bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundDuring 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.MethodWe 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.ResultAs 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].ConclusionMemory 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

AbstractBackgroundDementia (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.MethodWe 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.ResultsHazard 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.ConclusionWhile 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

AbstractBackgroundThere 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.MethodImmunohistochemistry 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.ResultCompositional 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.ConclusionThis 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

AbstractBackgroundMicroglia 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.MethodWe 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.ResultHere 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.ConclusionOur 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

AbstractBackgroundHeterozygous 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.MethodsWe 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.ResultsThrough 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.ConclusionOverall, 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

AbstractBackgroundSeveral 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).MethodNeuroimaging 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.ResultThe 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).ConclusionThe 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

AbstractBackground: 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.MethodWe 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.ResultThe 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).ConclusionCDH9+ 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

AbstractBackgroundThe 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.MethodWe 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.ResultWe 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.ConclusionOur 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

AbstractBackgroundTelomere 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.MethodSummary 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).ResultGenetically 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.ConclusionOur 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.