bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between accelerated long‐term forgetting of Complex Figure Drawing, cerebral amyloid deposition, brain atrophy and serum neurofilament light in 73‐year‐olds
Authors: Lu Kirsty , Keshavan Ashvini , Baker John , Nicholas Jennifer M , Street Rebecca E , Keuss Sarah E , Coath William , James Sarah‐Naomi , Weston Philip SJ , Murray‐Smith Heidi , Cash David M , Malone Ian B , Wong Andrew , Fox Nick C , Richards Marcus , Crutch Sebastian J , Schott Jonathan M 
Published: December 2023

AbstractBackgroundAccelerated Long‐term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer’s disease pathology in older adults, and how memory selectivity may influence which material is forgotten.MethodParticipants in ‘Insight 46’, a sub‐study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed cognitive and neuroimaging assessments at two time‐points (baseline at age ∼70; follow‐up ∼2.4 years later). At follow‐up, we assessed Complex Figure Drawing (copy; immediate recall; 30‐minute recall; 7‐day recall). Complex Figure items were categorized as ‘outline’ or ‘detail’ (Fig1), to test the hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies.ALF scores were calculated as the proportion of material retained after 7 days, relative to 30 minutes. Rates of cerebral atrophy between baseline and follow‐up were quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status (positive/negative) was determined from 18F‐Florbetapir‐PET. Baseline serum neurofilament light (NfL) was quantified (Quanterix Simoa assay).Multivariable regression models were used to investigate the effects (mutually adjusted) of β‐amyloid status, BBSI and NfL on ALF in n = 316 clinically‐normal individuals (50% female; 22% β‐amyloid positive; 30% APOE‐ε4 carriers), and to explore interactions between these predictors, adjusting for potential confounders including prospectively‐collected childhood cognitive ability and education.Result‘Outline’ items were better retained than ‘detail’ (Fig1). β‐amyloid‐positive participants had poorer ALF scores for ‘outline’ (but not ‘detail’) items (Fig1C; Table 1). Unexpectedly, higher NfL was associated with scores for ‘outline’ items (Table 1). Greater rate of cerebral atrophy predicted poorer retention among participants with elevated β‐amyloid and higher NfL (Table 1; Fig2).ConclusionThese results provide evidence of associations between biomarkers of brain pathologies and ALF in 73‐year‐olds. Interactions between different biomarkers merit further exploration. ALF may be a sensitive outcome measure for therapeutic trials in preclinical AD. Better retention of ‘outline’ (vs. ‘detail’) items illustrates the strategic role of memory selectivity.
Higher Dietary Inflammatory Index scores are associated with higher beta‐amyloid deposition in the Framingham Heart Study
Authors: Lent Debora Melo , Beiser Alexa S. , Yuan Changzheng , Jacques Paul F , Ghosh Saptaparni , Thibault Emma G. , Fakhri Georges El , Decarli Charles , Johnson Keith A. , Vasan Ramachandran S , Seshadri Sudha , Himali Jayandra Jung , Jacob Mini E 
Published: December 2023

AbstractBackgroundHigh Inflammatory content of diet enhances systemic chronic inflammation, a pathway which plays an important role in the development and progression of dementia. We investigated the cross‐sectional relationships between long‐term Dietary Inflammatory Index (DII) scores and beta‐amyloid(Aβ) and tau Positron Emission Tomography(PET) among participants of the community‐based Framingham Heart Study(FHS).Method343 adults (mean age 58 years [standard deviation (SD)], 10; 51% women]) completed a validated 126‐item Food Frequency Questionnaire (FFQ). We created a DII score (based on the published method by Shivappa et al. 2014) based on previous studies linking individual dietary factors to six inflammatory markers (i.e. C‐reactive protein, interleukin (IL)‐1β, IL‐4, IL‐6, IL‐10 and tumor necrosis factor‐alpha), consisting of 34 components. A cumulative DII score was calculated by averaging across two FFQs (administered at FHS Generation 2(GEN2) examination cycles 8(2005‐2008) and 9(2011‐2014), and at Generation 3(GEN3) examination cycles 2 (2008‐2011) and 3 (2016‐2019). Cumulative DII scores were examined as a continuous variable and using median‐split(‐1.11). Aβ and tau PET examinations were conducted(2016‐2021) using synthesized 11C‐Pittsburgh compound B(PiB) and/or F‐18‐flortaucipir(FTP) tracers. Examination cycles 9(GEN2) and 3(GEN3) were considered as study baseline. We used linear regression to relate the cumulative DII score to Aβ (Fronto‐lateral‐retrosplenial uptake(FLR) and precuneus) and tau (entorhinal, inferior temporal, rhinal, cortical composite and global composite) PET regions.ResultHigher cumulative DII scores, as compared to DII scores below the median, were associated with higher amyloid precuneus region (β±SE, 0.023±0.011,p = 0.042) after adjustment for age, age‐squared, sex, camera and time between DII exam and PET scan exam. No other relationships were observed between DII and Aβ and tau PET. Interaction analyses showed interactions between DII (median‐split) and age (median‐split 58y) when testing association between median‐split DII and Aβ regions and tau global composite region. Stratified analyses showed relationships between higher DII vs. below median DII and higher amyloid FLR and precuneus region (0.055 ± 0.055,p = 0.037; 0.050±0.022,p = 0.022,respectively) among individuals aged 58y>, but not among individuals <58y (‐0.004±0.006,p = 0.947;0.000±0.000,p = 0.999,respectively). There were no significant interactions by sex and apolipoproteinE4 status in the association between DII and Aβ and tau PET.ConclusionHigher DII scores were associated with increased Aβ deposition.
Investigating lysosomal exocytosis as a pathway of beta‐amyloid release from neurons
Authors: Tsang Adrianna R , Seah Claudia , Krupa Jordan M , Pasternak Stephen H 
Published: December 2023

AbstractBackgroundThe endosomal‐lysosomal system has long been linked to the production of beta‐amyloid (Aβ), but the specific intracellular compartments involved in Aβ secretion remain contentious. Conventionally, lysosomes are associated with Aβ degradation, yet studies have also shown that lysosomes are a site of Aβ accumulation. Lysosomal exocytosis is a major secretory pathway in non‐neuronal cells, but few studies have investigated this pathway in neurons. This project examined the role and mechanism of lysosomal exocytosis in neurons, and we hypothesized that lysosomal exocytosis is a pathway for Aβ secretion from neurons.MethodsWe have established human iPSC‐derived neurons in culture, including cells bearing the APP Swedish mutation. Cells were transduced with pH sensitive fluorescent (pHluorin/pHmScarlet) tagged compartment markers to examine neurosecretory granules (synaptophysin), early endosomes (Rab5), late endosomes (Rab9) and lysosomes (LAMP1). Cells were loaded with fluorescent exogenous Aβ or Amytracker to label endogenous Aβ. We then stimulated secretion with ionomycin and used live cell Total Internal Reflection Fluorescence (TIRF) microscopy to examine molecular events occurring within 250 nm to the plasma membrane. shRNA against proteins known to be involved with lysosomal secretion (Rab27b, Munc13‐4 and synaptotagmin‐7) were used as controls. Imaris software was used to analyze the number and timing of lysosomal secretory events and the secretion of Aβ.ResultsAs previously reported, exogenous Aβ in wild‐type cells and endogenous Aβ in APP Swedish cells accumulates in lysosomes, but not in early endosomes. TIRF microscopy captured videos of lysosomes approaching and fusing with the plasma membrane. Fusion appears as a reduction in normal fluorescent LAMP1 signal and an increase in pH sensitive fluorescent protein marker signal (reflecting the loss of luminal acidity due to fusion). Intracellular Aβ was released from neurons as lysosomes fused with the plasma membrane, seen as a simultaneous decrease in fluorescent Aβ labelling. Silencing of Rab27b significantly reduced lysosomal exocytosis and Aβ secretion, which confirmed that this is a lysosomal process.ConclusionOur results demonstrate that lysosomal exocytosis is a novel secretion pathway for Aβ in human neurons and identify potential pharmacological targets that regulate clearance of Aβ.
GFAP Upregulation by Astrocytes May Attenuate Phospho‐Tau Levels in a Tauopathy Mouse Model
Authors: Muñoz‐Castro Clara , Healey Molly A. , Jaisa‐Aad Methasit , Jayakumar Rojashree , Alla Srinija , Kashlan Zane D. , Noori Ayush , Fan Zhanyun , Calvo‐Rodriguez Maria , Das Sudeshna , Hudry Eloise , Hyman Bradley T. , Serrano‐Pozo Alberto 
Published: December 2023

AbstractBackgroundAstrocytes react to amyloid‐β plaques and phospho‐tau (pTau) neurofibrillary tangles in the Alzheimer’s disease brain but their net effect on these Alzheimer’s neuropathological hallmarks remains controversial. A well‐known feature of these so‐called “reactive astrocytes” is the upregulation of the intermediate filament glial fibrillary acidic protein (GFAP), which is thought to be necessary for astrocyte process motility and glial scar formation. Here we asked whether this cytoskeletal remodeling helps reactive astrocytes control the burden of pTau species and/or protect synapses and neurons.MethodWe overexpressed human GFAP isoform 1 specifically in astrocytes of 4‐month‐old, sex‐balanced, THY‐Tau22 mice (Thy1.2‐MAPT
G272V/P301S 1N4R, GFAP mice, n = 11)—when neurofibrillary tangles start to appear in the hippocampal CA1 subfield—using a viral transfer strategy with single retro‐orbital intravenous injection of AAV‐PHP.B (2.5×1011 vg) and the gfaABC1D promoter. We euthanized the mice at 11 months of age (i.e., prior to the tauopathy plateau) and performed immunohistochemical and/or biochemical analysis of astrocyte, tau, and synaptic markers. Negative control groups consisted of THY‐Tau22 littermates injected with either phosphate‐buffered saline (PBS mice, n = 9) or an AAV‐PHP.B vector encoding the enhanced green fluorescent protein (EGFP mice, n = 10).ResultsImmunohistochemistry confirmed the astrocyte‐specific expression of human GFAP with an apparent integration in their intermediate filament network. We observed statistically significant reductions or marginally significant trends toward decrease in hippocampal SDS‐soluble levels AT8/pTauSer202/Thr205 and AT8‐immunoreactive area fraction, and a shift of AT180/pTauThr231 from SDS‐soluble (decreased) to TBS‐soluble (increased) hippocampal protein fractions, in GFAP vs. EGFP and/or PBS mice, but no changes in soluble or insoluble total tau or AT270/pTauThr181 across groups. In the cortex, we detected no changes in soluble or insoluble total tau, AT8/pTauSer202/Thr205, or AT270/pTauThr181 levels, nor in AT8‐immunoreactive area. Lastly, we found no significant differences across groups in brain weight, cortical or hippocampal areas, nor in the cortical levels of synaptophysin, Psd95, or the glutamate transporters Eaat1/Glast‐1 and Eaat2/Glt‐1.ConclusionOur findings indicate that GFAP upregulation by astrocytes—a classic feature of reactive astrogliosis—may attenuate neuronal pTau burden in a tauopathy mouse model. Ongoing work will further elucidate whether this aspect of reactive astrocytes impacts pTau‐induced neurodegeneration.
Association of β‐amyloid, microglial activation, hypermetabolism and hypertrophy in Alzheimer’s disease
Authors: Cai Yue , Shi Dai , Lan Guoyu , Chen Linting , Jiang Yanni , Ma Shaohua , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundPlasma β‐amyloid (Aβ) Aβ42/Aβ40 measured by immunoprecipitation and liquid chromatography‐mass spectrometry assay has been demonstrated useful to identify Aβ PET positive individuals, but the concordance and discordance about the positivity of plasma Aβ42/Aβ40 (Plasma+/‐) and Aβ PET (PET+/‐) have not been fully characterized. Moreover, the association of Aβ deposition, cortical thickness (CTh), glucose metabolism, and microglial activation among different Plasma/PET profiles is poorly understood.MethodIn this study, we classified 173 ADNI participants into Plasma‐/PET‐ (N = 48), Plasma+/PET‐ (N = 43), and Plasma+/PET+ (N = 73) group based on thresholds of composite Aβ PET (18F‐florbetapir, FBP) standardized uptake value ratio (SUVR) (≥1.11) and plasma Aβ42/Aβ40 (≤0.1218). Part of them had longitudinal 18F‐fluorodeoxyglucose (FDG) PET, structural MRI, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) data. Baseline and slopes of FBP SUVRs of 68 Freesurfer‐defined ROIs were compared between different Plasma/PET groups. The associations of regional FBP SUVRs, CSF sTREM2, regional glucose metabolism (reflected in FDG‐SUVR), and CTh (measured using structural MRI) were investigated in different Plasma/PET groups.ResultPlasma Aβ42/Aβ40 might become positive earlier than Aβ PET (Fig.1A, McNemar’s test, p<0.001). Longitudinally, Plasma+/PET‐ participants showed faster rates of Aβ accumulation in bilateral BANKSSTS, supramarginal, and superior parietal cortices whereas demonstrated no difference in baseline FBP SUVRs than Plasma‐/PET‐ participants (Fig.1D‐E). Higher CSF sTREM2 level and faster rate of CSF sTREM2 increase were related to slower rates of Aβ accumulation in BANKSSTS (standardized β (βstd) = ‐0.418, p = 0.002) in Plasma+/PET+ but not in Plasma+/PET‐ individuals (Fig.2A and D). In contrast, thicker CTh (Fig. 4B‐C) and higher glucose metabolism (Fig. 4H‐I) in supramarginal and superior parietal cortices were coupled to faster rates of CSF sTREM2 increase in Plasma+/PET‐ rather than in Plasma+/PET+ individuals.ConclusionThese findings suggest that plasma Aβ42/Aβ40 might become abnormal earlier than Aβ PET, and plasma Aβ42/Aβ40 positive Aβ PET negative (Plasma+/PET‐) individuals accumulate Aβ plaques faster than Plasma‐/PET‐ individuals. Activated microglia may play a role in reducing fibrillar‐Aβ increasing rates in late amyloidosis stage, whereas it may be related to hypertrophy and hypermetabolism in early amyloidosis stages.
Metabolic changes in preclinical AD as detected by magnetic resonance spectroscopy
Authors: Falcon Carles , Garcia Marina , Julia‐Sape Margarida , Montesinos Paula , Sanchez‐Gonzalez Javier , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Carboni Margherita , Suarez‐Calvet Marc , Grau‐Rivera Oriol , Gispert Juan Domingo ,   ALFA study
Published: December 2023

AbstractBackgroundBiochemical changes, which may precede morphological changes, could be of great relevance in profiling preclinical AD. We aimed to investigate metabolic changes using magnetic resonance spectroscopy (MRS) in three AD‐relevant regions: right hippocampus, right angular gyrus, and right precuneus, focusing on myoinositol due to its role in glial activity (osmoregulation‐neuroinflammation).MethodThree hundred sixty‐six participants from the ALFA+ cohort underwent three single‐voxel MRS (PRESS sequence, TR = 2000ms; TE = 100ms chosen to invert myoinositol peak for more precise quantitation; volume of interest (VOI): 20×20×20mm3 [25×20×16mm3 for hippocampus]). Figure 1 shows VOI location and MRS samples. Concentrations of N‐acetyl‐containing compounds (NAA) that is a neuronal marker, total creatine (Cr) related to brain energy, myoinositol (mI), choline‐containing compounds (Cho) related to cell proliferation, and glutamate/glutamine were calculated with LCModel in arbitrary units (using water reference) with the default settings and basis set adapted to the acquisition conditions. Concentrations were corrected for VOI CSF content. Remaining VOI gray matter percentage was used as a confounder in all analyses, jointly with age, sex, and APOE‐e4 status (carrier/non‐carrier). We investigated the correlation of MRS metabolite concentrations with CSF concentrations of Aβ42/40 and ptau‐181 as biomarkers for AD (Elecsys®; Roche Diagnostics). For completeness, we also checked the dependency of MRS metabolites on age. MRS not meeting QA criteria were discarded (Cramer‐Rao lower bounds >20 for any of the metabolites or imprecise VOI location). The statistical threshold was set to p<0.05 for all the analyses.ResultTable 1 shows characteristics of the subsamples with MRS in each location. Higher myoinositol levels in hippocampus and angular gyrus were associated with lower CSF Ab42/40, but not in the precuneus, where it was associated with higher Cr/Cho ratio. Higher Cr and NAA were positively associated with higher CSF p‐tau181 levels in the angular gyrus. NAA was negatively associated with age on cortical regions, as well as Cr on the angular gyrus. Table 2 summarizes the main results.ConclusionMRS allowed determination of differential metabolite changes in AD‐related regions in preclinical AD. Further research is warranted to better characterize the nature of these metabolic changes and determine their impact on longitudinal outcomes of these participants.
Neurobehavioral Manifestations and Outcomes in Autoimmune Encephalitis: A Retrospective Study
Authors: Nanthasi Witsarut , Jitpapaikulsarn Jiraporn , Senanarong Vorapun , Prayoonwiwat Naraporn , Rattanabannakit Chatchawan 
Published: December 2023

AbstractBackgroundAutoimmune encephalitis (AE) could present with heterogeneous clinical manifestations. Neurobehavioral symptoms were presented diversely in each type of AE and may be misdiagnosed with psychiatric disorders. This study aimed to investigate and categorize the clinical manifestations and evaluate the treatment outcomes in patients with AE.MethodsA retrospective chart review study of AE was done at Siriraj Hospital, Mahidol University. The data between 2009‐2022 were extracted. Thirty‐seven patients were diagnosed with AE. Clinical manifestations were collected and classified into four categories: neurological, cognitive, neuropsychiatric manifestation, and autonomic dysfunction.ResultsAmong 37 patients who were diagnosed with AE, 32 patients (87.2%) were seropositive with ten different antibodies identified, and five patients (12.8%) were seronegative. The most commonly identified antibodies were anti‐NMDAR (n = 13, 33.2%) and anti‐LGI1 antibodies (n = 8, 20.5%). The neurological manifestation was most presented (92.3%), followed respectively by neuropsychiatric symptoms (76.9%), cognitive impairment (69.2%) and autonomic dysfunction (23.1%). The most frequent clinical features (>30%) were seizure (69.2%), memory impairment (64.1%), sensorium disturbance (51.3%), executive dysfunction (51.3%), abnormal movement (46.2%), and sleep problem (33.3%). All patients with anti‐NMDAR encephalitis had at least one neuropsychiatric symptom, which predominated in behavioral change (92.3%) compared with patients with other antibodies or seronegative (p = 0.02), such as agitation, aberrant motor behaviors, sleep and appetite change. Autonomic dysfunction was found only in anti‐NMDAR encephalitis patients (p<0.01), whereas the proportion of cognitive impairment and neurological deficit were not different among those with or without anti‐NMDAR antibodies. In this study, none of the patients presented solely psychiatric symptoms. The median following‐up duration after diagnosis was 38 weeks (IQR 14‐137). Treatment outcomes at 6‐12 months showed improvement or resolution of symptoms, but five patients (13.5%) developed emerging mood changes, particularly depression and irritability. Cognitive performance measured by Montreal cognitive assessment demonstrated improvement at 6 months of follow‐up (from 15.12±6.89 to 24.00±3.86, p<0.01) but not at 12 months.ConclusionsAE had various manifestations. Most of them had a combination of symptoms in the neurological, psychiatric, cognitive, and autonomic domains. A sole neuropsychiatric manifestation was rarely presented in AE. The symptoms showed improvement at 6‐12 months after treatment.
Cognitive Assessment for Tagalog Speakers (CATS): A pilot study
Authors: Deleon Jessica 
Published: December 2023

AbstractBackgroundAs the US population of Asian Americans and Pacific Islanders (AAPI) over the age of 65 increases, the incidence of Alzheimer’s disease and related disorders (ADRD) in this group is expected to triple between 2008 and 2030. This group includes over 4 million Filipino Americans, who comprise the largest AAPI population in California and 10 other states. Although there is scarce literature detailing the prevalence of dementia among AAPI subgroups, one study found that Filipino Americans had the highest incidence rate of dementia (Mayeda et al., 2017). Despite the expected increase in the number of Filipino Americans with ADRD, no studies to‐date have validated neuropsychological measures in the United States for speakers of Tagalog (Filipino), one of the major languages spoken by Filipino Americans and the 4th most widely spoken language in the US. A major barrier to dementia care and diagnosis is the lack of linguistically and socioculturally appropriate cognitive tasks for Tagalog speakers. To address this need, we developed and piloted the Cognitive Assessment for Tagalog Speakers (CATS), the first neuropsychological battery for the detection of ADRD in Filipino American Tagalog speakers.MethodWe translated, adapted, and constructed de novo to measure performance across four main cognitive domains: visual/verbal memory, visuospatial functioning, speech and language, and frontal/executive functioning. Tasks were developed with a team of bilingual English/Tagalog and bicultural Filipino American/Canadian experts, including a neurologist, speech‐language pathologist, linguist, and neuropsychologist.ResultTo‐date, the CATS battery has been administered to 15 healthy control participants (age 61.8 ± 5.4 yrs, 5M/10F) at the University of California, San Francisco. These preliminary results show the feasibility of the measures but also demonstrated the need to consider effects of bilingualism, language typology, and cultural factors in the interpretation of results.ConclusionThis project will lay the groundwork for norming and validation studies and will help solidify connections to a population that has been underrepresented in ADRD research. As we move towards treatment and cure of ADRD, linguistically and culturally appropriate cognitive tests become even more important for equitable care.