old Age
Authors: Gustavson Daniel E. , Archer Derek B , Elman Jeremy A. , Fennema‐Notestine Christine , Hagler Donald J. , Panizzon Matthew S. , Shashikumar Niranjana , Hohman Timothy J. , Jefferson Angela L. , Lyons Michael J. , Franz Carol E , Kremen William S.
Published: December 2022

Background

Cortical surface area, cortical thickness, and hippocampal volume are well‐studied in relation to later life cognitive impairments and AD. Fewer studies have investigated how white mater microstructure relates to cognition in late life. Existing work has focused on fractional anisotropy (FA) and mean diffusivity (MD) measures that are thought to capture demyelination and axonal degradation and relate to cognitive decline in normal aging and AD. However, these measures are susceptible to partial volume effects. Here, we evaluated whether executive function and memory are associated with FA and MD after deploying a free‐water (FW) elimination post‐processing method that separates fluid (FW) from tissue (FW‐corrected FA and MD).

Method

We examined 489 non‐demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Executive function was based on 6 tasks spanning inhibition, shifting, and working memory. Memory was based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FW‐corrected FA, and FW‐corrected MD. Analyses controlled for age, scanner, diabetes, hypertension, race, and ethnicity. We used false discovery rate to account for multiple testing.

Result

Better executive functioning was associated with lower FW across all 11 tracts. Better memory was associated with lower FW in 3 tracts: the superior longitudinal fasciculus (SLF) and two sections of the inferior frontal gyrus (opercularis and triangularis). Despite widespread differences with FW, there was only one significant association with intracellular metrics (executive function and FW‐corrected FA in the SLF). Finally, indicators of cognitive reserve (education or general cognitive ability assessed in early adulthood) did not moderate these associations between cognition and white matter microstructure.

Conclusion

Our findings leveraged a post‐processing method that separates extracellular fluid (FW) from intracellular tissue (FA, MD). We found that cognitive abilities in early old age are associated primarily with extracellular white matter microstructure (FW), which demonstrated global associations with executive function. Finally, there was no evidence that indicators of cognitive reserve influenced the strength of the association between cognition and white matter, at least in this sample of non‐demented men.
NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS): 2022 Update
Authors: Issen Heather , Kuzma Amanda B , Valladares Otto , Greenfest‐Allen Emily , Klamann Conor , Gangadharan Prabhakaran , Katanic Zivadin , Wilk Andrew , Zhao Yi , Qu Liming , Moon Michelle K , Rose Alexis Lerro , Manuel Joseph , Keskinen Peter , Thomas Carlos , Chou Shin‐Yi , Lee Wan‐Ping , Leung Yuk Yee , Naj Adam C. , Stoeckert Christian J , Schellenberg Gerard D. , Wang Li‐San
Published: December 2022

Background

NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer’s Disease Sequencing Project (ADSP), and the Genome Center for Alzheimer’s Disease (GCAD) allow NIAGADS to lead the effort in managing large AD datasets that can be easily accessed and fully utilized by the research community.

Method

NIAGADS is supported by National Institute on Aging (NIA) under a cooperative agreement. All data derived from NIA funded AD genetics studies are expected to be deposited in NIAGADS or another NIA approved site. NIAGADS manages a Data Sharing Service (DSS) that facilitates the deposition and sharing of genomic data and association results with approved users in the neurodegenerative research community. In addition, researchers are able to freely use the NIAGADS Alzheimer’s Genomics Database (www.niagads.org/genomics/) to search annotation resources that link published AD studies to AD‐relevant sequence features and genome‐wide annotations.

Result

As of January 2022, NIAGADS houses 82 datasets comprised of >93,000 samples including GWAS, sequencing, gene expression, annotations, deep phenotypes, and summary statistics. Qualified investigators can retrieve ADSP sequencing data with ease and flexibility through the NIAGADS DSS. As of January 2022, the ADSP and other contributing studies have completed whole exome sequencing (WES) of 20,503 samples and whole‐genome sequencing (WGS) of 16,905 samples. Raw WES and WGS files, quality controlled VCF files, and phenotype data files are available via qualified access. The next round of sequencing currently underway will generate around 18,000 additional genomes to be released at the middle of 2022.

Conclusion

NIAGADS is a rich resource for AD researchers, with the goal of facilitating advances in Alzheimer’s genetics research. By housing datasets from many projects and institutions, NIAGADS enables AD researchers to meet their research goals more efficiently. Datasets, guidelines, and new features are available on our website at https://www.niagads.org.