bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interactive effect of MCI subtype and white‐matter hyperintensity load on the expression of large‐scale neurofunctional networks
Authors: De Marco Matteo , Vettore Martina , Pallucca Claudia , Bendini Matteo , Gallucci Maurizio , Venneri Annalena 
Published: February 2022

AbstractBackgroundMild Cognitive Impairment (MCI) is a condition with a large degree of clinical heterogeneity. A major classification is that between 'amnestic' and 'non‐amnestic' patients. It is known that large‐scale neural networks differ between these two subtypes. White‐matter‐hyperintensities (WMH) load may contribute to affecting the efficiency of these networks. It is unknown, however, whether WMH burden influences the expression of major brain networks in a similar way in both amnestic and non‐amnestic MCI. We thus hypothesised that an interactive effect on brain networks would exist between MCI subtype and WMH load.MethodOne‐hundred‐and‐twenty‐three MCI patients were included in this study, retrospectively selected from our internal Ageing Database and the Treviso Dementia Registry initiative. They all completed an MRI protocol inclusive of resting‐state fMRI and neuroanatomical acquisitions. FLAIR scans were processed with the ‘Lesion Segmentation Tool’ to quantify global WMH volume (i.e., lower vs. higher). Resting‐state scans were preprocessed and denoised with the CONN toolbox and an independent component analysis was run to extract five major large‐scale networks: default‐mode, salience, left‐right frontoparietal and visual. Subtype‐by‐WHM load ANOVAs were run to test for significant interactions for each of the five inferential models, controlling for major confounding factors.ResultSignificant interactions were found in two models only. Within the salience network having a lower WMH load was associated with stronger connectivity in the right insula significantly more among amnestic patients. Within the left frontoparietal network, having a lower WMH load was associated with stronger connectivity in the right frontoinsular cortex significantly more among amnestic patients, and in the left mediotemporal lobe significantly more among non‐amnestic patients.ConclusionThe interplay of two important clinical variables such as MCI subtype and WMH load has a significant effect on the expression of two large‐scale brain networks that sustain stimuli selection and integration and executive control. This pattern is expressed in alignment with clinical symptoms of subtypes. WMH load contributes to down‐regulating the efficiency of large‐scale brain networks in a way that is dependent on MCI subtype and aligned with vulnerability of each subtype. This is an important element of prognostic utility.
Validation of locus coeruleus histological reconstructions to MRI
Authors: LaMore Tia , Chen Yuheng , Li Song , Tonsun Duygu , Otaduy Maria , Heinsen Helmut , Alegro Maryana , Grinberg Lea T. 
Published: February 2022

AbstractBackgroundThe Locus coeruleus(LC) is one of the first sites of tau aggregation and suffers from dramatic volume loss early on. Due to the shrinking of the LC preceding the onset of clinical symptoms of AD by decades, a precise understanding of the neurobiological correlates of MRI signal may turn LC neuroimaging into an early non‐invasive staging biomarker for AD. Though there are many efforts to image the LC in‐vivo, first, it is vital to confirm postmortem validation of the MRI signal. In this study, we are attempting to validate postmortem histological reconstructions of the LC to its corresponding postmortem MRI reconstructions, voxel‐to‐voxel.MethodWe used a pipeline developed in‐house employing brainstem processing, staining, and computer‐based algorithms for 2D and 3D registration to reconstruct the histological volume of the brainstem with structural detail. This pipeline allows for precise alignment of histology‐based cytoarchitectural 3Dreconstructions (Fig. 1A) of the brainstem to its 7T‐MRI counterpart (Fig. 1B). Photoshop and Freeview were used to manually segment the LC in digital images of cross sections of the brainstem labeled with Nissl staining (Fig. 2), to generate 2D LC masks in all 4 cases. We then registered the stained cross sections and their corresponding LC masks to the cross sections’ blockface to correct for any deformation of tissue during the staining process. We applied Freeview commands to reconstruct the 3D brainstems and their 3D LC masks. We registered the resulting 3D reconstruction and LC mask to matching MRI coordinates, enabling voxel‐to‐voxel comparisons. We will continue to demonstrate the value of our pipeline in regards to validating neuroimaging methods in AD with these structural masks of the postmortem LC registered to the MRI counterpart in 3 more cases.ResultThe histological 3D LC masks were registered onto the parallel 3D MRIs. In Freeview, we plan to run correlation analysis with an output of dice coefficient ranging from 0‐1, with a coefficient of 1 translating to the voxels of the LC masks and the MRI signal overlapping exactly.ConclusionOur pipeline enables voxel‐to‐voxel correlation analysis between histology and MRI scans for validation of LC neuroimaging. Current finalization of 3 other cases is ongoing.
The relationship between cortical grey to white matter signal contrast (GWC) and tau pathology in atypical AD
Authors: Flaherty Ryn , Krivensky Samantha , Brickhouse Michael , Carvalho Nicole , Eckbo Ryan , Salat David H , Dickerson Brad C. , Touroutoglou Alexandra , Putcha Deepti 
Published: February 2022

AbstractBackgroundGrey to white matter signal intensity ratio (GWC) has been studied as a novel metric of integrity and as a marker of neurodegeneration in Alzheimer’s disease (AD). Regions with reduced GWC co‐localize with regions of cortical atrophy in AD (Salat et al. 2011; Salat et al. 2009). Cortical atrophy in AD robustly colocalizes with tau pathology measured using tau PET ligands (Putcha et al. 2019). For this study, we hypothesized that GWC co‐localizes with tau pathology and shows greater sensitivity to tau pathology than cortical atrophy across the atypical phenotypic spectrum of AD.MethodWe studied 29 amyloid‐positive atypical AD patients, including 16 patients with posterior cortical atrophy (PCA), 10 with logopenic variant primary progressive aphasia (lvPPA), and 3 with an amnestic dysexecutive presentation. Whole‐cortex maps of GWC and cortical atrophy were generated for each individual using FreeSurfer. Tau PET (18F‐Flortaucipir) signal was projected for each individual to the cortical surface using PETsurfer. Eta squared (η2) was computed to determine the spatial overlap of each measure of neurodegeneration (GWC, cortical atrophy) with tau PET signal for each subject and then averaged across the whole group.ResultBoth GWC and cortical atrophy revealed a pattern of neurodegeneration consistent with AD, including in medial parietal, lateral parietal, and posterior lateral temporal cortices. Lower GWC was also observed in several regions beyond the areas of cortical atrophy in patients including in bilateral dorsolateral and dorsomedial prefrontal cortices. Supporting our hypothesis, there was greater spatial overlap between the GWC and tau PET maps (η2 = 0.30) compared to cortical atrophy and tau PET maps (η2 = 0.24; t=4.49, p=0.0001).ConclusionWhile both measures of neurodegeneration (GWC, cortical atrophy) showed a high degree of spatial overlap with tau PET signal across our sample of atypical AD participants, we conclude that GWC, a novel MRI‐derived biomarker of neurodegeneration in AD, correlates more strongly with AD‐related tau neuropathology than traditional cortical atrophy measures. This suggests that GWC could be a sensitive biomarker of AD‐related tissue changes that may represent neuronal injury or neurodegeneration. Further work is needed to establish how GWC tracks with tau pathology over time.
Brainstem volume is negatively associated with amyloid deposition in the Framingham Heart Study
Authors: Jacobs Heidi I.L. , O’Donnell Adrienne , Satizabal Claudia L. , Hanseeuw Bernard , Thibault Emma G. , Koijs Daniel , Sanchez Justin S. , Buckley Rachel F. , Yang Qiong , Sperling Reisa A. , Johnson Keith A. , Beiser Alexa S. , Seshadri Sudha 
Published: February 2022

AbstractBackgroundThe brainstem consists of various nuclei that accumulate tau early in the Alzheimer’s disease (AD) trajectory. Previous studies discovered the genetic loci linked to brainstem volume, revealing genetic overlap with several neurological disorders, including AD. We aimed to investigate whether the volume of distinct parts of the brainstem are related to AD pathology, amyloid or tau, and whether this effect is modified by APOE genotype. Finally, we evaluated whether genetic variants related to total brainstem volumes are related to AD‐pathology by aggregating previously reported genetic loci into a brainstem polygenic risk score.MethodWe included 267 individuals from the Framingham Heart Study who underwent 3T MRI, Flortaucipir (n=238) and PiB‐PET imaging on Siemens HR+ or GE‐Discovery GE PET cameras(mean age: 54 (SD:8) years, 51% male; 24% APOE‐E4; Figure 1). Subregional brainstem volumes were quantified using FreeSurfer 6.0 and adjusted for total cranial volume. Regional FTP‐PET, neocortical PiB‐PET signal were referenced to cerebellar grey and partial volume corrected (PVC). We performed several hierarchical regressions: 1) to associate each brainstem volume to neocortical PiB and tau in temporal lobe regions 2) to examine interactions between PiB and brainstem volumes on tau and 3) interactions between APOE and brainstem volume on tau. We then examined whether the brainstem polygenic risk score was associated with AD‐pathology. Covariates included age, sex and PET‐camera.ResultIn both the PVC and non‐PVC analyses, lower medulla and pons volumes were consistently associated with greater neocortical PiB binding (Figure 2). Midbrain volume was at trend‐level negatively associated with inferior temporal and amygdala tau. No other associations were observed with tau. We observed no interactions between brainstem volumes and PiB or APOE on regional tau. The brainstem polygenic risk score was not associated with AD‐pathology (Figure 3).ConclusionLower brainstem volume, in particular medulla and pons, is associated with amyloid deposition in a cohort of middle‐aged individuals. There is no evidence for associations with known brainstem loci, suggesting that these associations may occur via different or indirect pathways, or that lower brainstem volumes may be a reflection of overall disease progression and neurodegeneration.
Long‐term progression of amyloid and tau biomarker profiles: Four‐year follow‐up imaging study
Authors: Cho Hanna , Baek Min Seok , Kim Han‐Kyeol , Lee Jae Hoon , Chun Joong‐Hyun , Ryu Young Hoon , Lyoo Chul Hyoung 
Published: February 2022

AbstractBackgroundTo investigate long‐term progression of amyloid (A) and tau (T) image‐based biomarker profiles in a cohort with wide range of cognitive status.MethodIn 273 participants [96 cognitively unimpaired (CU), 106 mild cognitive impairment (MCI), and 71 AD dementia (DEM)] who completed 18F‐florbetaben and 18F‐flortaucipir PET studies for visit 1 (V1), 167 participants (62 CU, 68 MCI, and 37 DEM) completed visit 2 (V2) PET studies at two years, and subsequently 66 participants (23 CU, 33 MCI, and 10 DEM) completed visit 3 (V3) PET studies at about four years (mean 4.5 years) after the V1 study. A/T biomarker profiles were determined by using the cut‐off standardized uptake value ratios of composite regions most vulnerable to each pathology.Result5.6% (5/90) of participants converted from A‐ to A+ at V2 and 18.5% (5/27) at V3. Likewise, 4.2% (5/118) of participants converted from T‐ to T+ at V2 and 17.4% (8/46) at V3. In comparison with lower conversion rate from T‐ to T+ in the A‐T‐ participants [2.3% (2 A‐T+ / 86 A‐T‐) at V2 and 7.4% (2 A+T+ / 27 A‐T‐) at V3], A+T‐ participants exhibited higher conversion rate from T‐ to T+ [9.4% (3 A+T+ / 32 A+T‐) at V2 and 31.6% (6 A+T+ / 19 A+T‐) at V3].ConclusionPositive conversion of A/T biomarkers occurs steadily throughout the long‐term period. Compared to A‐ individuals, positive conversion of T biomarker occurs four times more frequently in A+ individuals.
Effect of comprehensive, individualized, person‐centered management (CI‐PCM) on psychotropic medication usage in advanced Alzheimer’s persons in a 28‐week randomized controlled trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Bao Jia , Torossian Carol , Dafflisio Gianna , Vedvyas Alok , Reisberg Barry 
Published: February 2022

AbstractBackgroundBehavioral and Psychological Symptoms of Dementia (BPSD) are burdensome and disturbing for caregivers and persons living with Alzheimer’s disease (AD). They are also a primary cause of institutionalization of Alzheimer’s persons. Physicians use psychotropic medications to treat the BPSD of AD. Many of these medications have deleterious consequences as evidenced in part by their black box warnings. We published results of a 28‐week, clinician‐blind, randomized, controlled trial of our CI‐PCM program in moderate‐to‐severe, community‐residing, Alzheimer’s persons receiving memantine (Reisberg…Kenowsky, Dement Geriatr Cogn Disord, 2017). The BPSD were examined using the Behavioral Pathology in Alzheimer’s Disease‐Frequency Weighted severity scale, which showed significant benefit in the CI‐PCM subject group at week 28 (p<0.05).MethodsWe examined the magnitude of usage of psychotropic medications used to treat BSPD in subjects from our 2017 study who were randomized to receive Usual Community Care (UCC) or the CI‐PCM Program. Psychotropic medications used to treat other conditions were excluded. Subjects were evaluated at baseline and weeks 4, 12 and 28. We examined the ratio of daily psychotropic medication usage in the two groups. Psychotropic medications were compared by examining the percent of the maximum daily dosage of each medication taken cumulatively throughout each study observation period from week 4 to week 28. The Wilcoxon rank sum test was used to analyze the difference between the two groups.ResultsAt baseline, the group randomized to UCC consumed significantly more psychotropic medication than subjects randomized to the CIPCM program (p<0.05). Because there was a significant difference between groups at baseline, we analyzed usage in comparison with baseline (see figure 1). The UCC subjects used more psychotropic medication on a per day average relative to baseline from week 4 to week 28 than the CI‐PCM subjects (p<0.01). The total amount of psychotropic medication taken, in comparison with baseline, was significantly lower in CI‐PCM subjects from weeks 4 to 28 (p<0.0001).ConclusionsCI‐PCM subjects took significantly less psychotropic medication and their BPSD symptomatology significantly improved. The CI‐PCM program is a safe, highly efficacious nonpharmacologic intervention that significantly reduces both BPSD symptomatology and psychotropic medication usage in advanced AD persons.
Tools validated for assessment of mental health and cognition in older adults of Latin America and the Caribbean: A scoping review
Authors: Miranda‐Castillo Claudia , León‐Campos María O , Molleda Pedro , Paddick Stella‐Maria 
Published: February 2022

AbstractBackgroundThe global population is ageing, with an estimated one in five people aged 60 by 2050. Latin America is one of the fastest ageing areas of the world and accurate clinical and research assessment measures of mental health in this ageing population are needed. It is not known which psychometric measures of older people’s mental health and cognition are validated in a Latin American context. This scoping review aims to address this question and outline current knowledge and research gaps.MethodBroad search terms were defined in English then translated and adapted to Spanish and Portuguese. Databases searched included Cinahl, Medline, Embase, Scielo, Scopus, Psychinfo, EBSCO and Web of Science. Inclusion criteria were validation or adaptation studies of tools for cognitive, mental health or psychosocial outcomes in older adults, conducted in Latin America or the Caribbean 1990‐2019. Titles and abstracts were reviewed blindly against search criteria using the RAYYAN application and conflicts resolved through discussion. PRISMA guidelines were utilized for reporting. Data extraction summarised psychometric procedures (reliability, construct/criterion validity, diagnostic accuracy, factor analysis etc), setting and participants.ResultsA total of 3805 articles were identified (3075 de‐duplicated) of which 526 underwent full‐text review. In total, 337 articles meeting the review criteria were identified and data were extracted. Psychometric evaluations of 138 different tools were identified, (90.3% conducted since 2006) though 46 were evaluated twice or less. Cognitive screening measures were the most numerous (n=107 45.1%) followed by depression and quality of life. Brazil had the largest number of studies (n=135). The most frequently evaluated tools were MMSE, MOCA, Geriatric Depression Scale (GDS) and Clock Drawing Test.ConclusionThe highest validation evidence was for cognitive measures. Most evidence relates to a small number of measures (cognition, depression and quality of life) originally developed in high‐income countries outside Latin America. The greatest evidence relates to, urban centres in Brazil.Though a large number of validation studies have been conducted, substantial research gaps remain. The majority of tools in current use have been insufficiently validated and their utility in clinical practice across different settings in Latin America remains unclear.
Characterizing amyloid positive individuals with normal tau PET levels five years later: An ADNI study
Authors: Josephs Keith A. , Weigand Stephen D. , Whitwell Jennifer L. ,   ADNI
Published: February 2022

AbstractBackgroundDiagnosing Alzheimer’s disease (AD) with biomarkers requires evidence of abnormal beta‐amyloid (Aβ) and tau. Individuals that are Aβ‐positive, but tau‐negative, are considered to have AD neuropathologic change, or early AD. The objective of this study was to determine whether some Aβ‐positive but tau‐negative individuals remain tau‐negative 5‐years later and describe the characteristics of such individuals.MethodWe identified 45 individuals from ADNI who were Aβ‐positive but tau‐negative on PET more than five years after their first abnormal Aβ‐PET (Amyloid+ Low Tau, ALT group). For comparison, we identified 157 Aβ‐positive individuals that had abnormal tau‐PET within five years of their first abnormal Aβ‐PET (i.e. biomarker‐AD). Aβ‐positivity was determined by ADNI‐provided cut‐points of 1.11 for AV45 and 1.08 for florbetapir. A negative tau‐PET scan was defined using Gaussian mixture modeling.ResultThe ALT and biomarker‐AD groups were similar in terms of sex and age at the time of their first Aβ‐PET scan. However, the ALT group was characterized by a lower proportion of APOE ε4 carriers (31% versus 67%, p<0.001), a lower median centiloid (36 versus 85, p<0.001, Figure) and lower likelihood of having a dementia diagnosis at first Aβ PET (2% versus 22%, p<0.001) compared to the biomarker‐AD group. The ALT group also performed better on tests of general cognition and had larger hippocampal volume compared to biomarker‐AD (p<0.001 for all). APOE ε4 status, centiloid and hippocampal volume were all associated with increased odds of elevated tau within 5 years from baseline Aβ‐PET (Table). Within the ALT group, 19 (42%) had high centiloid (>40): these individuals did not differ from the <40 centiloid individuals in clinical diagnosis, but there was some indication of a higher APOE ε4 frequency (42% versus 23%; p=0.30).ConclusionAmyloid‐positive individuals can remain tau‐negative for at least five years, and without becoming demented. Baseline characteristics can help identify these ALT individuals that have a low risk of progression. These findings beg the question of whether more conservative Aβ cut‐points are required for diagnosis of individuals with a high risk of developing AD.
Dorsal hippocampal surface reduction as a biomarker of neurodegeneration in subjects with subjective cognitive decline and MCI converters to dementia
Authors: Verdejo Juan , Cuesta Pablo , Torres Lucia , Fernández Ricardo Bruña , Maestú Fernando 
Published: February 2022

AbstractBackgroundHippocampal atrophy has been proposed as the main neurodegeneration marker in the Alzheimer’s disease (AD) continuum. However, scarce research has found differences on that measure at early stages, i.e. subjective cognitive decline (SCD), and between mild cognitive impairment (MCI) patients that convert or not to AD. Here, we explored whether group differences emerged when other brain characteristics, as the white matter microstructure or the hippocampal surface shape, are used.MethodThe sample was composed by 393 older adults (aged from 57 to 87) recruited from the “Hospital Universitario San Carlos” and the Center for elders at the Chamartín District, all located in Madrid, Spain. They were classified in three groups according to their cognitive and functional status and following the NIA‐AA criteria: 162 were catalogued as MCI, 99 with SCD and normal cognitive performance, and 132 healthy controls without cognitive concerns. 93 of the MCI participants were followed and classified according to their clinical outcome: 31 classified as progressive MCI (p‐MCI) and 62 as stable MCI (s‐MCI). All participants underwent a MRI scan session where structural and diffusion weighted images were collected. None of the participants exhibited a history of psychiatric or neurological disorders (other than MCI). We performed tract‐based spatial statistics analysis on DTI data and vertex‐wise statistics on the structural images to explore groups differences in white matter microstructure, and hippocampal volume and surface shape.ResultMCI patients exhibited reduced FA, increased MD, and reduced volume and surface of the hippocampus compared to both SCD and control groups. Differences between SCD and control groups emerged in the association between FA values and global hippocampal volume, and also in the surface shape analysis. Finally, when comparing MCI subgroups, the p‐MCI patients showed a reduced hippocampal volume and a bilateral dorsal reduction on the surface of both hippocampi compared to s‐MCI.ConclusionThese results provide evidence of the progressive subcortical degeneration that occurs at different stages of healthy and pathological aging. Furthermore, they highlight the potential advantage of the use of the shape analysis of the hippocampal surface and the association between different brain measures as predictive biomarkers.