bluuebunny/crossref_metadata_2025_split huggingface dataset:
Choroid plexus volume is associated with levels of CSF proteins predominantly expressed by the choroid plexus in non‐demented individuals with AD pathophysiology.
Authors: Delvenne Aurore , Tijms Betty M. , Gobom Johan , Redolfi Alberto , Barkhof Frederik , Zetterberg Henrik , Visser Pieter Jelle , Vos Stephanie J. B. ,   EMIF‐AD MBD study group
Published: December 2022

AbstractBackgroundThe choroid plexus (CP) is a structure located inside the brain ventricles and is responsible for the production of cerebrospinal fluid (CSF), transport of proteins across the epithelium to the CSF and clearance of proteins from the CSF. The CP undergoes changes with aging, which are exacerbated in Alzheimer's disease (AD) and could alter CP functioning. Nonetheless, the relation between CP functioning and AD pathophysiology is still unclear. Here, we investigated the association of CP volume with levels of CSF proteins predominantly expressed by the CP and amyloid positivity in non‐demented individuals.MethodWe included 235 individuals with normal cognition (NC) or mild cognitive impairment (MCI) from the European EMIF‐AD MBD study (49% women, mean age 67.9 (SD 7.9) years). Based on CSF Aβ1‐42 (A, data‐driven cut‐offs) and p‐tau (T, center‐specific cut‐offs), individuals were classified as cognitively normal with normal A and T (controls, n=54). Based on CSF Aβ1‐42, individuals with NC or MCI were classified as amyloid‐positive (CN A+, n=61; MCI A+, n=67). CSF proteomic data were centrally generated using TMT mass spectrometry and 5 CSF proteins with predominant expression in the CP were selected based on the Protein Atlas, Harmonizome and literature (TTR, MFRP, SLC5A5, FOLR1, SOD3). CP and hippocampal volumes on MRI were quantified using FreeSurfer. We used non‐parametric (Spearman) partial correlations corrected for age, gender and total intracranial volume (TIV).ResultLower Aβ42 levels were associated with higher CP volume in MCI (Figure 1). Higher levels of CP predominant expressed proteins were generally associated with increased CP volume in persons with amyloid positivity, in both preclinical and prodromal AD (Table 1). Lower Aβ42 levels were associated with lower hippocampal volume in MCI (Figure 2). Lower hippocampal volumes were associated with higher CP volumes in MCI (Figure 3). Nonetheless, hippocampal volume and the levels of CP predominant expressed proteins were generally not correlated (Table 2).ConclusionOur findings suggest that CP volume is associated with levels of proteins predominantly expressed by the CP in predementia stages of AD. This would suggest CP dysfunction in early AD. This is important for future research and AD treatment development.
Divergent magnetic resonance imaging atrophy patterns in Alzheimer’s disease and primary age‐related tauopathy
Authors: Quintas‐Neves Miguel , Teylan Merilee A. , Morais‐Ribeiro Rafaela , Almeida Francisco , Mock Charles , Kukull Walter A. , Crary John F. , Oliveira Tiago Gil 
Published: December 2022

AbstractBackgroundPrimary age‐related tauopathy (PART) is a pathological disorder characterized by the presence of tau‐positive neurofibrillary tangles (NFTs) and no amyloid‐beta (Aβ) deposition (“definite PART”). Currently, the diagnosis of PART is histologically assessed by the presence of tau positive NFT with Braak staging and a Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Aβ stage of 0.MethodOur study compared brain magnetic resonance imaging (MRI) with neuropathological findings in patients with PART and AD, while assessing the relationship between brain atrophy and clinical impairment. We analysed 233 participants: 32 with no plaques (“definite” PART ‐ CERAD 0), and 201 cases within the AD spectrum, with 25 with sparse (CERAD 1), 76 with moderate (CERAD 2) and 100 with severe (CERAD 3) degree of neuritic plaques.ResultUpon correcting for age, sex and age difference at MRI and death, there were significantly higher levels of atrophy in CERAD 3 compared to CERAD 1‐2 and a trend compared to CERAD 0. In the anterior temporal region, there was a trend for higher levels of atrophy in CERAD 0 compared to CERAD 1. We then assessed the correlation between regional brain atrophy and CDR‐sum‐of‐boxes score for PART and AD, and found that overall cognition deficits are directly correlated with regional atrophy in the AD continuum, but not in definite PART. We further observed correlation between regional brain atrophy with multiple neuropsychological metrics in AD, while PART showed only specific correlations between language deficits and anterior temporal atrophy.ConclusionOverall, these findings support PART as an independent pathologic process from AD.
Enabling Characterisation of the NAD+ Biosynthesis Pathway via in vitro CEST MRI
Authors: Slade Festus , Villano Daisy , Luo Jierong , Longo Dario , Collingwood Joanna F 
Published: December 2022

AbstractBackgroundThe Chemical Exchange Saturation Transfer (CEST) MRI properties of six metabolites required for synthesis of coenzyme nicotinamide adenine dinucleotide (NAD+) and to evaluate the potential for clinical imaging of altered NAD+ regulation in neurodegenerative disordersMethodCEST images of metabolites in the NAD+ biosynthesis pathway were acquired at physiological temperature with high‐field MRI (9.4T) running a modified magnetisation transfer (MTR) prepared RARE sequence over a range of saturation powers and frequency ofsets, for pH values 5.5‐7.4. CEST data were fitted using spline interpolation, the exchange rate was calculated, and frequency specific MTR maps were generated using pixelwise analysis.ResultTryptophan, nicotinamide, nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and NADH were evaluated. At pH 7.4, all molecules exhibited CEST contrast between 0.1 and 0.9 ppm, originating from the OH hydroxyl proton. NADH exhibited up to 15% CEST contrast in a B1 field of 2.4µT from its fast‐exchanging amine groups at 2 and 3 ppm, and showed a positive dependence of CEST efciency on pH. Tryptophan exhibited three independent peaks at 0.7, 2.6, and 5.4 ppm corresponding to pH 6.7, 5.5 and 7.4. NMN showed high CEST contrast at 0.7ppm originating from its phosphorous OH enabling higher CEST efciency due to enhanced charge delocalisation (Fig.1).ConclusionThis in vitro feasibility study demonstrates signal detection and characterization of NAD+ biosynthesis pathway precursor molecules over precise temperature, concentration and physiological pH ranges. All molecules exhibited a peak at 0.7 from the hydroxyl group with NMN showing highest CEST efficiency due to phosphate charge delocalisation. NADH showed a peak at 2 and 3ppm from amine group protons and a dependency on temperature and pH.
Using children’s drawings as implicit measurements in future Alzheimer’s research for the detection and alteration of negative stereotyping
Authors: Bormans Kasper , Zwakhalen Sandra 
Published: December 2022

AbstractBackgroundMany children have grandparents with dementia. These direct confrontations with decline are reinforced by one‐sided, negative portrayal in the media making youngsters internalize harmful images about old age and dementia. It is vital for the well‐being of future generations that education and research join forces to clearly map and transform these toxic mental representations in children about old age and dementia.MethodWe developed a novel educational trajectory for children regarding healthy ageing and dementia in Belgium and The Netherlands. Participating youngsters (n = 70) made sketches of the elderly before and after the positive interventions. Our innovative research resulted in materials for artistic expositions of children’s drawings (n = 560). The visual representations provide a unique insight into the hidden mental landscape of children and can thus function as a starting point for conversation in educational trajectories about positive aging. These deliverables are a source of inspiration for teachers, journalists, researchers, health professionals and the broader public.ResultChildren’s drawings are one of the most efficient ways to capture young people’s mental representations about old age and dementia. Children’s drawings are implicit measurements that circumvent social desirability.ConclusionChildren’s drawings are an underused instrument in Alzheimer’s research to gain insight into the content of destructive stereotyping and the possibilities for change of these mental representations.
Regional neuronal compensation in early and late stages of the Alzheimer’s trajectory
Authors: Nowell Joseph , Livingston Nicholas R , Raza Sanara , Edison Paul 
Published: December 2022

AbstractBackgroundGlucose hypermetabolism is suggested to occur as a compensatory response to early neuronal damage[1]. Hypermetabolism has been shown to arise in the prodromal phase of Alzheimer’s disease development as a mechanism to prevent against cognitive deficits or as a compensatory mechanism to maintain the neuronal function amidst of other neurodegenerative process. Here we aimed to evaluate whether there is regional glucose hypermetabolism as a proxy to neuronal function in response to tau deposition in different stages of Alzheimer’s disease.Method139 amyloid positive cognitively impaired subjects were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (n = 44 diagnosed with Alzheimer’s disease, n = 95 mild cognitive impairment). All subjects had [18F]AV1451 and [18F]FDG PET imaging and an anatomical T1 weighted MRI scan. PET scans were coregistered to the respective anatomical scan and normalised to MNI space in SPM12. Standard uptake value ratio (SUVr) images were created using cerebellar grey matter and pons uptake as reference region for [18F]AV1451 and [18F]FDG, respectively. Voxel‐wise linear regression was conducted between[18F]AV1451 and [18F]FDG. Pearson’s correlations were conducted between regions displaying a positive association.ResultVoxel‐wise analysis revealed a correlation between higher glucose metabolism and tau deposition localised to the pre and post‐central gyrus in our cognitively impaired cohort. We found evidence that higher tau deposition and higher glucose metabolism were associated in the left and right post‐central gyrus in Alzheimer’s subjects (n=44, r=0.361 p=0.016 and r=0.327 p=0.030, respectively). A significant correlation was observed in both the left and right pre‐central gyrus (n=95, r=0.418 p<0.001 and r=0.361 p<0.001, respectively) as well as the left (r=0.384 p<0.001)and right post‐central gyrus (r=0.324 p=0.001) in subjects diagnosed with mild cognitive impairment.ConclusionThis correlation between higher tau and higher glucose metabolism in pre‐and post‐central gyrus implies that there is still neuronal compensation occurring in response to tau deposition both in early and later stages of the disease process (Braak stages V‐VI). This suggests that neuronal compensation occurs on a regional basis throughout the Alzheimer’s disease trajectory and may reflect the ability of neurons to still respond to an effective treatment.
Does glucose metabolism dissociate from tau deposition in Alzheimer’s disease?
Authors: Nowell Joseph , Raza Sanara , Livingston Nicholas R , Edison Paul 
Published: December 2022

AbstractBackgroundAlzheimer’s disease progression is characterised by accumulation of tau and reductions in cerebral glucose metabolism. However, the spread of tau could be influenced by the presence of amyloid, while changes in cerebral glucose metabolism could be influenced by microglial activation, atrophy, synaptic dysfunction, along with oxidative stress and inflammation. Hence, the association between these biomarkers at a global cortical level remains unclear. Here we sought the establish the global cortical relationship in a novel single subject design.Method380 subjects were recruited from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu) (Table 1). Amyloid status (Aβ+/Aβ‐ ve) and T1‐weghted MRI scans were obtained for all participants. Dynamic PET scans were processed with SPM12 and standard uptake value ratio (SUVR) images were created. Cerebellum grey matter and pons were selected as reference region for [18F]AV1451 and [18F]FDG respectively. Each cognitively impaired SUVR image was compared against the healthy control group using Statistical Parametric Mapping software. We extracted the total number of voxels with increases of [18F]AV1451 and decreases of [18F]FDG compared to the controls; termed ‘global cortical tau load’ and ‘global hypometabolism’ for subsequent analysis.ResultIn this sample of 240 cognitively impaired subjects, in Aβ+ve AD subjects, there was no correlation between global cortical tau load and global hypometabolism. Interestingly, there was minimal correlation in Aβ+ve MCI subjects between global cortical tau and global hypometabolism (r=0.209, p=0.042). There were no significant correlations between global cortical tau load and global hypometabolism in Aβ‐ve cognitively impaired subjects.ConclusionGlucose hypometabolism and tau deposition dissociate at a global level in AD subjects; while in early stages there may be minimal association between these two processes. The dissociation between glucose metabolism and tau deposition in the later stages of AD trajectory suggests that other pathological features including microglial activation, inflammation, and oxidative stress all influence the metabolic decline in AD, perhaps explaining our apparent lack of association later in disease progression. As such, we argue changes in glucose metabolism and tau deposition have distinct trajectories in the context of Alzheimer’s disease and future clinical trials should consider separate evaluation.
Mild behavioral impairment and functional connectivity in dementia‐free elderly
Authors: Nathan Santhosh , Ghahremani Maryam , McGirr Alexander , Smith Eric E. , Ismail Zahinoor 
Published: December 2022

AbstractBackgroundMild Behavioral Impairment (MBI), characterized by de novo emergent and persistent neuropsychiatric symptoms in later life, may be used to improve early detection of neurodegenerative disease. While alterations in resting‐state networks have been demonstrated in early‐stage Alzheimer’s disease (AD), few studies have explored these networks in MBI. Here, we assessed activity in the default mode network (DMN) and the salience network (SN), using resting‐state functional magnetic resonance imaging (fMRI), in association with MBI. We hypothesized that the strength of functional connectivity (FC) within the DMN and SN would be reduced in dementia‐free persons with MBI (MBI+), relative to those without (MBI‐).MethodsData from dementia‐free participants in three prospective cohort studies were pooled. MBI+ status was determined using the MBI‐checklist. Imaging data were acquired using 3T MRI. Seed‐based connectivity analyses were performed using the CONN toolbox. The DMN included the posterior cingulate cortex (PCC), medial prefrontal cortex (MPFC), and lateral parietal (LP) regions, with the PCC as the seed. The SN included the anterior cingulate cortex (ACC), anterior insula (AI), rostral prefrontal cortex (RPFC), and supramarginal gyrus (SMG), with the ACC as the seed. FC maps of the DMN and SN were computed for each MBI group; difference maps were extracted to identify regions with significantly different connectivity across MBI groups. A threshold of p<0.05 was used with false discovery rate correction for multiple comparisons at the cluster level; a p<0.001 uncorrected for voxel level was used for group comparisons. All analyses were covaried for age, sex, years of education, and Montreal Cognitive Assessment scores.ResultsOf the 95 participants, 32 were MBI+ and 63 MBI‐ (mean age 71.7; 54.7% female). Within the DMN, MBI+ individuals had lower functional connectivity between the PCC and MPFC, compared to MBI‐ (β=‐0.15, p=0.004). Within the SN, MBI+ was associated with lower functional connectivity between the ACC and left AI (β=‐0.12, p=0.028).ConclusionOur findings suggest that in dementia‐free individuals, MBI is associated with decreased functional connectivity in networks disrupted in AD. This result lends additional support to MBI as a potential early marker of disease.
Visuoconstruction Errors in pathologically confirmed Alzheimer’s disease versus Alzheimer’s disease with Lewy Body disease patients
Authors: Hernandez Michelle , Soto Elizabeth , Fernandez Kayri K , Johnson Jordan , Azar Martina , Gu Yian , Stern Yaakov , Cosentino Stephanie 
Published: December 2022

AbstractBackgroundClinical differentiation of Alzheimer’s disease (AD) versus Lewy Body Disease (LBD; including mixed AD‐LBD) is challenging, as both diseases overlap in cognitive symptoms. This can lead to misdiagnosis with detrimental consequences to the patient’s health. While autopsy‐based studies reveal that visuoconstruction tends to be more preserved in AD versus LBD and mixed AD‐LBD, it is well established that patients with AD also have visuoconstructional difficulties. To this end, this study examined performance on three visuoconstruction tasks and qualitatively coded errors on overlapping pentagons to characterize the types of constructional difficulties in pathologically confirmed AD versus LBD and mixed AD‐LBD.MethodClinical and autopsy data were available for 30 individuals (19 AD; 11 LBD /mixed AD‐LBD). Overlapping pentagons were given a final score of either 0 or 1. Pentagons were then scored across six parameters: presence of two figures, overlapping figures, 5 sides on each figure, the correct overlap of figures (diamond in the middle), presence of overwriting, and closing‐in to stimulus. Copy of a cube and a circle/diamond figure was also scored as 0 or 1. Chi‐square analyses were used to examine the frequency of impairment on each visuoconstruction score among the pure AD versus LBD/mixed AD‐LBD groups.ResultThe combined LBD and mixed AD‐LBD group was more frequently impaired on circle‐diamond (p = .002), pentagons total score (p = .001), and two pentagons sub‐scores, including the presence of 5‐sides on each figure (p = .006) and the correct pentagon overlap (p = .006). The groups were impaired with equal frequency on the remaining pentagons sub‐scores, and on the cube copy (53% of AD and 37% of LBD/mixed AD‐LBD; p = .39).ConclusionAs expected, the combined LBD and mixed AD‐LBD group was more frequently impaired on several visuoconstruction tasks in comparison to the pure AD group. Specific pentagons errors were most sensitive to group differences. Of note, both groups were impaired with equal frequency on cube copy, suggesting that the three‐dimensional component of the task best captures the visuospatial difficulties characteristic of AD. Qualitative assessment of visuoconstruction may aid in differential diagnosis.
The coarse‐grained plaque is an Aβ plaque‐type in APOE Ɛ4+ Alzheimer’s disease that is associated with astrogliosis and p‐tau burden
Authors: Boon Baayla D.C. , Kouri Naomi , Labuzan Sydney A , Cabrera‐Rodriguez Janisse N , Tranovich Jessica , Frankenhauser Isabelle , Lachner Christian , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R. , Dickson Dennis W. , Murray Melissa E. 
Published: December 2022

AbstractBackgroundThe coarse‐grained plaque (CGP) is a divergent plaque‐type recently described in Alzheimer’s disease (AD)1. In the current study, we studied the CGPs distribution over the brain, and its association with APOE, p‐tau, and neuroinflammation.MethodThe cohort (N = 60) was selected from the Mayo Clinic brain bank in Jacksonville, USA. Brain tissue from the frontal ‐, parietal ‐, temporal cortex, and the hippocampus was immunohistochemically stained for Aβ (6F/3D), p‐tau (AT8), CD68, and GFAP. The CGP and classic cored plaque (CCP) were scored as previously described1. Total plaque burden was expressed as the sum of all cortical regions.ResultThe CGP was predominantly located in the neocortex and present in ∼60% of AD cases, who were younger at onset (p<0.05) and had a lower brain weight (p<0.05) than CGP negative cases. When stratified for APOE Ɛ4+ and Ɛ4‐, CGP burden was only in Ɛ4+ positively correlated with p‐tau, Aβ, and GFAP burden in the frontal and parietal cortex (Table 1). CGP burden was not correlated with CD68. The CCP was negatively correlated with p‐tau, and not with GFAP, Aβ or CD68 (Table 1). In APOE Ɛ4+ cases, the burden of CGPs was negatively correlated with the burden of CCPs (Fig.1).ConclusionThe neocortical CGP is correlated with increased p‐tau burden and astrogliosis in APOE Ɛ4+. The CGP is inversely correlated with the common CCP, suggesting an opposite effect of Aβ‐induced tau‐toxicity for the CGP versus the CCP.
1Boon et al., Acta Neuropathologica, 2020
Construct Validity of the ALLFTD Mobile App Cognitive Tests: Associations with Gold Standard Clinical Measures and Brain Volume
Authors: Staffaroni Adam M. , Clark Annie L , Taylor Jack C , Heuer Hilary W. , Wise Amy B , Manoochehri Masood , Forsberg Leah K. , Mester Carly T. , Rao Meghana , Brushaber Danielle , Rojas Julio C. , Kramer Joel H. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. , Consortium ALLFTD 
Published: December 2022

AbstractBackgroundRemote digital cognitive assessments validated for use in frontotemporal dementia (FTD) and other neurodegenerative diseases would benefit clinical trials and clinical care. The ALLFTD Mobile App includes several smartphone‐based measures of cognition, and prior studies have provided preliminary support for their reliability. Here we evaluate their validity by testing associations with gold standard clinical outcomes and expected neural correlates.MethodA diagnostically mixed sample of 92 participants (CDR®+NACC‐FTLD = 0 [n = 33]; CDR®+NACC‐FTLD = 0.5 [n = 15]; CDR®+NACC‐FTLD≥1 [n = 16]; unknown [n = 28]) were recruited from a UCSF healthy aging study (Hillblom Network) and a North American FTD study (ALLFTD). Participants were asked to remotely complete four ALLFTD Mobile App tests of executive functioning (EF) and a memory test on their smartphones. Gold standard clinical measures were also collected; outcomes were the UDSv3 EF composite, CVLT‐SF Total Immediate Recall (memory), and CDR®+NACC‐FTLD Box Score (disease severity). Volumetric brain MRI measurements were available for a subset (n = 37). Expected neural correlates were frontoparietal gray matter volume for EF tests and hippocampal volume for the memory test. Linear models were fitted to evaluate the association of app tests with the gold standard outcomes, controlling for education, sex, and total intracranial volume (imaging only).ResultSmartphone EF measures were strongly and positively associated with the UDS3‐EF composite (ß’s = 0.6–0.8, all p<.001). The memory test was strongly correlated with the CVLT‐SF (ß = 0.7, p<.001). Tests were less strongly associated with divergent cognitive domains (e.g., associations with a visuospatial test were ß’s = 0.1–0.3). Worse performance on all tests was significantly associated with greater disease severity (ß’s = 0.5–0.7, all p<.001). Worse app‐based EF scores were associated with lower frontoparietal volume (ß’s = 0.4–0.6, all p<.015) and worse memory scores with lower hippocampal volume (ß = 0.5, p<.001).ConclusionALLFTD Mobile App scores were strongly associated with gold standard neuropsychological tests of the same cognitive domain (i.e., convergent validity) and less associated with measures of a different domain (i.e., divergent validity). Worse performance on the smartphone tests was associated with increasing disease severity and volume loss in expected brain regions. These results provide preliminary support for the construct validity of the ALLFTD Mobile App cognitive tests.