bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking amyloid to clinical outcome: A quantitative semi‐mechanistic model based on the A/T/N biomarker framework to simulate the natural history of Alzheimer’s disease and the effects of anti‐amyloid treatment
Authors: Mazer Norman A , Hofmann Carsten , Lott Dominik , Gieschke Ronald , Klein Gregory , Boess Frank , Grimm Hans Peter , Kerchner Geoffrey A. , Baudler Monika , Smith Janice , Schobel Scott , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundAccording to FDA’s literature review of clinical trial data from a number of anti‐amyloid antibodies, a “clear relationship” was demonstrated between the extent of amyloid plaque removal measured by amyloid PET and the magnitude of clinical benefit measured by the placebo‐corrected difference in the CDR sum of boxes (CDR‐SB). To understand this relationship from a theoretical perspective we developed a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework (the Q‐ATN model) in order to simulate the natural history of disease progression and the effects of anti‐amyloid therapy.MethodPublished data and biologically plausible mechanisms were used to construct, calibrate and validate the components of the Q‐ATN model (anti‐amyloid effect, amyloid PET, tau PET, cortical thickness [CT] and clinical outcome [CDR‐SB]). A parabolic input function was used to describe the annual rate of increase of the amyloid PET level in placebo patients (in Centiloids/Yr) as a function of the baseline level. Clinical trial simulations corresponding to mean treatment responses were made for different anti‐amyloid antibodies using individualized pharmacokinetic (PK) and pharmacodynamic (PD) models of the anti‐amyloid effect. A 5‐Yr simulation of gantenerumab treatment, based on the dosing regimen employed in the ongoing phase 3 GRADUATE trials (NCT03444870; NCT03443973), was performed to illustrate the predicted long‐term effects of gantenerumab maintained at the target dose.ResultThe simulated time‐course of biomarkers and clinical outcomes were consistent with natural history studies and described the effects of several anti‐amyloid antibodies observed in trials with positive and negative outcomes. Figure 1A‐D shows the simulated 5‐Yr time‐course of gantenerumab and placebo treatment on A. amyloid PET; B. tau PET; C. medial temporal cortical thickness and D. CDR‐SB. The model predicts that the difference in CDR‐SB between active and placebo groups increases markedly with the time of treatment, reaching ‐5.2 units at the 5‐Yr endpoint of the simulation.ConclusionThe Q‐ATN model provides a novel theoretical approach for linking amyloid to clinical outcome based on the A/T/N framework. It illustrates the predicted disease‐modifying potential of gantenerumab – with increasing treatment benefits over time. The predictions of the Q‐ATN model will be compared with forthcoming clinical trial data.
Incident Dementia and Long‐Term Exposure to Constituents of U.S. Fine Particle Air Pollution: A National Cohort Study
Authors: Shi Liuhua 
Published: December 2022

AbstractBackgroundGrowing evidence suggests that PM2.5 likely increases the risks of neurological disorders, yet little is known about the relative contributions of different constituents. Understanding constituent‐specific effects are critical to targeting emission reductions of specific sources with the greatest health protection.MethodWe conducted a nationwide population‐based cohort study (2000‐2017), by integrating the Medicare Chronic Conditions Warehouse database and two sets of high‐resolution, multiple‐species, air pollution datasets to investigate the impact of long‐term exposure to PM2.5 constituents on incident dementia and Alzheimer’s disease (AD). and home health‐care claims. Hazard ratios for dementia and AD were estimated using single‐ and multi‐constituent Cox proportional hazards models, and penalized splines were used to evaluate potential nonlinear concentration‐response relationships.ResultsOf the 18.5 million dementia and 19.2 million AD individuals within these cohorts, 31.5% and 14.6% developed dementia and AD events, respectively. From the single‐pollutant models, an interquartile range (IQR) increase in PM2.5 mass was associated with an increase in dementia incidence ranging between 6‐7% using two exposure datasets. For different PM2.5 constituents, associations remained significant in black carbon (BC), organic matter (OM), sulfate (SO4
2−), and ammonium (NH4
+). Incident dementia was observed to have the strongest association with increases in exposure to SO4
2− and BC (10‐11% increase and 4‐6% per IQR increase, respectively). Effect estimates for AD were even larger. For both endpoints, all constituents had largely linear concentration‐response relationships in the low exposure range, but most tailed off at high exposure concentrations, particularly for AD.ConclusionOur study suggests that long‐term exposure to PM2.5 is significantly associated with increased incident dementia and AD, and that the different PM2.5 constituents may elicit differential neurotoxicity. Reduction of PM2.5 emissions, especially for the main sources of BC and SO4
2−, may reduce the burden of dementia or AD in the aging US population.
Medial temporal lobe subregional atrophy patterns in early‐ and late‐onset amnestic Alzheimer’s disease
Authors: Wuestefeld Anika , Wutt Hmon , Baumeister Hannah , Berron David , Binette Alexa Pichet , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , van Westen Danielle , Hansson Oskar , Wisse Laura EM 
Published: December 2022

AbstractBackgroundThe medial temporal lobe (MTL) is hypothesized to be relatively spared in early‐onset compared to late‐onset Alzheimer’s disease (AD). However, detailed examination of MTL subfields comparing amnestic early‐ and late‐onset AD is lacking. We investigate MTL subfield atrophy patterns in individuals with amnestic early‐ and late‐onset cognitive impairment (EOCI and LOCI).MethodsCognitively impaired (mild cognitive impairment and dementia) adults from the BioFINDER‐2 study with memory impairment (>1.5SD age‐ and education‐specific norms), amyloid‐beta (Aβ+ based on CSF Aβ42/40), and tau positivity were included (Table 1). [18F]RO948‐PET standardized uptake value ratios (SUVRs) were calculated for the MTL, and tau‐PET positivity was determined from a temporal meta‐ROI. EOCI individuals were <65 years, LOCI >70 years of age. Self‐reported age‐of‐onset matched with EO/LO status. Two reference groups of Aβ‐ cognitively unimpaired (CU) which were age‐matched to EOCI/LOCI were included. Hippocampal subfield volumes and thickness of entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex were obtained using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted MRI. We focused particularly on BA35, region with earliest tau accumulation. Episodic memory was determined (errors on delayed word‐list recall).ResultsCompared to CU, LOCI showed widespread atrophy across all MTL subfields, while the atrophy pattern in EOCI was slightly more restrictive (Fig. 1). Compared to EOCI, LOCI showed more severe atrophy in hippocampal subfields and entorhinal cortex.There was no difference between EOCI and LOCI for MTL tau‐PET SUVR (Fig. 2).Zooming in on BA35, there was a trend for an association between MTL tau‐PET SUVR and BA35 atrophy in LOCI. This association was stronger for EOCI but non‐significant, likely due to limited power (Fig. 2C). In both groups, smaller BA35 was associated with worse episodic memory (Fig. 3A). In LOCI, higher MTL tau‐PET SUVR was associated with worse episodic memory (Fig. 3B).ConclusionThe findings suggest that MTL tau‐PET uptake and atrophy is present in both amnestic LOCI/EOCI and is related to the observed memory impairment in these groups. The MTL atrophy pattern is more extensive in LOCI, which may be due to longer presence of tau pathology and/or the involvement of comorbid pathologies.
Spatial proteomics in the hippocampi of resistant and resilient individuals as compared to Alzheimer’s disease (AD) and primary age‐related tauopathy (PART).
Authors: Walker Jamie M. , Ajroud Kaouther , Gong Jingjing , Spencer Callen , Zamudia Carlos , Pladies Erica , Solano Leigh , Bieniek Kevin F , Seshadri Sudha , Castellani Rudolph J , Richardson Timothy E. , Flanagan Margaret E 
Published: December 2022

AbstractBackgroundAn intriguing group of individuals, termed “resilient,” demonstrate neuropathologic changes consistent with Alzheimer disease (AD), yet display no cognitive impairment. In addition, there are older individuals who resist the development of AD neuropathologic change despite their age, termed “resistant.” Herein, we analyzed protein expression in the hippocampi around normal and neurofibrillary tangle (NFT)‐bearing neurons in these resistant and resilient individuals as compared to those with AD and primary age‐related tauopathy (PART) with cognitive decline.MethodUtilizing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP) technology, we compared individuals with AD neuropathologic change and dementia to individuals with AD neuropathologic change and no dementia (resilient), as well as PART with dementia and resistant (PART without dementia) cases. The DSP panel allows for spatial analysis of the level of expression of 73 different proteins in multiple regions of interest (ROIs) on formalin‐fixed paraffin‐embedded sections. We analyzed hippocampal sections, with our ROIs being NFT‐bearing neurons, non‐NFT‐bearing neurons, and their surrounding microenvironments (non‐neuronal cells and neuropil), including a comparison of entorhinal cortex, CA1 and CA2 subregions (Figures 1 and 2).ResultAnalyses comparing NFT‐bearing neurons to non‐NFT‐bearing neurons, revealed 22 proteins with differential expression, including various p‐tau epitopes, Neprilysin, ADAM10, IDE and GPNMB (Figure 3). Comparing resilient and AD NFTs, we identified 17 proteins with differential expression, including Park 5, HSC70 and VPS35 (Figure 4). The microenvironment of the resistant compared to others highlighted several proteins with differential expression including GFAP, NRGN and NEFL (Figure 5). A comparison of NFT‐bearing neurons in non‐demented cases displayed regional protein expression differences between entorhinal and CA1 including alpha‐synuclein and CSF1R. Distinct regional protein expression differences in NFT‐bearing neurons in demented cases were also identified including EMP1 and ATG12 (Figure 6).ConclusionIn conclusion, using a novel spatial proteomic technique, we have demonstrated that resistant and resilient individuals display lower levels of inflammation and upregulation of protective pathways, that in turn lead to maintenance of neuronal integrity. In addition, although the resistant and resilient harbor PART and AD pathology (respectively), we have identified protein expression differences that may further our understanding of the mechanisms by which the resistant and resilient evade cognitive decline.
Neurofilament light chain cannot be measured in urine to distinguish frontotemporal dementia with primary psychiatric diseases
Authors: van Engelen Marie‐Paule E. , Heijst Hans , Willemse Eline A.J. , Oudega Mardien L , Vermunt Lisa , Scheltens Philip , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundClinical overlap of the behavioral variant of FTD and primary psychiatric diseases (PPD) hampers diagnostic distinction, leading to frequent misdiagnosis and diagnostic delay. NfL in CSF and blood has shown great potential to accurately distinguish bvFTD from PPD and controls. Measurement of NfL in urine would be a minimal invasive, patient‐friendly biomarker assessment and thereby beneficial for future clinical implementation. We aimed to evaluate the diagnostic value of urine NfL concentration to distinguish bvFTD from PPD and controls and to assess if urine and serum NfL levels correlate.Method55 subjects (n = 19 FTD, n = 19 psychiatric patients: functional neurologic disorder n =2; obsessive compulsive disorder n= 1; unspecified mental disorder n =1; bipolar disorder, depressive phase n =1; depression, n = 6; adjustment disorder n = 3; anxiety disorder n = 1; autism spectrum disorder n =1; personality disorder n =2; somatic symptom disorder n = 2, and n = 17 controls) were included with available paired urine and serum samples. All subjects underwent standardized extensive diagnostic assessment. Samples were analyzed with the ultrasensitive SIMOA NfL assay. NfL group comparisons were performed adjusted for age and sex.ResultsIn the majority of the cohort NfL concentrations were not detectable in urine (n = 6 samples above lower limit of detection (0.038 pg/ml): n = 5 FTD, n =1 PPD). The frequency of a detectable NfL level in urine in the FTD (5/19) group did not differ from PPD (1/19); Fisher Exact‐test p = 0.180). In the individuals with detectable urine NfL values there was no correlation between the urine and serum NfL levels. As expected, serum NfL levels were higher in bvFTD compared to psychiatric patients and controls (p < 0.000), adjusted for age and sex.ConclusionOur results implicate that using urine as matrix for NfL analysis is not suitable.
Association of Apathy with Amyloid‐β and Tau in Cognitively Unimpaired Older Adults: Findings from the Harvard Aging Brain Study
Authors: Katz Zoe S , Mimmack Kayden J. , Marshall Gad A , Blacker Deborah , Amariglio Rebecca E. , Munro Catherine E , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Yang Hyun‐Sik , Gatchel Jennifer R 
Published: December 2022

AbstractBackgroundApathy is one the most common neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) and is associated with elevated AD pathology in cognitively impaired individuals. However, it remains unclear if apathy is associated with AD pathology, specifically amyloid‐β and tau, in cognitively unimpaired (CU) older adults. Therefore, we examined cross‐sectional relationships between apathy and neuroimaging AD biomarkers in CU older adults from the Harvard Aging Brain Study (HABS).MethodHABS is a prospective cohort study that enrolled CU older adults. A random subset of HABS participants (n = 142, age: 80.53 ±6.0, 57% female) and their study partners (SP) completed the Apathy Evaluation Scale‐Self (AES‐S) and ‐Informant (AES‐I). The AES consists of 18 items rated on a 4‐point Likert‐type scale; lower scores indicate greater apathy. We used Pittsburgh Compound B (PiB) PET cortical composite distribution volume ratio to measure amyloid‐β (Aβ), and flortaucipir (FTP) PET standardized uptake value ratio in two regions (bilateral entorhinal (ER) cortex and inferior temporal (IT) cortex) to capture regional tau. We assessed the association of AES‐S or AES‐I (dependent variable) with Aβ, or each of the two regional tau values (independent variable), in linear models adjusting for age, sex, and education. We then explored Aβ‐independent associations between regional tau and AES‐I/AES‐S, by additionally adjusting for Aβ in each tau model.ResultElevated Aβ (β = ‐3.7, p = 0.015) and ER Tau (β = ‐6.0, p = 0.016) were associated with lower AES‐I, while IT tau was not (p = 0.14). None of the AD pathology measures were associated with AES‐S (all; p>0.23). ER tau was no longer associated with AES‐I once Aβ was also adjusted for in the model (β = ‐4.4, p = 0.100).ConclusionGreater Aβ and tau levels were associated with higher apathy in CU older adults. Our findings imply that even in CU older adults, apathy is closely related to AD pathology may be more accurately measured by study partner report than self‐report, which may reflect a measurement property of this NPS. Further study of apathy in preclinical stages is needed to provide understanding of potential interventions to prevent or delay behavioral symptoms of AD.
The gut microbiome is associated with markers of cerebral small vessel disease
Authors: Fongang Bernard , Satizabal Claudia L , Kautz Tiffany F , Himali Jayandra J , Ramnik Xavier , Cavazos José E. , Mahaney Michael C , Maestre Gladys E , DeCarli Charles S. , Vasan Ramachandran S , Seshadri Sudha 
Published: December 2022

AbstractBackgroundCerebral small vessel disease (cSVD) is a major cause of cognitive impairment and dementia in the elderly. Dysregulation of the gut microbiome has been linked to cSVD, stroke, and dementia in human and animal studies. However, whether dysbiosis is associated with markers of cSVD is unclear. We aimed to assess the cross‐sectional association between the gut microbiome and MRI markers of cSVD and executive function in the Framingham Heart Study (FHS).MethodWe included FHS participants from the Third‐generation cohort without a history of stroke or dementia. We estimated the gut microbiota composition using 16S rRNA gene sequencing. MRI markers of cSVD included white matter hyperintensities (WMH) and peak width of skeletonized mean diffusivity (PSMD). Executive function was assessed as the difference between the Trail Making Test (TMT) part B and A. We used multivariable regression analysis to evaluate the association between the gut microbiota and WMH, PSMD, and TMT, adjusting for age, age2, sex, BMI, and education. Additionally, we used differential abundance analysis to explore extremes of cSVD markers dichotomized by their distribution with the upper quintile representing the least healthy group. Finally, we used PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to gain insight into the functional profiles of the underlying microbial communities.ResultOur sample included 972 participants (age: 55 ± 10 years, 56% female). Using multivariable models, we found that greater abundance of genera Pseudobutyrivibrio and Ruminococcus were associated with lower (healthier) WMH and PSMD (p‐values < 0.001), as well as better executive function (p‐values < 0.01). Furthermore, the differential analysis indicated a lower abundance of the genus Prevotella in the group of participants with the highest (least healthy) PSMD and WHM (p‐values < 0.05). Finally, functional analyses using PICRUSt implicated various KEGG pathways, including carbohydrate metabolism, glycosaminoglycan, and fatty acid biosynthesis previously associated with cognitive performance.ConclusionOur study suggests abundance of certain gut bacteria in genus Pseudobutyrivibrio, Ruminococcus, and Prevotella, that produce butyric acid and other metabolites used by the human brain, are associated with healthier brain vasculature and better cognitive function in middle‐aged healthy adults.
Phenotyping of lenses from eyes of P301S tau mice
Authors: Moncaster Juliet A , Minaeva Olga , Goldstein Lee E 
Published: December 2022

AbstractBackgroundWe previously discovered that Aβ accumulates in the supranuclear region of the lens in the eyes of people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010) and also in the Tg2576 APP swedish mutation AD mouse model (Moncaster et al., 2022). Aβ interacts with crystallin proteins in the lens to create light scattering aggregates that eventually manifest as cortical cataracts. Tau has previously been reported to be expressed in the lens of the eye (Bai et al., 2007; Zhao et al., 2013). Here we investigated whether cataracts may develop in the P301S tau model.MethodP301S mice were bred and maintained at Boston University School of Medicine. Breeder mice were purchased from Jackson Laboratories, Bar Harbor, ME. Male and Female transgenic and non‐transgenic mice (n = 5‐6 per group) were sacrificed at ages 12‐13 months. This timepoint was chosen as it is the limit of lifespan for P301S transgenic mice. Mice were perfused with phosphate buffer saline, lenses were isolated and then imaged under two different sources of light using a D70 digital Nikon camera and a custom‐adapted Zeiss stereophotomicroscope.ResultThere was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. No cataracts were observed in these lenses at 12‐13 months of age.ConclusionThere was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. Based on our current and previous results, the data suggests that Aβ may play a more significant role in lens pathology in AD than tau.
Using Proteomics Analysis to Identify Cerebrospinal Fluid Biomarkers in Normal Pressure Hydrocephalus
Authors: LaCasse Kathryn , de Geus Matthijs B , Trombetta Bianca A. , Ramirez Christopher E. , El‐Mufti Leena H. , Riley Misha M. , McManus Alison J. , Wills Anne‐Marie , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E. 
Published: December 2022

AbstractBackgroundNormal Pressure Hydrocephalus (NPH) is a neurological condition where there is enlarged ventricular size with normal opening pressure at lumbar puncture. Etiology is uncertain but it is presumed to occur from an imbalance in the production and/or absorption of cerebrospinal fluid (CSF) leading to expansion of the ventricles. Clinical features include gait dysfunction, cognitive impairments, bladder incontinence. Diagnosis is challenging, given a large overlap in clinical and neuroradiological features and co‐morbidity with other more common diseases of aging, especially Alzheimer’s disease (AD) and Lewy body diseases. CSF amyloid and tau biomarkers can be helpful to identify AD pathology but do not exclude concurrent NPH. Currently, there are no biofluid biomarkers to assist in diagnosis of NPH. Here we describe a proteomic discovery pilot to identify candidate protein biomarkers associated with NPH.Method176 banked CSF samples from the MassGeneral Institute for Neurodegenerative Disease biorepository were separated into three groups: NPH (n=30), AD (n=65), and cognitively unimpaired neurological controls (CU‐N; n=81). Diagnoses were established based on comprehensive chart review and CSF AD biomarkers. For proteomic analysis, samples were prepared in batches and analyzed by LC‐MS/MS on an Orbitrap Fusion using a data‐independent acquisition method with non‐overlapping windows from 400‐1000 m/z. Batches were run sequentially, and raw files were searched per batch using Scaffold‐DIA and a custom data‐dependent generated library.ResultFive proteins present in hemoglobulin (HBD and HBB), immunoglobulins (LV39 and KV105), and fibrinogen (FIBA) were increased in NPH compared to AD (Benjamini‐Hochberg adjusted p‐value pAdj <0.05). CSF erythrocyte counts were undetectable in all but one NPH subjects suggesting that a traumatic LP was not the cause of the increased levels. Two neuron associated proteins (VGF and NPTXR) were detected at lower levels in NPH compared to CU‐N subjects (pAdj<0.0001). Alpha‐1‐antichymotrypsin (AACT), was detected at high concentrations both in NPH and AD compared to CU‐N subjects (pAdj<0.02).ConclusionProteomic analysis in NPH may identify novel pathological processes involved in the disease process and aid in the development of biomarkers in NPH.