julilili42/papers huggingface dataset:
Cross‐sectional comparison of the role of tau burden among Down Syndrome Alzheimer disease and autosomal‐dominant Alzheimer disease
2023-12-01

Abstract Background Adults with Down Syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia as they age. This is attributed to triplication of the amyloid precursor protein gene. Recent work demonstrated that amyloid is elevated in DS and accumulates in a similar topography to autosomal dominant AD (ADAD). Tau accumulation is the second hallmark of AD and may be measured using tau positron emission tomography (PET) imaging. The pattern of tau accumulation remains unknown in DS. Method In a cross‐sectional analysis we evaluated amyloid and tau positron emission tomography (PET) in 124 participants with DS (109 cognitively stable, 8 symptomatic, 7 no consensus), 29 ADAD mutation carriers (26 asymptomatic, 3 symptomatic), and 201 cognitively normal non‐mutation carriers (CN). Regional cortical standard uptake value ratios (SUVR) for tau imaging were obtained and compared by cognitive status. Similarly, regional cortical amyloid SUVR were obtained and converted to centiloids. We then compared the magnitude of tau burden as well as spatial spread of tau across groups relative to amyloid burden. Result Compared to CN, tau PET binding was elevated in participants with (μ DS = 2.12 ± 0.22 SUVR, μ ADAD = 2.52 ± 0.37 SUVR) and without (μ DS = 1.24 ± 0.15 SUVR, μ ADAD = 1.16 ± 0.19 SUVR) cognitive changes. For both groups, tau increased with increasing amyloid (centiloids). In some regions, DS had greater tau burden for a given amyloid level (centiloids) (Figure 1). There was increased spatial distribution of tau throughout the brain for participants with DS compared to CN. In contrast, tau burden was more focal in participants with ADAD with tau primarily elevated in posterior regions (Figure 2). Conclusion While tau burden was higher with symptomatic disease for both groups, significant differences existed in the overall amount and spatial spread. Tau spread was greatest in participants with DS and more diffuse compared to ADAD. These results indicate a substantial tau burden is present in DS, and suggest not only anti‐amyloid but also tau‐reducing agents should be considered for treating cognitive decline in adults with DS.
Investigating biological age as a predictor of symptom progression in Alzheimer’s disease
2023-12-01

Abstract Background Age is the strongest risk factor for dementia, including Alzheimer’s disease (AD). However, across individuals of the same chronological age there is considerable heterogeneity in rates of cognitive decline. These differences have been attributed to individual differences in age‐related biological processes, including brain protein expression. To capture these differences, we developed a measure of protein brain age from cerebrospinal fluid (CSF)‐proteins, and validated its predictive utility. Methods In older adults across the dementia continuum enrolled in DELCODE (training cohort; N = 488, 5‐year follow‐up) and patients with subjective cognitive decline and mild cognitive impairment (MCI) from the memory‐clinic based Fundació ACE (FACE) cohort (test cohort; N = 509, 3‐year follow‐up), 1063 CSF‐proteins were measured using OLINK‐technology. Proteins optimally predicting chronological age in A/T/N‐negative individuals without dementia from DELCODE (N = 196) were selected based on a LASSO‐regression and summarized into a BrainProteinAge‐score for all participants. A harmonized, age‐sensitive cognitive composite was created and the association between BrainProteinAge and cognitive decline assessed using structural equation modeling. Further, the predictive utility of ProteinBrainAge for incident all‐cause‐dementia was examined using time‐dependent ROC analysis in MCI patients from the test cohort. Results 118 CSF‐proteins were selected and used to calculate BrainProteinAge. In the training (Est[SE] = 0.06[0.02],p&lt;0.001) and test (Est[SE] = 0.04[0.02],p = 0.013) cohorts, BrainProteinAge predicted cognitive decline beyond demographic characteristics (chronological age, sex, education) and A/T/N profiles. ProteinBrainAge captured 40% of the processes linking chronological age and cognitive decline, and improved prediction to all‐cause dementia beyond demographic characteristics and A/T/N profiles in MCI‐patients (1‐year AUC: 0.78 versus 0.82, p(difference) = 0.006). Specifically, within the AD‐continuum, BrainProteinAge (HR[CI] = 1.056[1.004‐1.110]), compared to chronological age (HR[CI] = 1.022[0.990‐1.054]), has greater predictive utility. Whilst an 8.6‐year ProteinBrainAge difference corresponded to the same risk increase observed between A+/T+ and A+/T‐ MCI patients, a difference of 24.6‐years was required for chronological age. All results remained substantively unchanged when using an optimized BrainProteinAge based on 10 proteins most strongly linked to cognitive decline. Conclusions A new measure of biological age improves individualized prediction of cognitive decline and conversion to dementia in memory clinic patients. This provides an opportunity for precision medicine and a better understanding of age‐related biological processes contributing to dementia.
Multi‐omic profiling of isogenic ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes uncovers altered lipid metabolism and mitochondrial function of ApoE4 astrocytes
2023-12-01

Abstract Background As the main genetic risk factor for AD, glial ApoE4 has been implicated in a number of early disease relevant processes, such as lipid dyshomeostasis, mitochondrial dysfunction and altered immune function. This ApoE4 glial phenotype is not yet well characterized and this hampers the rationale design of ApoE4‐targeting interventions. Method We characterize the phenotypes of ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes by multi‐omic profiling. In addition, we use lipidomic and metabolic profiling of interventions in ApoE4 astrocytes to define compounds that normalize lipid counts and metabolic function. Result In the ApoE4 astrocytes we observe strong accumulation of cholesterol esters (storage product of cholesterol) and triglycerides (storage products of fatty acids), in comparison to the ApoE3 astrocytes. Interestingly, our proteomic and transcriptomic profiling of these cells reveal an increase in cholesterol synthesis, despite the already high levels of cholesterol esters in the cell. Moreover, our proteomic and transcriptomic results display an increase in mitochondrial pathways, such as beta‐oxidation, TCA cycle and oxidative phosphorylation and a decrease in glycolysis. Not only mitochondrial function is altered but also mitochondrial organization, as we see an upregulation of the most relevant proteins for mitochondrial fusion, MFN1, MFN2 and OPA1. Our lipidomic and metabolic profiling of ApoE4 astrocytes after treatment with a number of different interventions reveals new insights into these altered lipid metabolic pathways. Conclusion Our multi‐omic profiling of iPSC‐derived ApoE3/3 and ApoE4/4 astrocytes uncovers that ApoE4 astrocytes have altered lipid metabolism, mitochondrial function and mitochondrial organization. Treatment with interventions reveals new insights into these altered pathways.
Multiomics of iPSC‐derived ApoE3‐ and ApoE4 astrocytes and microglia uncovers cell type specific dysregulation of immunometabolism
2023-12-01

Abstract Background ApoE4 is the major genetic risk factor for Alzheimer’s disease and the main lipid transporter in brain. How ApoE4 drives AD pathogenesis, and how this is related to changes in lipid metabolism, is not well understood. This lack of mechanistic insight has hampered the development of interventions that can reverse the pathological effects of ApoE4. Methods Here we perform integrated multiomic analysis (lipidomics, metabolomics, transcriptomics and proteomics) on isogenic iPSC‐derived glia carrying an ApoE4/4, ApoE3/3 or ApoE‐knockout genotype. We employ pathway enrichment to identify candidate biological processes that contribute to AD pathogenesis and perform a number of biochemical‐ and intervention experiments to gain insight into the biological mechanism. We feed iPSC‐derived glia with different lipid species to better understand the interaction between lipids and immune dysfunction. Lastly, we generate a new open‐access resource (the Neurolipid atlas), to allow others in the field to interact with our lipid data. Results Our lipidomic analysis shows that ApoE4 has a major effect on lipid metabolism in human iPSC‐derived astrocytes and microglia. In both astrocytes and microglia, ApoE4 causes accumulation of cholesteryl esters (CE), triglycerides (TAG) as well changes in ceramide metabolism. Interestingly, transcriptomic and proteomic analysis in both cell types shows that ApoE4 glia have strongly upregulated cholesterol synthesis despite having already high levels of stored cholesterol (CE). Astrocytes and microglia show very distinct adaptations to ApoE4 in terms of energy production. Whereas ApoE4 astrocytes have higher levels of mitochondrial proteins, ApoE4 microglia downregulate mitochondrial proteins but have increased levels of key glycolytic proteins. Immune profiles, including DAM signatures in microglia, are changed in a similar direction in both ApoE4 astrocytes and microglia. Lipid feeding also directly affect these immune pathways. Conclusion Our data indicate that astrocytes and microglia display both common and distinct immunometabolic adaptations to the ApoE4 genotype. Interestingly, both ApoE4 microglia and astrocytes have increased stored cholesterol yet keep upregulating cholesterol synthesis, indicating a possibly pathogenic broken feedback loop. We also show that this altered lipid metabolism is tightly coupled to immune dysfunction and propose novel mechanisms and interventions that may normalize ApoE4 dysfunction in human glia in AD.
New in vitro tools to investigate the role of microglia in neurodegeneration
2023-12-01

Abstract Background Human induced pluripotent stem cells (iPSCs) have transpired as an attractive tool to investigate neurological diseases. And while immune cells, and in particular microglia, have emerged as important players in many neurological and in particular in neurodegenerative diseases, it remains a challenge to fully recapitulate an in vivo‐like phenotype ex vivo. This is due to the fact that microglial identity is shaped by the neural tissue environment. Method We have now developed a chimeric brain slice culture system, where we engraft iPSC‐derived microglia onto mouse (and human) organotypic brain slice cultures. Brain slice cultures offer the advantage that many aspects of the complex cytoarchitecture of the mature/aged living brain, including cortical layering, columnar organization and electrophysiological properties can be preserved over several weeks. Result We found that iPSC‐derived microglial precursors integrate and differentiate well in the brain slice cultures, with morphology, network characteristics and functional responses reminiscent of human microglia. Gene expression profiling of iPSC‐derived microglia revealed enhanced maturation over time. Upon induction of neurodegenerative disease pathology in these slice cultures, the iPSC‐derived microglia show transcriptional changes converging towards those observed in patients with neurodegenerative disease pathology. Conclusion This system is a novel cellularly complex tool allowing to dissect the dynamics and molecular mechanisms of microglial genetic risk factors of many neurological diseases, while preserving experimental amenability to test therapeutic approaches in a human(ized) system.
Imaging the brain to assess brain insulin action
2023-12-01

Abstract Background Ever since the brain was identified as an insulin‐sensitive organ, it was quickly appreciated that insulin action in the brain affects cognitive and metabolic processes [1]. Epidemiological evidence suggests a strong link between reduced peripheral insulin sensitivity and age‐related neurodegenerative processes, including Alzheimer’s disease (AD) [2]. Method Characterization of brain insulin resistance in humans is challenging and relies on different neuroimaging methods in combination with insulin stimulation techniques. In my talk, I will focus on the administration of intranasal insulin, which has been established over the last decades to disentangle peripheral from brain insulin effects [1]. In combination with functional neuroimaging, I will show recent data on the quantification of brain insulin sensitivity non‐invasively in humans of different age and weight groups [3]. Result We could show that intranasal insulin can affect region‐specific activity and functional connectivity of the human brain. These diverse central insulin responses largely depend on its action in the hypothalamus, amygdala, hippocampus, striatum and parts of the insula and prefrontal cortex and influences a variety of metabolic and cognitive processes [3]. Specifically, I will show that disrupted brain insulin action can result in increased accumulation of visceral fat and altered reward learning in persons at high risk to develop T2D [4], but also in healthy individuals after overconsumption of high caloric foods (unpublished). Moreover, I will show that the effect of intranasal insulin in the hippocampus decreases with age in women but not men and that brain insulin responsivity is affected by the menstrual cycle (unpublished). Moreover, just recently, we could link enhanced brain insulin action in the mesocorticolimbic circuitry with improved cognitive and metabolic functions [5]. Conclusion As brain insulin acts on striatal dopamine function and hippocampal plasticity, enhancing brain insulin action could lead to new treatment options in diabetes and aging‐associated diseases. References 1. Hallschmid, M. J Neuroendocrinol, 2021. 33 (4): p. e12934. 2. Frazier, H.N., et al. Exp Neurol, 2019. 313 : p. 79‐87. 3. Kullmann, S., et al. Lancet Diabetes Endocrinol, 2020. 8 (6): p. 524‐534. 4. Kullmann, S., et al. Nat Commun, 2020. 11 (1): p. 1841. 5. Kullmann, S., et al. JCI Insight, 2022. 7 (18).
Understanding the protective effect of the PLCG2 P522R variant in human microglia
2023-12-01

Abstract Background Although recent advances in the field suggest significant involvement of the shared pathway between the proteins ApoE and TREM2 in the pathogenesis of late onset Alzheimer’s disease (LOAD), the direction that disease‐modifying interventions targeting this pathway should take are still under debate. Interestingly, a variant of the Phospholipase C Gamma 2 (PLCG2), a downstream effector of the TREM2 receptor, has been associated with a reduced risk of developing dementia. This variant results in a single amino acid change, which was reported to increment enzyme activity. However, mutations in this same enzyme (S707Y, L848P), which also result in hyperactivity, were found to lead to auto‐inflammatory immune diseases or increased AD risk (M28L), suggesting that there may be specific modulatory effects of the P522R variant. Alternatively, the existence of diverging downstream signaling pathways may explain its protective potential. Method We have generated a complete set of human isogenic iPSCs derived from the Bioni037A parental line using Crispr/Cas9 edition to introduce the mutations for the different PLCG2 variants. We obtained homozygous and heterozygous clones with the protective P522R mutation, the immune disease related S707Y or L848P. We also acquired ApoE4 isogenic iPSCs. Microglia differentiation was induced from these iPSCs using a protocol involving embryoid bodies. Our approach includes lipidomics and proteomics analyses, with focus on microglial lipid metabolism. Results Here, we show the generation of new human isogenic iPSC lines to study PLCG2 mutations. Preliminary results from the characterization of human iPSC‐derived ApoE4 microglia employing this multi‐omics approach shows a reduced expression of TREM2 pathway components including the tyrosine kinases SYK and BTK. Since BTK and SYK are both PLCG2 kinases that result in enzyme activation, we are expanding this analysis to PLCG2 mutants and base our working hypothesis on the possibility that PLCG2 hyperactive variants show a reverse phenotype compared to ApoE4 microglia. Conclusion We present new tools and a rationale to explore the protective effect of the PLCG2 P522R variant against LOAD in human microglia.
Developing a mass spectrometric assay to measure granulin peptides in CSF for progranulin‐associated frontotemporal dementia
2023-12-01

Abstract Background Pathogenic mutations in the progranulin gene ( GRN ) are a key cause of frontotemporal dementia (FTD), inducing a reduced biofluid concentration of the progranulin protein (PGRN). PGRN is a cysteine‐rich glycoprotein with essential roles in inflammation and lysosomal function, made up of 7 granulin peptides and 1 paragranulin. The role of these peptides is unclear, but existing data suggests they may have contradictory roles to full‐length PGRN. With the development of numerous clinical trials aiming to treat progranulin‐associated FTD (FTD‐GRN) by increasing full‐length PGRN, it is important to establish effective outcome measures to assess treatment success and further our understanding of PGRN’s biology. Here, we aimed to develop an assay to quantify granulin peptides in cerebrospinal fluid (CSF) and determine whether they contribute to the pathology of FTD‐GRN. Method Based on previously published explorative data of endogenous CSF peptides, 12 peptides spanning the progranulin sequence, were selected for the development of targeted assays using a quadrupole Orbitrap hybrid mass spectrometer (Fusion Tribrid, Thermo). An analytical protocol was optimised involving reduction, alkylation, molecular weight cut‐off filtration and solid phase extraction, and using isotope labelled heavy standards for quantification. Additionally, tandem mass tag (TMT) proteomics was used to analyse tryptic peptides spanning granulin and paragranulin sequence regions in 248 CSF samples from the Genetic FTD initiative (GENFI) including 56 GRN mutation carriers and 76 mutation‐negative controls. Result Preliminary results reveal the presence of three endogenous peptides in CSF, which based on sequence matching, likely represent granulin 6 and 7 alongside the paragranulin peptide. TMT results showed significantly reduced relative peptide intensity across the granulin regions in GRN carriers CSF compared to controls (p&lt;0.0001), but no significant difference in the paragranulin region (p&gt;0.33). Conclusion These findings indicate that two granulins and paragranulin are quantifiable in CSF and may have key roles in progranulin biology and potentially FTD pathology. This is supported by TMT results of differential CSF paragranulin levels compared to granulins. Continuing work will quantify CSF granulin concentrations in the GENFI cohort to assess whether these peptides have key roles in FTD‐GRN’s underlying biology and as potential outcome measures in trials.
Longitudinal morphometry of medial temporal lobe subregions in earlyAlzheimer’s disease
2023-12-01

Abstract Background Structural MRI is frequently used to track Alzheimer’s disease (AD) progression in clinic, research, and pharmacological trials. It has been shown that established MRI‐derived measures lack diagnostic sensitivity particularly in early stages of AD. Here, we investigate if the utility of structural MRI for tracking early AD progression can be increased when focusing on subregions of the medial temporal lobe (MTL) which are known to exhibit earliest AD‐related neuropathological change. Method We used data from N = 143 participants enrolled in the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE). This included cognitively unimpaired participants who were either Aβ‐negative (CU Aβ‐; n = 67) or Aβ‐positive (CU Aβ+; n = 20), Aβ+ participants with subjective cognitive decline (SCD Aβ+; n = 38), and Aβ+ participants with MCI (MCI Aβ+; n = 18). Participants underwent annual assessments up to three years after baseline, including MRI (2.19 ± 0.86 follow‐ups) and a neuropsychological testing (2.18 ± 0.83 follow‐ups). Segmentations of MTL subregions were generated using a longiudinal, template‐based implementation of the Automated Segmentation of Hippocampal Subfields (ASHS; Yushkevich et al., 2015, Hum Brain Mapp .) algorithm (Figure 1). Linear mixed models were fitted to derive volumetric slopes and to test their relationship with longitudinal changes in Preclinical Alzheimer Cognitive Composite (PACC‐5) scores. Result We observed significant volume losses across diagnostic groups with the MCI Aβ+ group exhibiting the fastest rates. Compared with the CU Aβ‐ group, there were accelerated volume losses in the subiculum and dentate gyrus in the SCD Aβ+ group and, additionally, in the entorhinal cortex and Brodmann areas 35 and 36 in the MCI Aβ+ group. There was also a trend towards faster volume losses in the entorhinal cortex in the CU Aβ+ group. Higher rates of MTL subregional volume losses, particularly in the cornu ammonis 1 subfield, were related to a faster decline on the PACC‐5 in the MCI Aβ+ group. This effect remained significant when controlling for baseline volumes. Conclusion Our findings highlight the viability of subregional MTL morphometry for tracking earliest neurodegeneration and related cognitive decline due to AD.
Altered Resting‐state fMRI BOLD Signal Fluctuations in the Spectrum of Alzheimer’s Dementia and in Patients with White Matter Hyperintensities
2023-12-01

Abstract Background Altered fluctuations in blood oxygen level dependent (BOLD) signal during resting‐state functional magnetic resonance imaging (rs‐fMRI) have been considered indicative of decreased cerebrovascular health. Previous studies reported changes in BOLD fluctuations associated with Alzheimer’s dementia (AD) and white matter hyperintensities (WMH). However, to date, there has been no large‐scale study involving patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and control subjects (CON) that has explored local AD‐ and WMH‐related effects in BOLD fluctuations. Method We calculated the voxel‐based coefficient of variation (CV: standard deviation divided by the mean) and the relative CV (rCV: CV divided by the mean CV of the whole‐brain) of the rs‐fMRI BOLD signal in the large multicentric DZNE DELCODE cohort. After spatial preprocessing, regression of movement parameters, movement spikes, and scanner drift, low‐pass filtering and exclusion of subjects with high motion, CV and rCV maps were obtained and compared with respect to (A) clinical diagnosis (AD: n = 79; MCI: n = 113; SCD: n = 314; CON: n = 192) and cerebrospinal fluid Aβ42/40 (AD: n = 41; MCI: n = 64; SCD: n = 139; CON: n = 77); and (B) effects of vascular‐related lesions, here WMH. Result The CV and rCV of the precuneus and middle cingulum indicated increasingly reduced BOLD fluctuation across the clinical groups towards AD. Interestingly, we observed increases in rCV in the basal ganglia and frontal white matter in AD compared with CON. Of note, lower CSF Aβ42/40 (more pathological) was associated to reduced CV and rCV in the precuneus and with lower rCV in the right angular gyrus. Subjects with higher WMH volume showed widespread reductions of CV in white matter near the left angular gyrus and reduced rCV in large portions of white matter and subcortical gray matter. Conclusion The AD spectrum exhibits altered BOLD fluctuations that are at least partially tied to actual amyloid differences. Larger WMH are associated with reduced BOLD signal fluctuations consistent with widespread white matter pathology ‐ beyond the effects of diagnosis. We argue that rCV is a useful complement to CV to detect these changes that might reflect cerebrovascular impairment.