bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innate immune activation of the NLRP3 inflammasome pathway drives tau pathology
Authors: Ising Christina , Venegas Carmen , Zhang Shuangshuang , Scheiblich Hannah , Schmidt Susanne V. , Vieira‐Saecker Ana , Schwartz Stephanie , Albasset Shadi , McManus Roisin M. , Tejera Dario , Griep Angelika , Santarelli Francesco , Brosseron Frederic , Opitz Sabine , Stunden James , Kayed Rakez , Golenbock Douglas T. , Blum David , Latz Eicke , Buee Luc , Heneka Michael T. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease is characterized by the extracellular accumulation of amyloid beta (Aß), intraneuronal formation of neurofibrillary tangles made of hyperphosphorylated tau and activated microglial cells, the innate immune cells of the brain. Activation of microglia by Aß or other DAMPs results in the assembly of the NLRP3 inflammasome consisting of NLRP3, ASC and Caspase‐1. This leads to subsequent production and secretion of inflammatory mediators including IL‐1β and ASC specks. Here, we investigate a contribution of the NLRP3 inflammasome to the development and progression of tau pathology.MethodTau22 transgenic mice, that express human 4‐repeat tau mutated at sites G272V and P301S under a Thy1.2‐promotor, were crossed into either NLRP3 inflammasome knockout or ASC knockout mice and analyzed before development of tau pathology (3 month of age) and when robust tau pathology is present (11 month of age). Animals underwent behavioral phenotyping, analysis of pathology as well as assessement of microglial activation. Additionally, Tau22/NLRP3‐knockout and Tau22/ASC‐knockout mice received an injection of Aß‐containing APP/PS1 mouse brain derived lysates to study Aß‐induced spreading of tau pathology. For in vitro studies, primary mouse microglia were treated with different forms of tau and analyzed for NLRP3 inflammasome activation.ResultNLRP3 inflammasome activation was increased in fronto‐temporal dementia patients as well as in Tau22 mice. Knockout of ASC or NLRP3 in Tau22 mice decreased levels of active tau kinases while increasing activity of phosphatase PP2A in the hippocampus. This strongly protected from accumulation of hyperphosphorylated, misfolded tau in ASC knockout and more robustly in NLRP3 knockout mice while attenuating behavioral deficits. Furthermore, loss of NLRP3 inflammasome function ameliorated Aß‐induced tau pathology. In vitro, treatment of microglia with tau‐containing mouse brain homogenates or recombinant tau monomers and oligomers resulted in IL‐1β release in a NLRP3‐dependet manner, most likely mediated via TLR4. However, the same concentration of recombinant tau fibrils did not evoke this response.ConclusionThese findings are in line with the hypothesis that innate immune activation represents an important pathogenic factor for tau pathology. In Alzheimer’s disease, early Aß deposition may cause subsequent tau pathology and neuronal demise through NLRP3‐mediated innate immune pathways.
Predicting future regional tau accumulation in preclinical Alzheimer’s disease
Authors: Giorgio Joseph , Jagust William J. , Baker Suzanne L. , Landau Susan M. , Tino Peter , Kourtzi Zoe 
Published: December 2020

AbstractBackgroundCurrent models of AD pathogenesis hypothesise that b‐amyloid induces downstream tau deposition leading to cognitive decline. Here, we use machine learning with baseline data to predict dynamic changes in cortical tau in preclinical AD populations.MethodsUsing individuals from the ADNI (n=307) we train a machine learning algorithm that derives a continuous index using baseline medial temporal atrophy, amyloid‐PET, and APOE genotype. The index is generated to discriminate between cognitively normal (CN) individuals who remained normal over ≥ 3 years (n=145) (34 amyloid positive at baseline) and non‐demented progressing (NDP) individuals (CN/MCI at baseline) who developed dementia (n=162) (135 amyloid positive at baseline) The index combines information from multivariate data to maximise between class separation and minimise within class variability. We test the hypothesis that this index is predictive of future tau accumulation in two out‐of‐sample cohorts. In a separate ADNI cohort (ADNI‐3; 72CN/43MCI) with longitudinal flortaucipir PET(FTP) scans we derived the index and related it to future tau accumulation (FTP‐PET slope over time in Desikan‐Killiany ROIs normalised to eroded subcortical white matter) for individuals classified as NDP. Next, for cognitively normal individuals from the Berkeley Aging Cohort Study (BACS; n=56) we derived the index and tested predictions of regional future rate of tau accumulation for individuals classified as NDP.ResultsThe algorithm using baseline data separated CN from NDP individuals with high accuracy (86.4%). Testing on ADNI‐3 individuals classified 54/115 individuals as NDP. These NDP individuals accumulated global cortical tau 2.8 times faster than non‐NDP individuals (Figure 1); for NDP individuals this index also predicted individual variability in regional future tau accumulation (Figure 2a). For BACS participants classified as NDP (n=23), the individualised regional predictions explain up to 38.5% of the observed variance in longitudinal tau accumulation in the temporal cortex (mean=27%) and 32% of the variance in superior and medial regions of the posterior parietal cortex (mean=23%) (Figure 2b).ConclusionMachine learning derived a continuous prognostic index from baseline data that was capable of predicting changes in regional tau accumulation in both MCI and cognitively normal people. This could have clinical applications in developing clinical trials or furthering our understanding of AD pathophysiological mechanisms.
Associations of nutritional parameters with clinical progression in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer’s disease: The NUDAD project
Authors: Doorduijn Astrid S , de Leeuw Francisca A , de van der Schueren Marian , van de Rest Ondine , Hendriksen Heleen MA , Teunissen Charlotte E , Scheltens Philip , Visser Marjolein , van Der Flier Wiesje 
Published: December 2020

AbstractBackgroundPoorer nutritional status is more often observed in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia compared to patients with subjective cognitive decline (SCD), but it is not known whether nutritional status contributes to clinical progression. Therefore, we investigated longitudinal associations of body mass index (BMI), fat‐free mass (FFM), modified Mini Nutritional Assessment (MNA) score and diet quality with clinical progression in a memory clinic cohort.MethodWe included 219 patients with SCD (age 61±8 years), 135 with MCI (66±8 years) and 197 with AD dementia (67±8 years), with a mean follow‐up of 2±1 years. Nutritional parameters at baseline were transformed into z‐scores. Progression was operationalized as presence of at least one of the following: 1) in SCD, progression to MCI or dementia; in MCI, progression to dementia; in AD dementia, an increase of ≥ 1 point on Clinical Dementia Rating scale; 2) passed away or admitted to a nursing home; 3) self‐reported progression of cognitive symptoms. We used age and sex adjusted Cox proportional hazard models in the total sample and stratified for baseline diagnosis. We performed a sensitivity analysis in amyloid positive patients to determine specificity of results for AD.ResultProgression was observed in 25 (11%) patients with SCD, 45 (33%) MCI and 100 (51%) AD dementia. A lower modified MNA score was associated with a higher risk of clinical progression in the total sample (Table 1). Stratification revealed that the association was mainly attributable to patients with MCI and AD dementia. Lower BMI, FFM and diet quality score was associated with a higher risk of clinical progression in the total sample. After stratification on baseline diagnosis, significance was lost. In amyloid positive patients, a lower modified MNA score was associated with a higher risk of clinical progression, but there were no significant associations for BMI, FFM and diet quality with clinical progression.ConclusionPoorer nutritional status is associated with a higher risk of clinical progression, especially in patients with MCI and AD dementia. This observation provides support for future studies investigating whether improving nutritional status contributes to slowing down clinical progression.
Evaluation of the novel 18F‐labeled PET tracer SMBT‐1 for imaging astrogliosis in healthy elderly controls and A+/T+/(N+) Alzheimer's disease patients
Authors: Villemagne Victor LL , Harada Ryuichi , Dore Vincent , Furumoto Shozo , Mulligan Rachel S , Kudo Yukitsuka , Burnham Samantha C , Krishnadas Natasha , Huang Kun , Yanai Kazuhiko , Rowe Christopher C , Okamura Nobuyuki 
Published: December 2020

AbstractBackgroundNeuroinflammatory changes, characterized by reactive astrocytes and activated microglia, contribute greatly to neurodegeneration throughout the course of Alzheimer’s diseases (AD). Reactive astrocytes overexpress monoamine oxidase‐B (MAO‐B) in the outer mitochondrial membrane. For imaging astrogliosis in the human brain, we developed the novel MAO‐B PET tracer named 18F‐SMBT‐1. We aimed to investigate the binding properties of 18F‐SMBT‐1 in healthy elderly controls and AD patients.MethodsAfter in silico preclinical evaluation were performed for the assessment of binding affinity and selectivity of 18F‐SMBT‐1, 9 participants, 5 healthy elderly controls (3F/2M, 78.5±6.0 yrs, 3 A‐/T‐/(N‐) and 2 A+/T‐/(N‐)) and 4 A+/T+/(N+) AD patients (3F/1M, 76.8±1.4 yrs), underwent 18F‐SMBT‐1 PET, amyloid PET with 18F‐NAV4694, tau PET with either 18F‐MK6240 (n=7) or 18F‐PI2620 (n=2), and 3D‐MPRAGE MRI. While Ab burden was expressed in Centiloids, tau tissue ratios were generated using the cerebellar cortex as reference region. 18F‐SMBT‐1 studies were expressed as SUV or as tissue ratios using the cerebellar white matter as reference region. To ascertain 18F‐SMBT‐1 selective binding to MAO‐B, participants underwent a second 18F‐SMBT‐1 scan after receiving 5mg selegiline twice daily for 5 days.ResultsSMBT‐1 showed strong and reversible binding to MAO‐B, and low binding affinity to other enzymes, receptors and misfolded proteins such as amyloid‐β and tau.18F‐SMBT‐1 yielded high contrast images at 60‐90 min post injection, with high tracer retention in basal ganglia, intermediate in neocortical regions, and lowest in cerebellum which tightly follows the known regional brain distribution of MAO‐B (R2=0.82). In AD patients, 18F‐SMBT‐1 retention was significantly higher in parahippocampus, fusiform and inferior temporal gyrus. More than 85% of 18F‐SMBT‐1 signal was blocked and no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO‐B.Conclusions18F‐SMBT‐1 is the highly selective MAO‐B tracer, which will enable the assessment of astrogliosis in the human brain. The confirmation of these preliminary findings with 18F‐SMBT‐1 will require examination of a much larger series, including participants with MCI and prodromal AD.
AB42 and polyamines: Elucidating a potential mechanism of amyloid‐mediated apoptosis and aggregation
Authors: Sandberg Alexandra A. , Johnson Austin , Fudge Dylan , Melgar Stephanie , Hicks Carrie , Patterson David , Vacano Guido , Margittai Martin , Weismiller Hilary , Harvey Sebastian , Hernandez Luis , Caviedes Pablo , Ledreux Aurélie , Qin Yan , Granholm Ann‐Charlotte , Linseman Daniel , Paredes Daniel 
Published: December 2020

AbstractBackgroundThe dysfunctional accumulation of amyloid beta (Aβ) plaques in neuronal cells is widely regarded as a hallmark sign of Alzheimer’s disease (AD). However, the mechanisms by which Aβ causes the rampant apoptosis that leads to the characteristic memory loss and dementia observed in AD patients are much less understood. In this study, we investigated the regulatory relationship between Aβ42, a particularly toxic member of the Aβ peptide family, and polyamines (PA), a ubiquitous class of molecules associated with cell growth, proliferation, and immune response. Increasing evidence has suggested that the PA pathway is changed in AD. For example, increased levels of enzymes in the PA synthesis pathway and altered PA metabolomics have been found in the AD brain. Here, we sought to investigate the relationship between PA synthesis and disease pathogenesis, specifically Aβ aggregation and in turn, neuronal death.MethodHT22 hippocampal cells were transiently transfected with bicistronic plasmids allowing for expression of DsRed alone or co‐expression with Aβ42. We then examined the effects of Aβ42 on expression of the rate limiting enzyme for PA synthesis, ornithine decarboxylase (ODC) and in turn, PA levels. Irreversible ODC inhibitor, L‐difluoromethylornithine (DFMO) was used to examine effects on Aβ42 aggregation and neuronal apoptosis. Hippocampal tissue from human sporadic AD and age matched controls were also assessed for PA concentration and ODC expression.ResultsWe found that Aβ42 increased PA levels in a dose‐dependent fashion through enhanced expression of ODC in HT22 hippocampal cells. Treatment with DFMO significantly reduced this increase in PA as well as aggregation of Aβ42 and Aβ42‐induced apoptosis. Lastly, levels of spermidine and spermine as well as ODC expression were significantly increased in sporadic AD human hippocampal tissue in comparison to age‐matched controls.ConclusionThese data suggest that increased intracellular concentrations of PA are not only a response to Aβ42, but they also promote Aβ42 toxicity by enhancing aggregation. Secondarily, DFMO may be a novel therapeutic to mitigate Aβ42 toxicity and reduce amyloid plaque load in patients with AD.
Evolution of unawareness of memory decline in individuals with autosomal dominant Alzheimer’s disease
Authors: Vannini Patrizia , Hanseeuw Bernard J. , Gatchel Jennifer R. , Sikkes Sietske A.M. , Alzate Diana , Zuluaga Yesica , Moreno Sonia , Mendez Luis , Baena Ana , Lopera Paula Ospina , Tirado Victoria , Henao Eliana , Acosta‐Baena Natalia , Giraldo Margarita , Lopera Francisco , Quiroz Yakeel T. 
Published: December 2020

AbstractBackgroundWhile loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease (AD) dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the pre‐dementia stages of the disease. Here, we investigated the evolution of memory awareness in the AD‐course in a large cohort of individuals who carry mutations for autosomal dominant AD (ADAD; a population that are genetically determined to develop early‐onset dementia, and have a well‐characterized disease trajectory from pre‐symptomatic to clinical stages) and compared it with family members who do not carry the mutation.MethodsPseudo‐longitudinal analyses using linear mixed‐effect models was used to predict self‐awareness (assessed using an awareness index based on the discrepancy score between participant and study‐partner report on the Memory Complaint Scale (Spanish version),in a total of 2,379 members of a Colombian kindred including 396 ADAD (14.9% impaired) and 1,983 non‐carrier family members (Table 1). Age was entered as a fixed and random factor in the models.ResultsThe mutation carriers complained significantly more than their study‐partner until the mean age of 35, and complained significantly less (unawareness/anosognosia) than their study‐partner around the age of 43 (Figure 1A), approximately 6 years prior to their estimated median age of dementia onset (49yo). Cognitively‐unimpaired non‐carriers complained significantly more than their study‐partners (heightened awareness/hypernosognosia) between ages 20‐60 (Figure 1B). Using the awareness index (Figure 2) we observed a decrease with age (est.=‐0.04 discrepant‐points/year,se=0.02,t=‐2.2,p=0.03) in the non‐carriers and an even steeper decline in the mutation carriers (est.=‐0.21 discrepant‐points/year,se=0.04,t=‐5.1,p=2.8*e‐7). The awareness index was significantly different between groups from age 22.5, indicating less awareness of memory in the mutation carriers as compared to the non‐carriers.ConclusionHypernosognosia was observed in both groups, indicating that heightened awareness of memory function is common and non‐specific in this cohort. In mutation‐carriers, awareness of memory decreased in the pre‐dementia stages, reaching anosognosia 6 years before dementia onset. These findings provide further support for the usefulness of informant‐reported cognitive decline and add to the sporadic AD literature suggesting that individuals who become unaware of cognitive change in preclinical stages may represent a specific risk group to develop AD dementia.
Neuropathologically‐defined subtypes of Alzheimer’s disease
Authors: Murray Melissa E 
Published: December 2020

AbstractBackgroundNeuropathologic studies have demonstrated the importance of recognizing atypical patterns of neurofibrillary tangle pathology in Alzheimer’s disease (AD). Utilizing corticolimbic patterns to operationally classify neuropathologically‐diagnosed AD cases, we identified three subtypes: hippocampal sparing AD, typical AD, and limbic predominant AD (Murray 2011). While amyloid‐β plaque pathology does not differ across AD subtypes (Murray 2015), the frequency of co‐existing pathology does differ.MethodThe FLorida Autopsied Multi‐Ethnic (FLAME) AD cohort was reviewed (Hanna Al‐Shaikh 2019). Co‐existing α‐synucleinopathies was examined, including Lewy body disease and the presence of amygdala predominant Lewy bodies which are often observed in the context of severe AD pathology. The severity of cerebrovascular disease was examined using the modified Kalaria score (Deramecourt 2012), which provides a score from 0‐10.ResultOut of 1361 AD cases, 175 (13%) were classified as hippocampal sparing AD, 1014 (74%) as typical AD, and 172 (13%) as limbic predominant AD. Limbic predominant AD cases were older at death (86 years) compared to typical AD (81 years) and hippocampal sparing AD (72 years) (p<0.001). A higher proportion of limbic predominant AD (26%) and typical AD (26%) had co‐existing Lewy body disease compared to hippocampal sparing AD (14%) (p=0.003). Amygdala predominant Lewy bodies were more frequently observed in limbic predominant AD (25%) compared to typical AD (17%) and hippocampal sparing AD (12%) (p=0.006). Limbic predominant AD has more severe cerebrovascular disease score (median=5, interquartile range 2‐6) compared to typical AD (4, 2‐6) and hippocampal sparing AD (4, 2‐5).ConclusionCorticolimbic patterns of neurofibrillary tangle pathology provide key insight into the neurobiology underlying clinical heterogeneity of AD. We observed a greater frequency of co‐existing pathologies in limbic predominant AD and typical AD. Future biomarker studies and efforts of targeted therapeutics should consider the effect of multiple comorbid pathologies. It will be of great interest to examine how these co‐existing pathologies influence clinical progression and heterogeneity of clinical presentations in Alzheimer’s disease patients.
Social connection, not loneliness, predicts dementia risk in Swedish older adults
Authors: Beam Christopher R , Kim Alice J 
Published: December 2020

AbstractBackgroundGreater loneliness has been found to predict increased dementia risk in older adult populations. Yet, factors rather than loneliness, like objective social connections and depressive symptomatology, may explain away effects of loneliness on dementia risk. In a longitudinal sample of Swedish twins, we examined whether baseline scores and change in loneliness predict dementia risk. Additionally, we examined whether familial factors (shared genes and/or environments) confound the predictive utility of loneliness on dementia status. Finally, we hypothesized the observed effects of loneliness on dementia risk would be greater in women than men.MethodThe sample included 2,543 adult Swedish twins who completed baseline measures of loneliness and survived beyond age 60. Twins were followed until they were diagnosed with dementia, deceased, or lost to follow‐up. Analyses included first fitting latent growth curve models to evaluate change in loneliness over time; Cox regression models to test whether baseline and change in loneliness predicted dementia risk; and biometric regression models to test whether genetic and environmental pathways mediated effects of loneliness on dementia status.ResultLatent growth curve models suggest that loneliness did not change over time. Baseline loneliness did not correlate with dementia status (r = .02, t = 0.82, df = 2574, p = .413), although greater number of close friends/family predicted lower odds of dementia (Odds Ratio: 0.63, .95CI: [0.45,0.88]). As loneliness did not correlate with dementia risk), which were confirmed in biometric regression models: loneliness did not correlate with dementia via genetic or environmental pathways. The only gender difference observed was that women reporting the highest levels of loneliness were diagnosed with dementia at significantly greater rates than men reporting the highest levels of loneliness.ConclusionLoneliness did not predict dementia risk over a 30‐year follow‐up period. Despite these null findings, women reporting the highest levels of loneliness appeared to confer greater dementia risk compared to their male counterparts. Consistent with previous results, social connection (as measured by greater number of close ties) lowered dementia risk, suggesting that measures of social network density may provide greater clinical utility than perceived social isolation.
Tracking neurodegeneration in frontotemporal dementia and Alzheimer’s disease: A comparative study of plasma tau and neurofilament light chain
Authors: Illán‐Gala Ignacio , Lleó Alberto , Karydas Anna M. , Staffaroni Adam M. , Zetterberg Henrik , Sivasankaran Rajeev , Grinberg Lea Tenenholz , Spina Salvatore , Kramer Joel H. , Ramos Eliana Marisa , Coppolla Giovanni , Joie Renaud , Rabinovici Gil D. , Perry David C. , Tempini Maria Luisa Gorno , Seeley William W. , Rosen Howard J. , Boxer Adam L. , Rojas Julio C. 
Published: December 2020

AbstractBackgroundThe comparative clinical utility of plasma Tau and neurofilament light chain (NfL) in frontotemporal lobar degeneration syndromes (FTLD‐S) and Alzheimer’s disease (AD) was determined.MethodWe measured plasma Tau and NfL with Simoa in 265 participants: 167 FTLD‐S, 43 AD and 55 healthy controls (HC), including 82 pathology‐proven cases (50 FTLD‐Tau, 18 FTLD‐TDP, 2 FTLD‐FUS and 12 AD) and 98 participants with amyloid PET. We compared cross‐sectional and longitudinal biomarker concentrations between groups, and studied their correlation with baseline clinical measures of disease severity and cortical thickness and their ability to predict disease progression and survival.ResultPlasma NfL, but not plasma Tau, discriminated between FTLD‐S, AD and HC (AUC = .97, 95% CI .95 – .99, p < .001 for FTLD‐S vs HC, and AUC = .94, 95 CI .89 ‐ .98, p < .001 for AD vs HC). In pathologically‐confirmed cases, plasma NfL levels were higher in FTLD‐TDP (85.6 ± 46 pg/mL), compared to FTLD‐Tau (50.4 ± 26 pg/mL), after accounting for age, and disease severity (p < .001; partial η
2 = .20). High plasma NfL, but not plasma Tau, predicted disease progression in both FTLD‐S (2.3 points increase in CDRsb per log NfL ng/mL increase per time interval, 95% CI 0.4 – 4, FDR‐corrected, p=.007) and AD (2.9 points increase in CDRsb per log NfL ng/mL increase per time interval, 95% CI 0.2 – 5.6, FDR‐corrected, p = .035) and shorter survival (Log‐Rank = 14.4, p < .001) in FLTD‐S. Plasma NfL, but not plasma Tau, correlated with reduced cortical thickness in frontal regions in FLTD‐S and temporoparietal regions in AD. The combination of plasma NfL with plasma Tau did not improve the diagnostic prognostic performance of plasma NfL alone.ConclusionPlasma Tau has limited diagnostic and prognostic value. Plasma NfL discriminates FTLD and AD from healthy individuals and is associated with disease progression in FTLD and AD and may be have important clinical value for prognostic purposes.