bluuebunny/crossref_metadata_2025 huggingface dataset:
Very high interrater reliability for manual segmentation of the medial perirhinal cortex
Authors: Henzen Nicolas A. , Reinhardt Julia , Blatow Maria , Kressig Reto W. , Krumm Sabine
Published: February 2022

Background

Intracellular neurofibrillary tangles (NFT) belong to the main characteristics of Alzheimer’s disease (AD) pathology and occur first in the medial perirhinal cortex (mPRC; also referred to as “transentorhinal region”). Adjacent regions such as lateral perirhinal cortex (lPRC), entorhinal cortex (ERC), and hippocampus are affected at a later stage of NFT progression. Therefore, mPRC integrity potentially serves as a promising imaging biomarker in early AD. Due to the high anatomic variability of the collateral sulcus, which defines mPRC boundaries, it is important to evaluate the interrater reliability of manual segmentation. Today, automated segmentation protocols only exist for the whole PRC (i.e. mPRC and lPRC together). However, discrete analysis of mPRC integrity is crucial to detect AD related pathology as early as possible.

Method

Forty‐four adults (20 men; mean age = 69.2 ± 10.4 years) from different diagnostic groups (e.g. normal controls, mild cognitive impairment, Alzheimer's dementia or major depression) were included in the analyses. All subjects received structural magnetic resonance imaging in a 3‐Tesla scanner (MAGNETOM Verio, Siemens). Regions of interest (mPRC, lPRC, and ERC) were drawn by‐hand by two raters (SK, NAH) blinded for diagnoses. Bilateral cortical thickness estimates were extracted using FreeSurfer. Intraclass correlation coefficients (ICC) were calculated in SPSS based on a single‐rating, absolute‐agreement, 2‐way mixed‐effects model.

Result

A high degree of reliability was found between both raters with an average measure ICC of .876 for the left mPRC (F[43,43]=14.954, p<.001, 95% confidence interval [CI] =.784 ‐ .930) and .873 for the right mPRC (F[43,43]=14.472, p<.001, 95% CI=.779 ‐ .929). Similar results were found for lPRC (left: ICC=.984; F[43,43]=118.834, p<.001, 95% CI=.970 ‐ .991; right: ICC=.953; F[43,43]=40.344, p<.001, 95% CI=.915 ‐ .974) and ERC (left: ICC=.969; F[43,43]=62.657, p<.001, 95% CI=.944 ‐ .983; right: ICC=.961; F[43,43]=49.390, p<.001, 95% CI=.930 ‐ .979).

Conclusion

The ICC analysis showed a very high interrater reliability for manual mPRC segmentation as well as for lPRC and ERC. These results indicate that the applied segmentation protocol, which considers collateral sulcus variability, allows different raters to achieve highly similar results and may serve as a reference to establish future automated segmentation protocols.
Baseline CSF phosphorylated tau as an indicator of subsequent tau accumulation on tau PET
Authors: Cogswell Petrice M , Wiste Heather J. , Mielke Michelle M. , Schwarz Christopher G. , Weigand Stephen D , Lowe Val J , Therneau Terry M. , Knopman David S. , Graff‐Radford Jonathan , Vemuri Prashanthi , Senjem Matthew L. , Gunter Jeffrey L. , Petersen Ronald C. , Jack Clifford R.
Published: February 2022

Background

Alzheimer’s disease biomarkers of tau pathology may be assessed by both CSF and PET. Cross‐sectional associations between CSF phosphorylated tau (p‐tau) and tau PET have been studied and regional tau PET SUVR has been shown to have similar diagnostic performance as CSF p‐tau. The association between CSF p‐tau and longitudinal tau PET has not been studied. CSF measures may be thought of as a result of the imbalance of influx vs efflux of soluble tau, whereas, tau PET reflects total tau accumulation into insoluble aggregates to date. We therefore hypothesize that baseline CSF p‐tau may be a leading indicator of future tau PET accumulation.

Method

We identified Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with diagnoses of cognitively unimpaired, mild cognitive impairment, and amnestic dementia who had CSF p‐tau (Elecsys p‐tau [181P]) and subsequent serial tau PET (flortaucipir) exams. The first tau PET scan was within 3 years of the CSF p‐tau collection. A longitudinal pipeline with two‐compartment partial volume correction was used to measure change in tau PET in a temporal‐lobe meta‐ROI (amygdala, fusiform, middle/inferior temporal, entorhinal, and parahippocampal regions) with a composite reference region (eroded supratentorial white matter, pons, and whole cerebellum). Spearman correlation was used to assess the association between CSF p‐tau and annual percent change in tau PET. A linear mixed effects model was fit to assess the association adjusting for age and sex.

Result

The study included 143 participants (76% cognitively unimpaired) (). CSF p‐tau was significantly associated with annual percent change in tau PET overall (Spearman R=0.19, p=0.023) () and after adjusting for age and sex (p<0.001) (). There was nonlinearity in the CSF p‐tau effect, with higher values (>20 pg/mL) having a greater association with annual change in tau PET than lower values.

Conclusion

In a group of cognitively unimpaired and impaired participants, CSF p‐tau predicted subsequent tau PET accumulation rate. A threshold effect is suggested with subsequent tau PET accumulation primarily in participants with elevated CSF p‐tau levels near the Mayo threshold of 22 pg/mL.
Danish national film archives available for reminiscence activities
Authors: Jensen Anders Møller , Gregersen Rikke
Published: February 2022

Background

Among important elements’ in person‐centred care is knowledge about a person’s life, and how this ties into his/her daily activities and care. Finding historical film footage about a particular local setting, or a relevant topic, is time‐consuming and difficult for the care staff. The Danish Film Institute – a government institution under the Ministry of Culture – set out to develop a platform that made part of their historical archive available for staff, to support the national agenda of creating a dementia‐friendly society.

Method

Based on knowledge from reminiscence theory, suitable archive footage was selected and grouped into four packages, consisting of several short film clips and supportive documents. The platform was tested on eight nursing home residents with a dementia diagnosed, in two groups of four. Each group performed one session per week for three weeks at the nursing home. Due to COVID‐19 restrictions, only proxy data was collected in terms of interviews with a group leader and two on‐site observers after every session, about their experiences with the material and their observed participant reactions. Data collection without the voices of the participants themselves was performed due to the need for obtaining at least proxy data on the effect of targeted film clip to stimulate frail elderlies with dementia – also in a pandemic lockdown situation. Informed consent from all participants was obtained. Data and ethics approval was done in accordance with Danish law.

Results

Although the archive content was not targeted people with declining cognitive function, the staff assessed the effect of this pedagogical dissemination of well‐designed film clip content, as very positive in relation to the participants with dementia. The sessions managed to stimulate engaging discussion and storytelling about the participant's own life in what can be described as deep memory recollections. Some instances of transference of new knowledge about life history to daily care of the participants were reported.

Conclusion

The study instances that tailored archived film content can be used in professional person‐centred care to stimulate memories of people with dementia and quality moments in participant`s daily life.
Individualized MR‐based prediction of cognitive performance in subjects at risk of dementia
Authors: Nemali Aditya Sai Ram , Yakupov Renat , Schütze Hartmut , Spottke Annika , Ramirez Alfredo , Schneider Anja , Metzger Coraline D. , Christoph Laske , Bittner Daniel , Brosseron Frederic , Priller Josef , Wiltfang Jens , Buerger Katharina , Fließbach Klaus , Heneka Michael T. , Peters Oliver , Speck Oliver , Nestor Peter J. , Teipel Stefan J. , Pross Verena , Glanz Wenzel , Wagner Michael , Jessen Frank , Düzel Emrah , Ziegler Gabriel
Published: February 2022

Background

Neuroimaging markers based on MRI often provide better prediction than traditional neuropsychological scores. With advancements of machine learning, data patterns may offer opportunities to personalize clinical practice that leads to better outcomes for patients at risk of dementia such as Alzheimer’s disease (AD) (Davatzikos et al., 2019). AD is a multifactorial process associated with ageing, brain atrophy, genes, proteins, vascular risk, and brain state activity (Frisoni et al., 2010). These processes do covary and interact in a complex fashion which needs to be accounted when aiming at predicting clinical outcomes for staging and stratification of disease‐modifying treatments.

Method

In our probabilistic predictive framework we focus on data from the DZNE DELCODE cohort (Jessen et al., 2018) consisting of T1‐weighted and FLAIR images to assess distributed patterns of Voxel‐based Morphometry (VBM) and White Matter Lesions for 929 subjects; subject‐specific demographics (age, sex, education) and available CSF biomarkers for 438 subjects. We developed a machine learning framework for brain‐based predictions of (A) memory performance (Wolfsgruber et al., 2020) and (B) CSF Amyloid 42/40 and p‐tau biomarker status using a Gaussian process multi‐kernel (GP‐MKL) learning approach (Rasmussen & Williams, 2006). The proposed GP‐MKL model combines multiple features (atrophy patterns, demographics age, sex, education, white matter lesions volume & apoe4) expected to characterize the transition from healthy ageing towards dementia in terms of cognitive symptoms and biomarker status (Figure 1). We evaluate predictive models and different feature combinations using 10‐fold cross‐validation.

Result

The framework enabled optimal individual prediction of memory performance (highest correlation true vs. predicted of r = 0.751 ± 0.082, R2 = 0.56, Fig. 2) using a combination of demographics, brain tissue segments (GM & CSF) & CSF biomarkers (Aß42/40 & p‐tau). When estimating the CSF biomarker positivity, the AUC‐ROC score achieved 0.735 for Aß42/40 (Fig. 4A) and 0.802 for p‐tau (Fig. 4B) using a combination of brain tissue segments (GM & CSF), demographics, and cognitive testing.

Conclusion

In conclusion, multiple domains and imaging facets contribute to reliable estimation of individual cognitive memory performance and biomarker positivity in dementia and enable promising predictive technologies for staging and treatment stratification.
Age‐related association between white matter integrity and cerebral blood flow in white matter
Authors: Jekel Ciara , Kim Donghoon , Hughes Tim M. , Lockhart Samuel N. , Whitlow Christopher T. , Craft Suzanne , Baker Laura D. , Okonmah‐Obazee Stephanie , Bobinski Matthew , Jung Youngkyoo
Published: February 2022

Background

Alzheimer’s disease (AD) has a long preclinical phase that is often preceded by reduced white matter (WM) integrity; further, impaired cerebrovascular function is associated with AD biomarkers. However, the intersection of WM structure and cerebrovascular function in the risk and progression of Alzheimer’s disease is unclear. We examined the relationship between WM structure and cerebrovascular function in younger and older adults at risk for AD.

Method

Participants enrolled in the Wake Forest Alzheimer’s Disease Research Center Clinical Core underwent: 3T MRI scan including neurite orientation dispersion and density imaging (NODDI) and arterial spin labeling (ASL), clinical exams, cognitive testing, and adjudication. Intra‐cellular volume fraction (ICVF) and cerebral blood flow (CBF) were obtained from NODDI and ASL, respectively. Multivariable linear regression analyses were performed to investigate the relationship between ICVF and CBF in 48 WM regions (JHU ICBM‐DTI‐81 atlas). Analyses were performed separately on participants grouped by age (median split at ≥71 years) and adjusted for covariates: sex, race, and cognition status, and grouped by cognitive status and adjusted for covariates: sex, race, and age. The Benjamini & Hochberg false discovery rate method was used to test multiple hypothesis across ROIs.

Result

330 participants completed MRI sequences for WM structure and perfusion (mean age: 70.3±8 yrs.; M/F: 105/225; 283 White, 47 Black or African American; 198 cognitively normal, 132 mild cognitive impairment (MCI)). The older group had lower mean ICVF and mean WM CBF (0.70±0.05; 18.9±3) than the younger group (0.73±0.04; 19.7±3). In the older group, mean ICVF was positively related to mean WM CBF (p<0.01). In older participants (≥71) there were eight regions where ICVF and CBF were positively related (corrected p<0.05). In younger participants (<71) there was one region where ICVF and CBF were positively related (fornix column and body; corrected p<0.05). When grouped by cognitive status (normal/MCI), no association was found between mean ICVF and mean WM CBF.

Conclusion

Generally, reduced integrity in WM structure is associated with reduced CBF. This association appears related to age, not cognitive status. Differences in the associated regions by age suggest potential effects of brain aging on WM structure and CBF.
Evaluating participant and coordinator satisfaction with telephone assessments
Authors: Pun Kelly , Sewell Margaret , Neugroschl Judith A , Zhu Carolyn W , Zeng Xiaoyi , Greenberg Jonathan , Velasco Nelly , Sheppard Faye , Tocco Carly , Evans Kirsten , Ardolino Allison , Meuser Caroline , Kinsella Michael T , Li Clara , Loizos Maria , Grossman Hillel , Sano Mary
Published: February 2022

Background

In response to the COVID‐19 pandemic, the Alzheimer’s Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai began conducting evaluations for the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) by telephone in March 2020. The ADRC designed a survey to evaluate participant and research coordinator satisfaction with telephone evaluations.

Method

Following UDS evaluations, participants rated their satisfaction on 5 items: voice quality on telephone, respect for privacy, degree of comfort using the telephone, and confidence that the information collected was accurate. Coordinators were asked to gauge their satisfaction on similar items. To calculate satisfaction scores, responses were assigned values: “Very” = 3, “Fairly” = 2, and “Not at all” = 1. Maximum satisfaction score was 15 for participants and 18 for coordinators.

Result

Data was available for 130 participants evaluated by telephone between March 2020 and January 2021. Of these, 68.5% were female, 53.7% were white, with an average age of 76.4 and 16 years of education. 74% of participants had a Global Clinical Dementia Rating (CDR) score of 0; 22% CDR 0.5; 4% CDR 1. Participants with CDR >1 were evaluated by caregiver interviews without testing, and those with CDR=1 were offered testing at the discretion of their family and examiners. Average total satisfaction rating was 14.2/15 for participants and 16.8/18 for coordinators. 98% of participants felt their privacy was “very” respected (mean 2.98/3). When looking at global CDR scores, 89.6% of participants with CDR=0 and 88.2% with CDR ≥0.5 were “very” confident in the accuracy of the information collected. In contrast, coordinators were “very” confident in the accuracy of their evaluation 84.4% of the time when participants had a CDR=0 and 67.7% of the time when participants had a CDR ≥0.5.

Conclusion

Overall satisfaction with telephone evaluations was high, but participant and coordinator confidence in the accuracy of assessments varied, with coordinator satisfaction lower for more cognitively impaired participants. Future work will analyze satisfaction with ongoing remote assessments and evaluate the impact of additional demographic and diagnostic variables.
Gait changes among older adults during a virtual wayfinding task: The role of spatial disorientation and heart rate variability
Authors: Amaefule Chimezie O , Lüdtke Stefan , Kirste Thomas , Teipel Stefan J
Published: February 2022

Background

Aging has been associated with decline in cognitive and motor performance, often expressed in dual‐task walking situations, such as wayfinding. A major barrier to successful wayfinding is spatial disorientation, occurring mostly at intersections. Although gait changes have been observed in various walking conditions, little is known about the effect of spatial disorientation on gait in wayfinding among older adults.

Method

24 participants (16 female) were measured in 3 conditions: 6 young controls (mean age = 23.50 years, SD = 0.54), 9 old controls (mean age = 68.77 years, SD = 2.72; mean MMSE = 28.85, SD = 0.89) and 8 old experimental (mean age = 71.87 years, SD = 5.38; mean MMSE = 29.14, SD = 0.80). Participants performed a wayfinding task consisting of about 14 decision points (i.e. intersections) within a virtual environment (VE), on a self‐paced treadmill equipped with a marker‐based optical motion‐capture system. The VE was held constant for the controls, and manipulated (e.g. moved landmarks) for the experimental participants. Heart rate was continuously monitored as a measure of psychophysiological response. Statistical analyses using Linear Mixed Effects Models and t‐tests, focused on hypothesis‐driven outcome measures extracted from decision points.

Result

Initial evaluation of the outcome measures show considerable effects of the disorientation intervention on gait; both the old control (constant VE) and experimental (manipulated VE) participants showed some variation in walking speed during instances of disorientation. This effect was, however, more pronounced, t(39) = ‐3.66, p<.001, for the old experimental condition participants (Figure 1).

Conclusion

Understanding underlying motion and psychophysiological signatures of spatial disorientation among older adults is a necessary first step, towards developing efficient situation‐aware assistive devices necessary for independent mobility. Initial findings show increased gait variability during instances of disorientation. The association of the disorientation effect with psychophysiological response is also being investigated. Further results will be presented by July 2021.
Strategies for activity maintenance in patient and family care and clinical trial adherence of GNA social plan in context of COVID‐19 health emergency
Authors: Andrade‐Villegas Angela M , Aguillon David , Gómez Manuela , Gómez‐Henck Clara , Zuluaga Maria , Rassi Sofia , Ramos Claudia , Madrigal Claudia , Uribe Claramonika , Saldarriaga Amanda , Alzate Diana , Ruiz Alejandra , Giraldo Andrea , Giraldo‐Chica Margarita , Reiman Eric M , Sink Kaycee M , Rios‐Romenets Silvia , Madrigal Lucia , Lopera Francisco
Published: February 2022

Background

The current pandemic COVID‐19 caused by SARS‐CoV2 has become a public health challenge, causing difficulty in patient care and follow up of people with cognitive impairment due to Alzheimer's disease. This situation motivated changes and adjustments to the Group of Neurosciences of Antioquia’s (GNA) Social Plan to guarantee effective continuity in patient care, family follow‐up, community interventions and adherence to the Alzheimer’s Prevention Initiative (API) Colombia clinical trial. This was an opportunity to innovate, create, reinvent and expand forms of care and intervention during confinement and pandemic to promote access through virtual media and the well‐being of beneficiaries.

Methods

The Social Plan program involves free access to basic care supplies for patients, home‐visits, support groups, cognitive stimulation groups and virtual community outreach activities like workshops for caregivers/interested public, Alzheimer's Day Commemoration “Cuidarme – Cuidarte” event (with available recorded resources), symposiums for caregivers, and informative meetings with participants of the API Colombia clinical trial.

Results

In the period of mandatory preventive confinement, 30 families obtained diapers, 23 families received prescription drugs not provided by health maintenance organizations (HMO) and 48 families received groceries. A total of 32 home‐visits were made: 7 in rural areas and 25 in urban areas. At the end of the mandatory preventive confinement, outpatient medical consults were resumed, no participants withdrew from the trial during this period. Thirty‐six people with MCI or dementia participated in virtual cognitive stimulation activities. Caregiver remote workshops held in the first semester of 2020 had a total attendance of 80 people, and events held in the second semester, such as the Commemoration of Alzheimer's Day and the Symposium for Caregivers, had a total attendance of 1,665 people and 1,000 people respectively.

Conclusion

GNA’s Social Plan and the amended which includes strategies of social support, knowledge and patient/caregiver empowerment strengthened the interaction between the community and GNA and likely favorably influenced adherence and retention in the API Colombia clinical trial in the face of challenges from the global pandemic.
Disentangling disease heterogeneity from neuroimaging data via adaptive distribution modeling–based collaborative clustering
Authors: Liu Hangfan , Grothe Michel J. , Rashid Tanweer , Labrador‐Espinosa Miguel , Toledo Jon B. , Habes Mohamad
Published: February 2022

Background

Neurodegenerative diseases, including Parkinson’s disease (PD), are clinically heterogeneous, with distinct subtypes encompassed within the same clinical diagnosis. Heterogeneity in brain diseases makes it challenging to recruit ideal patients into trials for suitable treatment or develop markers that capture the disease’s signals. Data‐driven clustering coupled with high dimensional neuroimaging data could further our understanding of heterogeneous disease biology and assigning specific patients groups to individualized treatments.

Method

We propose an Adaptive Distribution based COllaborative Clustering (ADCoC) method, which simultaneously clusters subjects and features via nonnegative matrix tri‐factorization. For denoising, we further introduce adaptive regularization based on coefficient distribution modeling. Unlike related sparsity techniques [1], we form the distributions using the data of interest to better fit the coefficients. We studied structural MRI data from 170 PD patients and 77 healthy controls enrolled in the Parkinson Progression Markers Initiative (PPMI). ADCoC partitioned the patients into 2 clusters. We compared the distribution of ICV normalized grey matter volumes in different regions between the two patient clusters and the healthy control group by student’s t‐test. Then we analyzed neuropsychological test data to compare the cognitive performance of the two patient clusters and the control group.

Result

Test statistic values of regions with FDR corrected p‐values smaller than 0.05 are plotted in Figure 1. Comparisons with the healthy control group show that PD cluster PD‐Post (54.7% of the PD samples) is characterized by a posterior cortical‐medial temporal atrophy pattern with worse cognition compared to PD cluster PD‐Front which had atrophy circumscribed to the frontal lobe areas. Analysis of neuropsychological test data further demonstrates that these MRI‐defined patient subtypes also show differences in clinical presentation, where PD‐Post show statistically significant lower cognitive performance compared to PD‐Front (Montreal Cognitive Assessment [MoCA] scores: 27.1 ± 2.4 [PD‐Post] vs 27.9 ± 1.7 [PD‐Front], p = 0.014).

Conclusion

When applied to a clinical dataset of MRI data from PD patients, ADCoC identified two stable and highly reproducible patient clusters characterized by frontal and posterior cortical‐medial temporal atrophy patterns. References: [1] H. Liu et al., "Adaptive sparsity regularization based collaborative clustering for cancer prognosis," MICCAI'19.
Microglia activation predicts tau positivity beyond Aβ in Alzheimer’s disease
Authors: Ottoy Julie , Bezgin Gleb , Savard Mélissa , Mathotaarachchi Sulantha , Pascoal Tharick A. , Chamoun Mira , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro
Published: February 2022

Background

Deposition of amyloid‐beta (Aβ) plaques and hyperphosphorylated tau are known hallmarks of Alzheimer’s disease (AD). In addition, neuroinflammation or microglia activation plays a role in AD pathophysiology and may be a potential driver of abnormal tau deposition. This study demonstrated the important brain regions where microglia activation, in addition to Aβ, is driving tau positivity in AD.

Method

120 participants from the TRIAD cohort underwent 18F‐AZD4694 amyloid‐PET, 18F‐MK620 tau‐PET, and 11C‐PBR28 neuroinflammation‐PET. All images were normalized to the ADNI template and quantified as SUVR in 35 regions‐of‐interest using cerebellar gray as the reference region. ANCOVA was used to assess the differences in levels of microglia activation between tau‐positive (T+; n=38) vs. tau‐negative (T‐; n=82), corrected for age, sex, APOE‐e4, education, and global Aβ. Tau status was based on both visual rating with elevated uptake in Braak1and2 and quantitative cut‐off of 1.22. In addition, step‐wise logistic regression was conducted to predict T+ in three steps: 1) the covariates, i.e. age, sex, APOEε4, and education, 2) covariates + global Aβ, and 3) covariates + global Aβ + activated microglia in each of the 35 ROIs, corrected for multiple comparisons using FDR. Our prediction model was trained based on a randomly selected 70%/30% training/test set. In order to investigate the stability of our model, this procedure was repeated 500 times.

Result

Levels of microglia activation were significantly increased in T+ compared to T‐ in the posterior cingulate (p=0.0001), middle (p=0.02) and inferior (p=0.0005) temporal, fusiform (p=0.0004), and orbitofrontal cortex (p=0.005). Based on logistic regression and a likelihood‐ratio test between each step, we found that the ‘covariates + global Aβ model’ performed significantly better in predicting T+ than the ‘covariates‐only’ model (χ2(1)=72.64, p<0.0001). In the 3‐step model, the addition of activated microglia showed a significant improvement of the model’s performance to predict T+, particularly the activated microglia in the hippocampus (p=0.001), middle (p=0.006) and inferior (p=0.001) temporal, and fusiform (p=0.001) cortex. Receiver operating characteristic curves (ROC) and AUCs are shown in Fig 1.

Conclusion

Our study demonstrated that activated microglia in the Braak2 to Braak4 regions play an important role in predicting tau positivity in addition to Aβ.
Discovering genetic biomarkers for Alzheimer’s disease using 2D‐CNN and GWAS
Authors: Pan Dan , Rong Huabin , Zeng An , Huang Yin , Jia Longfei , Song Xiaowei
Published: February 2022

Background

To identify candidate neuroimaging and genetic biomarkers for Alzheimer’s Disease (AD) and other brain diseases, especially for little‐known brain disorders, in a data‐driven way, we advocate an approach which incorporates an adaptive classifier ensemble model by combining Convolutional Neural Network (CNN) and Ensemble Learning with Genetic Algorithm (GA), i.e., the CNN‐EL‐GA method, into Genome‐Wide Association Studies (GWAS).

Method

In the CNN‐EL‐GA method, a large number of base classifiers, i.e., CNN models, were trained utilizing a set of sagittal, coronal, or transversal magnetic resonance imaging slices, and the CNN models with strong discriminability were then selected and integrated into a single classifier ensemble with the GA for classifying AD. While the generalization capability of the acquired classifier ensemble was maximized, the intersection points were decided by the most discriminative slices among the sagittal, coronal, and transversal slice sets. The gray matter volumes of the top ten discriminative brain regions which contained the most intersection points were utilized to carry out GWAS together with the genotypic data. The pipeline of the proposed approach incorporating the CNN‐EL‐GA method into GWAS for discovering candidate genetic biomarkers of AD is shown in Figure 1.

Result

Six genes of PCDH11X/Y, TPTE2, LOC107985902, MUC16 and LINC01621 as well as Single Nucleotide Polymorphisms, e.g., rs36088804, rs34640393, rs2451078, rs10496214, rs17016520, rs2591597, rs9352767 and rs5941380, were identified.

Conclusion

This approach overcomes the limitations associated with subjective factors while adaptively achieving more robust and effective candidate biomarkers in a data‐driven way. The approach is promising to advance the discovery of effective candidate genetic biomarkers for brain disorders.
White matter integrity is associated with self‐awareness of financial decision‐making in cognitively healthy older adults
Authors: Sunderaraman Preeti , Gazes Yunglin , Ortiz Gema , Chapman Silvia , Joyce Jillian L. , Langfield Christopher , Mensing Ashley , Stern Yaakov , Cosentino Stephanie
Published: February 2022

Background

Reduced awareness of one’s financial decision‐making abilities (financial awareness) can result in costly financial mistakes (e.g., forgetting to pay credit card dues) and increase one’s vulnerability to financial exploitation (e.g., getting scammed). In cognitively healthy older adults, thinner right medial temporal cortex is associated with overconfidence in one’s financial decision‐making abilities. However, it is important to examine other neuroimaging metrics to create a comprehensive picture of the links between brain and financial awareness in healthy older adults. In the current study, we examined the white matter correlates of financial awareness and hypothesized that the tracts connecting the right temporal‐frontal regions would be most strongly correlated with financial awareness.

Method

Design ‐ Cross‐sectional, prospective study. Setting ‐ Community‐based. Participants: 44 individuals were included with mean age=68.43 years (SD=5.1), mean education=15.88 (SD=2.41), 60% = women, 67% = White, 30% = Black and 3% = other races, and 95% = non‐Hispanics. Measures: Awareness Metrics – Financial awareness was measured by integrating metacognitive ratings into the Objective Financial Competency Assessment Inventory. Before each item, we obtained confidence ratings regarding performance on that item. Level of awareness was operationalized via a calibration score reflecting the difference between average performance and average confidence, reflecting the extent to which individuals were over‐ or under‐confident. Mean Diffusivity – Data were processed with Tracts Constrained by Underlying Anatomy toolbox distributed as part of the FreeSurfer library (v5.3) which produced averages of mean diffusivity for 18 white matter tracts. Lower mean diffusivity values indicated higher white matter integrity.

Result

The right superior longitudinal fasciculus–temporal (r = 0.437, p = 0.003) and parietal (r = 0.433, p = 0.003) bundles had the strongest correlations with calibration scores such that higher (i.e., worse) diffusivity was associated with values reflecting over‐confidence.

Conclusion

Our findings converge with the growing literature on the unique role of the right hemisphere temporal connections in supporting financial awareness. We find an equally important role for right parietal‐frontal connections in financial awareness. Our findings are in line with studies on financial exploitation in which the right parietal and temporal pathways were found to be involved in scam susceptibility.
A novel MRI approach for evaluation of microstructural neurodegeneration in early Alzheimer disease
Authors: Kothapalli Satya V.V.N. , Benzinger Tammie L.S. , Aschenbrenner Andrew J. , Perrin Richard J. , Hildebolt Charles F. , Goyal Manu S. , Fagan Anne M. , Raichle Marcus E. , Gordon Brian A. , Morris John C. , Yablonskiy Dmitriy A.
Published: February 2022

Background

Currently, brain tissue atrophy serves as in vivo structural MRI biomarker of neurodegeneration in Alzheimer Disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that AD‐related memory loss begins when neurons are lost. Hence, in vivo detection of neurodegeneration preceding detectable atrophy is essential for early AD diagnosis.

Method

Our innovative approach to assessing neuronal damage in vivo is based on (a) quantitative Gradient Recalled Echo (qGRE) MRI technique and (b) genetically‐informed relationships between qGRE metrics and major components of brain tissue cellular structure (neurons/neurites and glia) that were obtained using gene expression profiles across the human brain provided by the Allen Human Brain Atlas. Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®)=0, amyloid β (Aβ)‐negative), n=34] HC; Preclinical AD (CDR=0, Aβ‐positive, n=19), PC; and mild AD (CDR=0.5 or 1, Aβ‐positive, n=17), AD.

Result

Preliminary data show that qGRE identified new biomarkers in AD brain characterizing tissues with significantly lower (termed Dark Matter) and relatively preserved (termed Viable Tissue) concentrations of neurons. The fraction of Dark Matter showed clinically important and significant differences between HC and PC groups in hippocampus, middle temporal, fusiform, postcentral, and inferior parietal brain regions. However, no HC vs. PC group difference was detected by the volumetric measurements (Figure 1). Further, measurements of the Dark Matter fraction in the hippocampus showed strong associations with Cerebrospinal fluid (CSF) amyloid Aβ42 (r=‐0.52), CSF ptau (r=0.60), 18F‐AV1415‐PET tau imaging (r=0.60), and PiB‐PET amyloid imaging (r=0.60). These associations were significantly stronger compared with volumetric measurements: CSF amyloid Aβ42 (r=0.18), CSF ptau (r=‐0.24), PET tau imaging (r=‐0.39), and PiB‐PET amyloid imaging (r=‐0.17)). Importantly, the Dark Matter fraction had a significant inter‐regional association (r=0.87) with neuronal count in the hippocampal subfields obtained from histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration (Figure 2).

Conclusion

qGRE‐based measurements identify the microstructural changes in early AD‐related neurodegeneration that are not recognized by structural MRI atrophy measurements, therefore providing new biomarkers for early AD detection.
Cross‐cultural issues in AD risk factors and assessment: A Nigerian perspective
Authors: Ucheagwu Valentine A
Published: February 2022

Background

Roles of demographics, anthropometry and metabolic syndrome (Mets) on cognition in mid adults from rural part of Nigeria were examined to determine their contribution to dementia.

Method

One hundred and seventy two (172) middle aged adults from a rural community in Anambra state Nigeria were recruited for the study. Their age range were between 50 – 70 years with a mean age of 57.48 and SD age of 5.48. The Montreal Cognitive Assessment (MoCA) Symbol Digit Modality Test (SDMT) and Digit Symbol Test (DST) were used to assess the participants’ cognition. The anthropometric measures assessed were the body mass index (BMI), height, weight and waist circumference while the Mets assessed were blood sugar level and total cholesterol and blood pressure. Gender, occupation and education were included as demographic factors assessed in the study.

Result

Findings show the BMI, weight and waist circumference as predictors of general cognition, but the blood pressure and height were not significant predictors. Equally, mixed findings were got on processing speed. The variables measured were not significant predictors of SDMT as a measure of processing speed while they to significant extent predicted processing speed when DST was used.

Conclusion

Contrary to findings from western world blood pressure as a cardiovascular marker did not predict general cognition and processing speed while mets had significant contribution on general cognition and processing speed.
Subthreshold amyloid pathology and changes in functional brain networks in patients with delayed cognitive decline after stroke
Authors: Lim Jae‐Sung , Lee Jae‐Joong , Woo Choong‐Wan , Shin Dong Woo , Lee Keon‐Joo , Kim Hang‐Rai , Yang Mi Hwa , Jang Myung Suk , Baek Min Jae , Kim Beom Joon , Kim Sangyun , Bae Hee‐Joon
Published: February 2022

Background

In clinical practice, some of the stroke survivors who have normal cognitive function until three to six months after index stroke, develop cognitive decline gradually after then. Although amyloid deposits and advanced small vessel disease are reported to be the possible predictors, pathogenesis for delayed cognitive decline has not been identified yet. Thus, we aimed to explore the brain network characteristics in those with delayed cognitive decline after stroke compared to those without.

Method

Using a prospective stroke registry, we identified patients with ischemic stroke who had undergone the cognitive evaluations including mini‐mental state examination (MMSE) twice or more after index stroke. We included patients whose baseline cognitive evaluation (between 1 and 12 months after stroke) was normal and who had one or more follow‐up evaluations after more than 6 months from the baseline evaluation. Among 222 eligible patients, decliners were defined as having a decline in 3 or more per year or an absolute decline of 5 or more between baseline and follow‐up MMSE, while non‐decliners as having a decline of 1 point per year or less and an absolute decline of less than 3 points. Brain network attributes were analyzed using resting‐state functional MRI, and superimposed amyloid positivity was assessed using 18F‐florbetaben PET.

Result

Eleven patients (5%, 11/222) met the criteria for decliners, and ten matched non‐decliners were enrolled. For about 5.7 years of follow‐up, the mean change of MMSE scores was ‐9.1 points in the decliners, while ‐0.2 point in the non‐decliners. Ten (10/11) decliners were amyloid‐negative on the amyloid PET, and the APOE e4 allele was identified in one decliner. However, the global SUVR value showed a negative correlation with the final MMSE scores as well as the amount of MMSE change. Normalized transitivity was lower in decliners compared to non‐decliners. Mean connectivity strengths were averaged based on the seven canonical functional networks, and the intra‐network connections within the frontoparietal network showed the considerable differences between groups. (Figure)

Conclusion

This study suggests that alteration of brain networks may explain the pathogenesis of the delayed post‐stroke cognitive decline independent of amyloid PET positivity and APOE genotype.
Data‐driven cut‐off values for 18‐F‐AV‐45 tau PET staging in AD
Authors: Quattrini Giulia , Ferrari Clarissa , Pievani Michela , Frisoni Giovanni B. , Marizzoni Moira
Published: February 2022

Background

The identification of unbiased cut‐off for amyloid and tau positivity is fundamental to early AD classification. While cut‐offs for amyloid markers are relatively established, tau markers cut‐off definition is controversial as they are influenced by the reference population. Moreover, several not modifiable risk factors (i.e., Apolipoprotein E ε4 allele [APOE4], age, and sex) may affect tau pathology. The aim of the present study is to define data‐driven cut‐off values for cortical tau staging and to assess the effect of APOE4, age, and sex.

Method

Data were derived from the Alzheimer's Disease Neuroimaging Initiative consortium (ADNI). Amyloid‐PET (18‐F‐AV‐45) standardized uptake value ratio (SUVR) was used to classify subjects as amyloid positive (A+) or negative (A‐). Tau PET (18‐F‐AV1451) SUVR, APOE4, age, sex and clinical information were then collected. For 18‐F‐AV1451 SUVR, we applied a staging system according to Braak. Data‐driven stage‐specific 18‐F‐AV1451 cut‐offs were computed by applying Gaussian mixture model (GMM) to the subsample including A‐ cognitively normal (CN‐A‐) and AD dementia (AD‐A+) (n=194). We also investigated the effect of age, APOE4 status, and sex on 18‐F‐AV1451 SUVR distribution and cutoff extraction applying the GMM to 18‐F‐AV1451 SUVR distribution adjusted for these covariates. Finally, the cut‐offs sensitivity was assessed in preclinical AD (CN‐A+; n=45), prodromal AD (MCI‐A+; n=22), and AD‐A+ (n=19) subjects.

Result

In tau stage regions I–VI, 18‐F‐AV1451 cut‐off values for positivity ranged between 1.21‐1.35. The cut‐offs sensitivity increased from CN‐A+ to MCI‐A+ and AD‐A+ in all tau stages regions: from 20% to 64% and 90% for tau stage I‐II, from 16% to 46% to 90% for tau stage III, from 11% to 46and 90% for tau stage IV, from 0% to 18% and 53% for tau stage V, and from 0% for CN‐A+ and MCI‐A+ to 32% for tau stage VI. A similar sensitivity progressive pattern was detected within each tau stage region. Finally, APOE4, age, and sex significantly impacted 18‐F‐AV1451 regional SUVR of each tau stage.

Conclusion

Data‐driven 18‐F‐AV1451 SUVR cut‐offs for in‐vivo tau staging could be useful to index regional tau deposition. The impact of APOE4, age, and sex should be also considered.
Cerebral white matter microstructure in superagers: A diffusion MRI study of a population over the age of 80 with youthful episodic memory
Authors: Pascual Marta Garo , Zhang Linda , Strange Bryan A.
Published: February 2022

Background

Superagers are people over the age of 80 who possess the episodic memory function of a person 20‐30 years younger. We have recently identified the grey matter signature of this population, with preserved volume in episodic memory‐related areas and motor thalamus. Here we extend these observations by characterising superagers’ cerebral white matter microstructure using diffusion MR imaging.

Method

A sample of 64 superagers (mean age 81.9 years ± 1.9 std, 59.4% women) and 55 age‐matched controls (mean age 82.4 years ± 1.9 std, 63.6% women) from the Vallecas Project cohort in Madrid, Spain, were selected according to their episodic memory score in the Free and Cued Selective Reminding Test. Superagers scored at or above the mean value of a 50‐56yo person, whereas controls scored within one standard deviation for their age. Differences across groups in two measures derived from DTI data were tested, comprising fractional anisotropy (FA), and mean diffusivity (MD). Voxelwise analyses were carried out using TBSS (Tract‐Based Spatial Statistics, [Smith 2006]), in FSL software.

Result

Superagers showed higher FA than controls in bilateral frontal tracts and the anterior thalamic radiation (p < 0.05, FWE‐corrected). Lower MD were found in superagers compared to controls in an extensive network comprising the forceps major and minor, superior and inferior longitudinal fasciculus, inferior fronto‐occipital fasciculus, anterior thalamic radiation, corticospinal tracts and cingulum bundle (p < 0.05, FWE‐corrected).

Conclusion

Higher FA and lower MD can be indicative of preserved white matter microstructure. Superagers exhibit higher FA in frontal tracts and lower MD across the main cerebral white matter tracts relative to healthy controls with normal‐memory‐for‐age. These results suggest an association between preservation of white matter microstructure and extraordinary memory function in old age.
Cognitive resilience to tau and amyloid burden in a memory clinic population
Authors: Ribaldi Federica , Altomare Daniele , Quattrocchi Lara , Tomczyk Szymon , Garibotto Valentina , Frisoni Giovanni B.
Published: February 2022

Background

Cognitive resilience (CR) is defined as the capacity to sustain a better‐than‐expected cognitive performance based on pathological burden. There is high variability in the individuals’ CR, and it has been demonstrated that individuals with high resilience develop symptoms later than those with low CR. The aim of this study it to investigate the association between demographic and clinical features and individual CR.

Method

144 subjects from the Geneva memory center cohort (N=37 cognitively unimpaired, N=84 mild cognitive impairment, N=23 dementia) that underwent amyloid PET, tau PET and an extensive neuropsychological battery were included. A linear regression model between amyloid and tau global standardized uptake value ratio (SUVr) vs Mini‐Mental State Examination (MMSE) was performed, and the residuals of the model were used as a measure of individual CR. A multivariate linear regression was used to assess the association between CR and age, sex, education, and white matter hyperintensities.

Result

Mean age was 72.2 (sd = 7.8), 72 were female (50%), and mean years of education was 13.9 (4.1). Greater CR was associated with better education (β = 0.26, p = 0.001), older age (β = 0.25, p = 0.002) and low white matter hyperintensities (β = ‐0.17, p = 0.037). No associations were observed between CR and gender (gender, β = 0.06, p = 0.455).

Conclusion

We confirmed in our population that education is strongly associated with CR. Future development of this study will be to investigate brain resilience (BR), defined as the relationship between atrophy and amyloid and tau, and the longitudinal cognitive trajectory of the individuals with high BR and/or CR compared to those with low BR and/or CR. the definite article More (Definitions, Synonyms, Translation)
Brain architecture changes across the FTLD spectrum
Authors: Cividini Camilla , Agosta Federica , Basaia Silvia , Spinelli Edoardo Gioele , Castelnovo Veronica , Canu Elisa , Riva Nilo , Magnani Giuseppe , Caso Francesca , Filippi Massimo
Published: February 2022

Background

To explore structural/functional MRI connectomic features of the motor neuron disease (MND) and behavioral variant of frontotemporal dementia (bvFTD) spectrum.

Method

115 MND (including amyotrophic lateral sclerosis [ALS] and primary lateral sclerosis), 35 bvFTD patients and 61 controls underwent clinical/cognitive and MRI evaluations. MND patients were divided in 79 pure‐motor (MND‐motor) and 36 cognitive/behavioral impaired (MND‐ci/bi). A sub‐analysis was performed on ALS patients only (54 ALS‐motor, 21 ALS‐ci/bi and 8 ALS‐FTD). Graph analysis and connectomics assessed structural/functional topological network properties at global, lobar and regional level.

Result

Globally, bvFTD showed altered structural and functional network properties compared to all other groups. At lobar level, bvFTD showed altered structural and functional network properties within the frontotemporal and basal ganglia areas relative to all groups. Structural alterations in the parietal lobe discriminated bvFTD from controls and MND‐motor only. MND groups showed altered structural properties within sensorimotor and basal ganglia areas relative to controls. Regionally, bvFTD showed widespread structural damage and decreased functional connectivity relative to all groups. MND showed disrupted structural architecture and enhanced functional connectivity within sensorimotor, basal ganglia and frontotemporal areas relative to controls. Similar results have been found in ALS sub‐analysis.

Conclusion

The disruption of the structural architecture in MND worsens in relation with cognitive deficits. Functional changes are characterized by enhanced functional connectivity in presence of exclusive motor impairment that intensifies with the occurrence of cognitive impairment in MND. The Italian Ministry of Health (GR‐2011‐02351217; GR‐2013‐02357415; RF‐2011‐02351193), AriSLA (ConnectALS), European Research Council (StG‐2016_714388_NeuroTRACK).