bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of automatically segmented enlarged perivascular spaces with neuropathology and cognitive decline in a community cohort of older adults
Authors: Petit Carles Javierre , Tamhane Ashish A. , Evia Arnold M. , Makkinejad Nazanin , Agam Gady , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: December 2020

AbstractBackgroundEnlarged perivascular spaces (EPVS) have been linked to increased risk of stroke, lower cognitive function, and vascular dementia. However, neuropathologic correlates of EPVS, and their contributions to cognition, are unclear. In this work, a deep‐learning algorithm for automatic segmentation of EPVS was developed, and allowed full quantification of EPVS in the whole brain and regionally. Then, neuropathologic correlates of EPVS and contributions of EPVS to cognition were analyzed within each region in a large community‐based cohort of older adults.MethodThis work included 287 participants of two longitudinal studies, Rush Memory and Aging Project, and Religious Orders Study (Figure 1). Ex‐vivo T2‐weighted images, and detailed neuropathologic examination by a board‐certified neuropathologist (blinded to all data) were obtained for one brain hemisphere from each participant. A total of 10 neuropathologies were assessed (Figure 2).The data from 10 participants with varying EPVS severity and manually segmented EPVS were used to train a deep learning model (Figure 3) to automatically segment EPVS in the ex‐vivo MRI data of all participants.Relative EPVS volume (EPVSrel), meaning EPVS volume normalized by white matter volume, and total number of EPVS (EPVSnum) was calculated for each participant. Similar measurements were made per lobe and basal ganglia (e.g. EPVSnum‐parietal). All measures were square root transformed to reduce skewness.ResultThe deep learning model achieved a mean Dice Similarity Coefficient of 0.655 ± 0.058 (comparison in Figure 4). Whole brain relative EPVS volume and number were associated with gross infarcts (Figure 5). Regional EPVS were associated with gross infarcts in most of the brain, and with cerebral amyloid angiopathy mainly in the occipital and temporal lobes (Figure 5). Relative EPVS volume in the occipital lobe was negatively correlated with semantic memory (‐0.443, p = 0.03) and perceptual speed (‐0.311, p = 0.048) above and beyond what was explained by neuropathologies and demographics.ConclusionThis investigation provides robust evidence on the neuropathologic correlates of EPVS and the contributions of EPVS on cognition in a large community‐based cohort of older adults. Fully quantitative assessment of EPVS was facilitated by automatic EPVS segmentation using deep learning. EPVS were shown to have associations with gross infarcts and cerebral amyloid angiopathy, and independent contributions on cognition.
Neuropsychiatric index and relationship quality for caregivers of older Mexican Americans
Authors: Cantu Phillip A , Aranda Maria P 
Published: December 2020

AbstractBackgroundInformal caregivers play a key role in supporting older Mexican Americans, as they are less likely to enter nursing facilities than other racial/ethnic groups in the U.S, even when faced with high levels of physical and cognitive impairment. The quality of caregiving relationships is directly related to caregiver stress. However, there is little research on the correlates of caregiver assessment of relationship quality. Assessment of caregiver relationship quality is especially important for Mexican American older adult caregivers due to the high prevalence of cognitive impairment and dementia in this population.MethodsUsing data from caregiver supplement of the wave 7 of the Hispanic Established Population for the Epidemiologic Study of Elderly (HEPESE)(n=460) study of very old (Age 85+) Mexican Americans we examine the association of relationship quality with care recipient health, caregiver health, and caregiver finances. Caregiver relationship quality is measured using both positive and negative relationship assessments separately. We use linear regression to examine the correlates of caregiver relationship quality net of caregiver and care recipient demographics, care recipient physical (caregiver‐rated health, ADL and IADL disability) and mental health (caregiver‐rated NPI and care recipient MMSE), caregiver health (caregiver‐rated health and depression) caregiver finances (income and financial burden).ResultsCaregivers who were married to the care recipient reported both less positive and more negative assessments. Male care recipients, married caregivers, and caregiver depression were related to positive but not negative assessments. Both positive and negative assessments were significantly associated with IADL disability and NPI score but not MMSE score.ConclusionsRelationship quality for Mexican Americans among the very old is related to hands‐on care tasks and not financial strain. Disability status suggests that early changes in functional status are more stressful than more severe disability due to adjustment periods. Married caregivers may report higher relationship quality due to additional support from spouses in caregiving roles. NPI status is the most strongly associated correlate of both positive and negative relationship quality, while MMSE was not significantly related to either. Our results suggest that caregiver assessments of behavioral disturbances are more important to relationship quality than care recipient tested cognitive functioning.
Reduced cortical thickness in World Trade Center responders with cognitive impairment
Authors: Clouston Sean , Deri Yael , Horton Megan , Tang Cheuk , Diminich Erica D , Pellecchia Alison , Carr Melissa , Gandy Samuel , Sano Mary , Bromet Evelyn , Lucchini Roberto , Luft Benjamin 
Published: December 2020

AbstractBackgroundRecent reports suggest that World Trade Center (WTC) responders are at increased risk for cognitive impairment (CI). The current study utilized neuroimaging to determine whether WTC responders with CI have reduced cortical thickness (CTX).MethodWTC responders (N=99) with and without CI, recruited from an epidemiologic study of cognitive aging among WTC responders, participated in a neuroimaging study that included a T1‐MPRAGE protocol. CTX was computed in 34 Desikan‐Killiany atlas regions of interest (ROIs). Regional CTX between CI and non‐CI responders were compared using t‐tests and reported using Cohen’s D, and whole‐brain surface‐based morphometry using threshold‐free cluster analysis. Sensitivity analyses were used to examine possible associations of CTX with symptoms of PTSD and/or severity of WTC exposure. Analyses were adjusted for multiple comparisons using the false discovery rate (FDR = 0.05).ResultsParticipants were aged 55.84 years on average, and 47 had CI as determined by clinical mental status examination using the Montreal Cognitive Assessment (MoCA≤20). When compared to unimpaired responders, responders with CI had reduced mean whole‐brain CTX (P = 0.002). Region‐based analyses identified reduced CTX in 21/34 bilateral ROIs (D = ‐0.60) with the largest effects centered in the precentral gyrus (D = ‐0.74, P = 0.007). Surface‐based morphometry revealed that CTX was reduced across large parts of the frontal, temporal, and occipital lobes, all of which remained significant following adjustment for multiple comparisons. While more regions were identified as reduced in responders with both PTSD and CI (18 versus 9 ROIs in responders with PTSD and CI versus CI alone respectively), sensitivity analyses were not able to distinguish CI with PTSD as compared to CI alone.ConclusionsResults from structural imaging revealed that WTC responders with CI had reduced cortical thickness across multiple brain regions including but not limited to those commonly affected by Alzheimer’s disease. This study represents the first neuroimaging study investigating CTX as an indicator of CI in WTC responders at midlife.
Sex, tau, and cortical thinning in the temporal lobe: Findings from the Harvard Aging Brain Study
Authors: Manning Lyssa K , Properzi Michael J , Scott Matthew R , Hampton Olivia L , Rubinstein Zoe B , Mayblyum Danielle V , Hanseeuw Bernard J , Schultz Aaron P , Rentz Dorene M , Johnson Keith A , Sperling Reisa A , Buckley Rachel F 
Published: December 2020

AbstractBackgroundRecent work suggests regional tau burden is proximal to cortical thinning in clinically‐normal older adults. Clinically‐normal older females show higher levels of temporal tau burden than males, but it remains to be seen whether the association between tau pathology and cortical thinning is significantly impacted by biological sex. We hypothesized that females with higher tau burden would show faster cortical thinning than their male counterparts.Method123 clinically‐normal older adults from the Harvard Aging Brain Study (clinical dementia rating = 0; age (SD) = 73.6(6.1); female = 58%) underwent cross‐sectional Pittsburgh Compound‐B (PiB)‐PET, Flortaucipir (FTP)‐PET and longitudinal MRI (2.95 years; range = 1.3‐5.3 years post‐tau scan). FTP‐PET was introduced after onset of the study, so the first FTP‐PET scan was used as ‘baseline’. We selected temporal tau ROIs based on our previous results (HABS & ADNI) showing sex differences in tau signal (e.g. entorhinal, inferior temporal, fusiform, middle temporal). We conducted iterative linear mixed models examining the interaction of sex*time*tauROI on cortical thinning across 34 ROIs, covarying for baseline age*time. To assess the impact of PiB on this relationship, we also examined PiB+ and PiB− groups separately (based on HABS PiB DVR cut‐off = 1.186).ResultFemales with higher inferior temporal tau burden showed significantly faster cortical thinning than males in the entorhinal cortex only, t = −2.40, p = 0.02 (see Figure 1). This result was significant in the PiB+ group (n = 33: t = −2.28, p = 0.03), but not PiB− (n = 90: t = −1.60, p = 0.11), suggesting this relationship was driven by a sex effect in PiB+ individuals (see Figure 2). We also found a similar association using fusiform tau (p = 0.03).ConclusionIn the context of high inferior temporal tau burden, females exhibit significantly faster entorhinal cortical thinning than males. This result suggests that sex may moderate the effect of tau burden on cortical thinning, and for a given level of tau burden, females may be more susceptible to cortical atrophy in temporal lobe structures. We did not adjust for multiple comparisons, so replication is required in another cohort. This relationship between tau pathology and entorhinal neurodegeneration in females provides further insight into how sex‐related cortical structural vulnerability may correspond to pathology over time.
Clinical and neurodegenerative features associated with amyloid‐β‐negative medial temporal tau deposition as measured by multimodal PET imaging
Authors: Grothe Michel J. , Moscoso Alexis , Schöll Michael 
Published: December 2020

AbstractBackgroundThe combined accumulation of amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles is the defining feature for Alzheimer’s disease (AD) pathology. However, tau can also accumulate in the medial temporal lobe in the absence of Aβ pathology, a neuropathological condition termed primary age‐related tauopathy (PART) that can result in amnestic impairments similar to early stage AD. Here we aimed to describe clinical and neurodegenerative characteristics of older amnestic individuals with Aβ‐negative medial temporal tau deposition as revealed by in‐vivo PET imaging.MethodIn the ADNI cohort we identified a total of 174 older individuals with amnestic deficits (155 amnestic mild cognitive impairment (aMCI), 19 mild AD‐type dementia (ADD)), who had tau‐sensitive ([18F]flortaucipir) and Aβ‐sensitive ([18F]florbetapir or [18F]florbetaben) PET acquisitions, as well as structural MRI and [18F]FDG‐PET scans. Presence/absence of Aβ and tau pathology was determined by applying sensitive cutoffs to Aβ‐PET‐derived centiloid values (>12 centiloids) and entorhinal flortaucipir SUVR (inferior cerebellum reference; >1.175 SUVR, corresponding to the highest value observed in Aβ‐negative healthy controls below 65y (N=13, 56‐63y)). Clinical, genetic, and neuroimaging data of patients with Aβ‐negative tau deposition (A‐/T+, N=19, 17/2 aMCI/ADD) was contrasted to A+/T+ (N=81, 65/16 aMCI/ADD) and A‐/T‐ patients (N=38, 37/1 aMCI/ADD) as well as to A‐/T‐ healthy controls (N=40).ResultA‐/T+ patients had a markedly lower proportion of APOE‐ε4 carriers (16%) compared to A+/T+ (69%, p<0.001), and a higher proportion of APOE‐ε2 carriers (42%) compared to A+/T+ (1%, p<0.001) and A‐/T‐ (15%, p=0.04). A‐/T+ patients had comparable memory and executive deficits compared to A‐/T‐, but were less impaired than A+/T+, even when excluding ADD patients. In brain‐wide neuroimaging analyses, tau deposition in A‐/T+ was mainly restricted to the medial/inferior temporal lobe and related limbic structures (Fig‐1). These areas also showed marked hypometabolism, but only subtle gray matter atrophy. By contrast, A+/T+ patients showed a widespread neocortical tau distribution, as well as marked neurodegeneration on both FDG‐PET and structural MRI. A‐/T‐ patients did not show significant neuroimaging abnormalities.ConclusionAβ‐negative tau deposition as evidenced by PET associates with distinct clinical, genetic, and neurodegenerative features that resemble that of neuropathologically‐defined PART and may allow to study this condition in‐vivo.
Is Type 2 diabetes mellitus associated with an increased pathological burden in clinically and pathologically diagnosed Alzheimer's dementia?
Authors: Sadrolashrafi Kaviyon , Miller Justin B. , Decourt Boris , Adem Abdu , Sabbagh Marwan N. 
Published: December 2020

AbstractBackgroundEpidemiological evidence suggests that Alzheimer’s disease (AD) and Type‐2 Diabetes Mellitus (T2DM) share pathophysiological processes. T2DM causes central insulin resistance, which generates a hypoglycemic microenvironment in the brain. The oxidative stress established as a result leads to mitochondrial dysfunction, inflammation, advanced glycation end‐product (AGE) production, insulin receptor signaling pathway impairment, and insulin‐degrading enzyme (IDE) inhibition. These widespread repercussions catalyze amyloid‐β (Aβ) plaque and neurofibrillary tangle (NFT) formation. Here, we hypothesize that T2DM is associated with an increased AD pathological burden in clinically‐ and pathologically‐diagnosed AD.MethodAll data were obtained from the Uniform Data Set (UDS) v3, the Neuropathology Data Set, and the Researcher’s Data Dictionary‐Genetic Data from the NIA funded National Alzheimer’s Coordinating Center (NACC). The data was compiled by NACC in a dataset querying, the following keywords: “Alzheimer’s disease”, “Type 2 diabetes mellitus”, “Thal phase (A score)”, “Braak neurofibrillary stage (B score)”, “Neuritic plaque score (C score)”, and “Alzheimer's disease neuropathology change (ABC score)”. The dataset relies on autopsy‐confirmed data in clinically‐diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. In our analysis, there were 271 AD cases with T2DM and 8,431 cases without. Differences in scores were explored using one‐way ANOVA. Effect sizes were calculated using sample means and standard deviations (Cohen’s d).ResultThe differences in pathology staging between AD‐confirmed individuals with T2DM and those without were statistically significant, with effects ranging from medium (d = ‐0.34; r = ‐0.17) to large (d = 0.53 and 0.51; r = 0.25). The presence of recent or active T2DM was associated with a higher Thal phase of amyloid plaques (μdiff = 1.89) as well as a higher NIA‐AA Alzheimer’s disease neuropathologic change, ADNC (μdiff = 1.57). The presence of T2DM was also correlated to a lower Braak stage for neurofibrillary degeneration (μdiff = ‐0.30).ConclusionThese findings suggest that there is more amyloid burden in individuals with AD and T2DM than AD without T2DM. Our results indicate that individuals with T2DM have significantly higher amounts of plaques by Thal stage, as well as higher ABC scores.
Eigen analysis on ultrafast FMRI data shows altered dynamic functional connectivity in MCI individuals
Authors: Park Sung Min , Rane Swati 
Published: December 2020

AbstractBackgroundResting state functional connectivity (rsFC) is a powerful tool to detect brain dysfunction. Recent studies show that resting state networks are not static, but dynamic and alter connectivity in seconds. The use of simultaneous multislice imaging technology allows sub‐second fMRI acquisitions in ADNI3. We leverage eigenanalysis to compare brain connectivity states and their temporal dynamicity between cognitive normal older adults (NC) and MCI participants.MethodWe analyzed 105 ADNI subjects (50 MCI [22M], age = 74 ± 8 and 55 NC [35M], age = 75 ± 8) with T1 and BOLD fMRI acquisition (TR = 600 ms). Processing included motion correction, detrending, despiking, physiological noise correction and registration to standard space. We performed harmonization using ComBat to minimize site‐related variability. We employed a sliding window approach followed by eigenanalysis1 to extract spatially independent connectivity states between regions derived from 4 networks (see Table 1). For each connectivity state, we identified whether the timecourse was different between NC and MCI subjects and created a final difference network comparing the brain state between the two groups.ResultFigure 1 shows the 10 brain connectivity states, spanning 32 regions and 4 networks, identified using eigennetwork analysis. Figure 2 shows the timecourse for each of the connectivity states. Finally, Figure 3 shows the difference network for the MCI group with and without harmonization. Harmonization appears to have a considerable effect on the connectivity state pattern. We then compared the harmonized difference network to within‐site difference networks. RMSE was smaller for the harmonized network than that of the unharmonized network.ConclusionWe demonstrate the use of eigennetwork analysis to determine a dynamic brain connectivity state in MCI that is different than NC. The advantages of this approach are two‐fold: One, all brain regions and resting state networks are considered as a whole instead of studying each network separately. Two, it allows us to study the temporal properties of the networks in addition to their spatial characteristics. This analysis enables us to capture a more accurate depiction of the connectivity of the brain and its dynamic nature.
RPS16 and NOL6 splice region variants are associated with early onset Alzheimer's disease
Authors: Guen Yann Le , Napolioni Valerio , Belloy Michael E. , Eger Sarah J. , Kennedy Gabriel , Morgan Kevin , Greicius Michael D. 
Published: December 2020

AbstractBackgroundCommon genetic polymorphisms identified by genome wide association explain less than half the genetic variance of Alzheimer’s disease (AD). Rare genetic mutations with larger effect sizes than common variants are expected to contribute to this missing heritability. We developed an extreme phenotype filtering‐based approach to identify rare candidate causal variants.MethodFigure 1 describes our analysis pipeline. Briefly, we removed AD cases who had a discordant pathology diagnosis, or a known pathogenic mutation, and duplicated individuals (using identity‐by‐descent). We then restricted the analysis to APOE4‐negative cases with age‐at‐onset below 70 and required controls to be cognitively normal over 75. We started with variants present in ADSP whole exome sequencing data to guarantee a minimum number of control subjects for filtering. We restricted our analysis to variants with impact equal to high, moderate, or modifier annotated by Ensembl Variant Effect Predictor. We removed any variants seen in controls over 75 and in less than four early‐onset cases (heuristic threshold). For this case‐filtering step, we limited variant‐count contribution from ADSP extension to two cases because this cohort contains early‐onset pedigrees. We determined the carriers’ ancestral background using SNPWeight and prioritized variants seen in multiple ancestries (assuming that variants increasing AD risk across ancestries are more likely to be causal). UK Biobank was used as a replication cohort for remaining variants (provided that their calls in subjects with both WES data and SNP‐array imputed data demonstrated sufficiently accurate imputation metrics). Variants association with AD diagnosis and AD in siblings was tested, covarying by sex, APOE2 and APOE4 dosages, and the first 10 genetic principal components accounting for population structure. Genes harboring identified variants were tested for differential expression between cases and controls.ResultOur pipeline identified two variants (Table 1). Table 2 presents the carriers demographics. Table 3 shows the imputation quality and association results in the UK Biobank. Figure 2 emphasizes that NOL6 is upregulated in AD compare to controls across brain regions, while Figure 3 underlines that RPS16 is downregulated.Conclusion
NOL6 splice region and RPS16 splice donor variants may increase AD risk and should be tested in additional cohorts.
Familial Alzheimer’s disease in Australia
Authors: Bechara Jacob A. , Brooks William S. , Kwok John B. , Halliday Glenda M. , Schofield Peter R. 
Published: December 2020

AbstractBackgroundFamilies with dementia occurring in multiple generations suggest the possibility of inheritance of a single gene disorder. Since the discovery of the Amyloid Precursor Protein gene (APP) Val717Ile London mutation (Goate et al., 1991) and of variants in the Presenilin‐1 and ‐2 (PSEN1 & PSEN2) genes in 1995 (Sherrington et al., 1995), many such families with Alzheimer’s disease (AD) have been able to obtain a genetic diagnosis for their condition. Here we report details of 28 families in Australia and New Zealand who have been found to carry a pathogenic variant in one of these three genes.MethodFamilies with young‐onset dementia seeking a genetic diagnosis in Australia were studied according to the following protocol. Family history and clinical characterisation: we enquired about the presence of dementia in siblings, parents and grandparents of the proband. Clinical features of the illness were recorded. We sought consent for DNA studies from living affected individuals: DNA was screened for variants in APP, PSEN1 and PSEN2. Neuropathology: we sought consent for post‐mortem examination of the brain of affected family members for neuropathological characterisation.ResultSince 1988, at least 28 families in Australia and New Zealand have been found to carry pathogenic AD variants. There were 6 families with variants in APP and 22 with variants in PSEN1. No families have yet been found to carry a pathogenic PSEN2 variant. 24 families have had AD confirmed neuropathologically. Only one proband with a pathogenic variant had no known family history of dementia. This individual carried a PSEN1 Arg278Thr variant and died at 41 of dementia and spastic paraparesis. Brain biopsy showed AD. One parent had died of cancer at 65; the other parent was unaffected on examination at 67 and did not carry the PSEN1 variant.ConclusionFamily history of young‐onset dementia in at least two generations suggests dominant inheritance and DNA studies may reveal a pathogenic variant. Such variants can occur in individuals without a family history, but we found this to be uncommon.