bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive symptoms in early postmenopausal women: Relationship to brain structure
Authors: Newhouse Paul A. , Conley Alexander C. , Albert Kimberly , McDonald Brenna C. , Saykin Andrew J. , Boyd Brian , Kim Shin‐Gyeom , Dumas Julie 
Published: December 2020

AbstractBackgroundMenopause is associated with increasing cognitive complaints and older women are at increased risk of developing Alzheimer’s disease (AD) compared to men. One proposed reason for this reduced cognitive performance is the loss of estrogen following the menopause transition. However, there is difficulty in delineating effects of age and estrogen loss in samples of aging women. The aim of this study was to identify whether in sample of younger postmenopausal women, the level of menopause‐associated cognitive complaints (mCC) was associated with changes in gray‐matter volume and objective cognitive performance. We hypothesized that higher endorsement of cognitive complaints would be associated with smaller gray matter volume in the medial temporal lobe. Additionally, we examined whether the number of endorsed vasomotor, somatic, and mood symptoms was related to cortical gray matter volume.Method44 early postmenopausal women (aged 50‐60 years) with differing levels of mCC completed subjective measures of cognitive complaints and postmenopausal symptoms as well as cognitive performance tests of verbal episodic and working memory and completed a structural MRI scan. VBM analysis was performed using the SPM12 package in combination with Matlab 2017b. To assess the effect of mCC on gray‐matter volume, a linear regression model in SPM12 with CCI score as the continuous between‐subject’s factor was run.ResultCognitive complaints were significantly associated with lower gray‐matter volume in the right medial temporal lobe. Increased depressive symptoms and somatic complaints were also significantly related to increased cognitive complaints and smaller medial temporal volumes, however the somatic complaints did not mediate the relationship between cognitive complaints and gray‐matter volume. There was no association between objective performance on the memory tasks and subjective cognitive ratings, or gray‐matter volume.ConclusionThe findings of the present study identify a relationship between the number of endorsed mCC and structural brain differences in younger postmenopausal women. Cognitive complaints but not cognitive performance was associated with lower gray‐matter volume in the right medial temporal lobe. The development of significant menopause‐related cognitive symptoms may represent early brain morphologic and functional changes that may indicate increased risk for cognitive decline.
Tau deletion promotes peripheral insulin resistance
Authors: Al‐Lahham Rabab , Mukherjee Abhisek , Soto Claudio 
Published: December 2020

AbstractBackgroundSeveral epidemiological data revealed an association between Alzheimer’s disease (AD) and type 2 diabetes, indicating that each disease is a substantial risk factor for the other. Brains from AD patients displayed down regulation of insulin signaling. Moreover, GSK‐3β, a downstream key kinase in insulin signaling cascade, is also implicated in the phosphorylation of the microtubule‐associated protein tau (tau), one of the pathological hallmarks of AD. While insulin resistance is an important risk factor for AD, the exact mechanistic link remains unknown. Also unclear is whether insulin resistance is a cause or a consequence of AD. Researchers focusing on brain insulin resistance often consider AD a type 3 diabetes, however little is known about the link between systemic insulin resistance and AD. Furthermore, it is not clear whether brain insulin resistance precedes peripheral insulin resistance or if it is a consequence. The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of AD by testing the hypothesis that tau is important for peripheral insulin sensitivity, and its deletion or loss‐of‐function promotes peripheral insulin resistance.MethodsPrimary hepatocytes were isolated from transgenic mouse models (P301L, tau KO) as well as wild type mice (C57BL/6), and their insulin sensitivity was assessed using biochemical analysis of insulin signaling markers, as well as glucose uptake assays. To confirm the involvement of tau in the regulation of peripheral insulin signaling, we treated wild type hepatocytes with tau aggregates and investigated their effect on insulin sensitivity.ResultsWe found that primary hepatocytes isolated from P301L as well as tau KO mice exhibit reduced glucose uptake after an insulin challenge accompanied by inhibition of insulin signaling proteins signifying peripheral insulin resistance. Furthermore, exposure of wild‐type primary hepatocytes to sub‐toxic levels of tau aggregates resulted in inhibition of insulin signaling and glucose uptake.ConclusionThis is the first study testing the potential role of tau in peripheral insulin resistance using multiple mouse models. Our findings suggest that functional tau is required for insulin sensitivity, therefore, any loss of function by mutations, aggregation or deletion would result in insulin resistance.
Recruitment for a multi‐site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial
Authors: LaCroix Andrea Z , van Dyck Christopher H , Okonkwo Ozioma C , Tam Steven P , Fairchild Jennifer Kaci , Li Clara , Welsh‐Bohmer Kathleen A , Shadyab Aladdin H , Matthews Genevieve , Bennett Daniel , Shadyab Alexandre , Schafer Kimberly A , Morrison Rosemary H , Kipperman Sean A , Tan Donna , Feldman Howard H , Cotman Carl W , Baker Laura D ,   EXERT Study Group
Published: December 2020

AbstractBackgroundEXERT is a large multi‐site randomized controlled trial testing the effects of aerobic exercise vs. stretching (control) on cognition and biomarkers of brain health in sedentary adults with MCI. Here, we describe challenges and successes of strategies used to recruit the EXERT cohort.MethodEXERT recruited sedentary adults 65‐89 years old who were willing to exercise 4 days/week at the YMCA with trainer supervision for 12 months, and unsupervised for an additional 6 months. The trial is conducted at 14 clinical sites that include 30 corresponding YMCAs. The ADCS serves as the Coordinating Center, and intervention oversight is provided by Wake Forest School of Medicine in partnership with the YMCA.ResultEXERT recruitment occurred over 43 months and several strategies were deployed to address recruitment challenges. The most notable challenge was that EXERT aimed to recruit adults with a cognitive impairment that is mentally/physically taxing given the expectations of an intensive exercise intervention study. For these individuals, transportation to the YMCA was also often a barrier to participation. Early recruitment methods relied on memory clinic patient rosters and electronic health records, which yielded only a few enrollments. Use of other common strategies (e.g., newspaper advertising) was only minimally successful in identifying candidates. Recruitment gained momentum only after geotargeted mailings of pictorial postcards and brochures were initiated. After the first mailing at 3 sites, the rate of in‐person screenings increased by more than 100% (Figure 1). In total, 500,000 geotargeted mailings across all sites were sent from which more than 50% of all randomized participants were recruited. Recruitment also benefited from high‐profile media coverage (Maria Shriver video, NPR) in 2018 and 2019. Early in 2019, the ADCS established centralized telephone prescreening to reduce burden on site staff. A total of 692 mailing responders were prescreened by the ADCS, of whom 228 were referred to sites. As of January 2020, 984 study candidates completed in‐person screening and 278 participants were enrolled into EXERT.ConclusionAge and geotargeted mass mailings combined with centralized telephone prescreening and national media campaigns proved to be effective strategies for enrolling people with MCI in a long‐term exercise trial.
White matter microstructure and episodic memory in adults with down syndrome: A Tract‐Based Spatial Statistics (TBSS) Study
Authors: Patrick Austin M , Hartley Sigan L , Wu Minjie , Dean Douglas C , Zammit Matthew D , Johnson Sterling C. , Tudorascu Dana L , Cohen Ann , Cody Karly Alex , Laymon Charles M , Klunk William E , Zaman Shahid , Handen Benjamin L , Alexander Andrew L , Christian Bradley T 
Published: December 2020

AbstractBackgroundNearly all persons with Down Syndrome (DS) will show pathology of Alzheimer’s Disease (AD) in their 40s. Our study of non‐demented DS individuals showed that episodic memory was the first cognitive domain to decline in this population (Hartley et al., 2014). We have shown that diffusion tensor imaging (DTI) measures of white matter (WM) microstructure are related to amyloid burden in DS (Patrick et al., 2019). The parietal (Berryhill et al., 2007), prefrontal (Fletcher et al., 1998), and medial‐temporal (Nyberg et al., 1996) lobes have been shown to be involved in episodic memory. In this work, we examined the relation between white matter microstructure, assessed using tract‐based spatial statistics (TBSS), and episodic memory.MethodDTI scans (b = 1000 s/mm2 and 48 encoding directions) of 43 adults (N = 43; mean age = 39.8+/‐7.0 years) with DS were acquired at 3T at two imaging sites in the Alzheimer’s Biomarker Consortium‐Down Syndrome. A composite score of episodic memory was calculated based on summing the z‐scores of the 1)Free and Cued Recall test (Buschke et al., 1984), a measure of verbal episodic memory and the 2)Rivermead Behavioural Memory Test for Children‐Picture Recognition (Wilson et al., 1991), a measure of visual episodic memory. Voxelwise statistical analyses of fractional anisotropy (FA) and mean diffusivity (MD) were carried out using TBSS. The associations between episodic memory with FA and MD were analyzed using a general linear model in FSL, controlling for imaging site and baseline intelligence assessed using the Peabody Picture Vocabulary Test (Dunn et al., 2007).ResultAdjusting for site, baseline intelligence, and multiple comparisons, episodic memory and FA were significantly (p<.05) positively correlated in the right occipital, parietal, and temporal regions and bilateral prefrontal regions. MD and episodic memory were significantly negatively correlated in much of the association white matter in all lobes and survived additional correction for age.ConclusionOur results show significant correlations of episodic memory with FA and MD in multiple areas. There is a strong correlation of both FA and MD with age, which makes disentangling age and AD‐related neurodegeneration difficult; however, these results suggest FA and MD as potential indicators of episodic memory decline in DS populations.
Hypothalamic melanin‐concentrating hormone neurons, key sleep cycle modulators, degenerate early in Alzheimer’s disease
Authors: Mladinov Mihovil , Oh Jun Yeop , Eser Rana A. , Petersen Cathrine , Li Song , Theofilas Panos , Spina Salvatore , Seeley William W. , Bittencourt Jackson Cioni , Neylan Thomas , Grinberg Lea Tenenholz 
Published: December 2020

AbstractBackgroundSleep disorders represent one of the leading causes of life impairment and a major therapeutic challenge in patients with Alzheimer’s disease (AD) and tauopathies. However, the disease specific neurobiological basis of these sleep disturbances remains mostly elusive. Melanin‐concentrating hormone (MCH) neurons are a conserved neuronal population in the lateral and posterior hypothalamus with critical sleep/wake and metabolic control functions in animals, but largely underexplored in humans. Here, we used unbiased stereology to examine the involvement of MCH neurons in Alzheimer’s disease (AD) as a 3R‐tauopathy, and progressive supranuclear palsy (PSP) as a 4R‐tauopathy featuring hyperinsomnia.MethodWe used unbiased stereology to quantify total and MCH‐positive neuronal numbers and tau burden in the region of interest (ROI) of 5 AD and 6 PSP brains (for detailed demographics see Table 1). Data were analyzed using Wilcoxon signed rank and Mann‐Whitney U tests.ResultBoth AD and PSP subjects show significant neuronal tau‐burden in the ROI. There was no statistically significant difference in the absolute number of MCH‐neurons and non‐MCH‐neurons (Figure 1), or proportion of MCH neurons in the total neuronal population between AD (26.5%) and PSP (24.9%). Whereas there was no difference in the proportion of tau+ non‐MCH neurons between AD and PSP, the proportion of tau+ MCH‐neurons was significantly higher in AD relative to PSP (p=0.0043) (Figure 2). Contrary to AD, where MCH and non‐MCH neurons had similar tau‐burden (18.8% and 17.1%, respectively), in PSP there was a significantly lower involvement of MCH‐neurons (4.9%) in comparison to the total neuronal population (19.9%, p=0.0313) (Figure 2). In the PSP group there was a positive correlation between Braak stages and the proportion of tau+ MCH neurons (p=0.023), but not total tau+ neurons.ConclusionOur preliminary data show a trend for lower neuronal numbers in AD and in PSP, lower neuronal numbers correlated with higher Braak stages. Together, it suggest an early vulnerability of MHC to AD and a moderate vulnerability to PSP. We are analyzing further cases to increase the power of analysis. Different involvement of MCH‐neurons in AD and PSP may reflect the specific patterns of sleep disorders in those tauopathies.
Head‐to‐head comparison of [18F]MK‐6240 and [18F]flortaucipir (AV‐1451) in autosomal dominant Alzheimer disease
Authors: Flores Shaney E. , Gordon Brian A. , Su Yi , Dincer Aylin , Keefe Sarah J. , Feldman Rebecca L. , Shady Kristine E. , Mansor Syahir , Zhou Yun , Hornbeck Russ C. , Swisher Laura , Cash Lisa , Tu Zhude , Morris John C. , McDade Eric , Bateman Randall J. , Benzinger Tammie L.S. ,   Dominantly Inherited Alzheimer's Network
Published: December 2020

AbstractBackgroundThe accumulation of misfolded tau proteins in the brain is an early pathological indicator of Alzheimer disease (AD). The introduction of [18F]flortaucipir (AV‐1451), has enabled early investigations of tau spatial dispersion in vivo but has prominent off‐target binding in the choroid plexus and basal ganglia. More recent tau tracers, such as [18F]MK‐6240, may improve the ability to detect pathology, but direct comparisons between these imaging agents are limited. We provide preliminary data from a direct head‐to‐head comparison of AV‐1451 and MK‐6240 in a sample of asymptomatic and symptomatic autosomal dominant AD (ADAD) participants and healthy controls.MethodTau PET imaging using AV‐1451 and MK‐6240 was acquired on consecutive days for 14 adult Dominantly Inherited Alzheimer Network (DIAN) participants. [11C]PiB‐PET amyloid and T1‐weighted head MR scans were also collected. MR images were segmented into 40 bilateral regions of interest (ROIs) using FreeSurfer‐5.3. ROI standardized uptake value ratios (SUVrs) were calculated for the 80‐100 minute and 90‐110 minute post‐injection time windows for AV‐1451 and MK‐6240, respectively, with cerebellar gray as the reference region. Partial volume correction (PVC) was applied using a geometric transfer matrix approach. For analysis, bilateral SUVrs were correlated between the tau tracers to assess their spatial and quantitative agreement.ResultExemplar voxel‐wise PET images are shown for ADAD participants in Figure 1 and healthy controls in Figure 2. Visually, MK‐6240 appears to capture many of the high binding regions of AV‐1451. MK‐6240 also displayed diffuse signal along pial/leptomeningeal surfaces in 42% of participants, regardless of amyloid status. This may relate to arterial, venous, or glymphatic uptake. Quantitatively, regional SUVrs between the two tracers for tauopathy regions, such as inferior temporal and precuneus, were strongly correlated before and after PVC (see Figure 3). PVC reduced correlation strengths in areas thought to have minimal true tau uptake. The tracers were highly correlated amongst amyloid(+, n=2) but less so amongst amyloid(‐, n=12; see Figure 4).ConclusionMK‐6240 and AV‐1451 display a relatively strong quantitative and spatial relationship amongst those with AD. Future studies should further investigate off‐target leptomeningial binding in MK‐6240 and its influence in quantitative tau PET studies.
A multi‐study analysis of the spatial‐temporal progression of amyloid deposition and its utility for longitudinal studies
Authors: Alves Isadora Lopes , Collij Lyduine , Fantoni Enrico R , Heeman Fiona , Salvadó Gemma , Buckley Christopher , Farrar Gill , Gispert Juan Domingo , Barkhof Frederik ,   the AMYPAD Consortium
Published: December 2020

AbstractBackgroundAlthough a dichotomous and visual interpretation of amyloid PET is sufficient in clinical routine, regional image assessment may yield additional opportunities in the research setting. Understanding the regional‐temporal evolution of amyloid pathology may enable earlier pathological identification, as well as a more fine‐grained assessment of the extent and associated risk of amyloid pathology beyond traditional dichotomous measures. This multi‐study analysis of neuropathology and PET studies assessed the potential for the detection of regional amyloid deposition patterns and its utility for staging amyloid pathology in vivo.MethodA total of 15 studies (neuropathology and PET imaging based) have been included for review. First, an overall assessment of the similarities and discrepancies in the described ordering of amyloid pathology was performed in view of the methodological differences and limitations. Secondly, a multi‐tracer amyloid PET staging system was performed with a variety of cohorts to demonstrate the utility of such a methodology in comparison with traditional global dichotomous measures of pathology. The chosen system has been developed based on cross‐sectional PET data from 400 subjects (100 per tracer, including [11C]PiB, [18F]florbetapir, [18F]florbetaben, and [18F]flutemetamol), applied to >3000 scans and related to clinical and biological markers of Alzheimer’s disease.ResultAlthough methodological discrepancies between studies need to be considered, it can be observed that 1) cortical generally precedes striatal accumulation, 2) medial neocortical regions are seen to accumulate amyloid earlier than lateral regions in PET studies (influenced by signal distortion), and 3) the placement of temporal regions in the pathological ordering is remarkably variable across studies (Figure 1). Multiple PET‐based staging systems have been successfully applied to various cohorts, but a multi‐tracer approach demonstrated that between‐tracer discrepancies influence the observed regional ordering and should be taken into account (Figure 2). Finally, PET‐based amyloid stage strongly relates to demographic and clinical measures, detects pre‐global amyloid burden, characterizes distinct levels of pathology beyond a CSF plateau phase, and predicts future cognitive decline (Figure 3).ConclusionWith modest agreement to neuropathology, models for staging amyloid pathology using PET imaging could improve subject selection into secondary prevention trials and potentially guide visual assessment in clinical routine.
Current status and quantitative results of the AMYPAD prognostic and natural history study
Authors: Alves Isadora Lopes , Gispert Juan Domingo , Gray Katherine R , Collij Lyduine , Heeman Fiona , Salvadó Gemma , Saint‐Aubert Laure , Payoux Pierre , Vellas Bruno , Boutoleau‐Bretonnière Claire , Gabelle Audrey , Pasquier Florence , Dumurgier Julien , Dubois Bruno , Connelly Peter , Grau‐Rivera Oriol , Martinez‐Lage Pablo , Boada Mercè , Marquie Marta , Vandenberghe Rik , Hanseeuw Bernard , Kivipelto Miia , Schöll Michael , Frisoni Giovanni B , Scheltens Philip , Ritchie Craig W. , Stephens Andrew W , Buckley Christopher , Ford Lisa , Molinuevo Jose Luis , Farrar Gill , Barkhof Frederik ,   the AMYPAD Consortium
Published: December 2020

AbstractBackgroundUnderstanding the role of amyloid imaging in the earliest stages of Alzheimer’s Disease (AD) becomes increasingly relevant for secondary prevention. In this context, the AMYPAD Prognostic and Natural History Study (PNHS) is an open‐label, prospective, multi‐centre cohort study (http://amypad.eu/) to determine the value of quantitative amyloid PET imaging in determining AD dementia risk. The study aims at enrolling 2000 non‐demented individuals from several European cohorts, with a focus on those with emerging amyloid pathology.MethodAs of January 31th 2020, 438 participants have consented into AMYPAD PNHS across 15 active sites. Of those, 347 are from EPAD LCS, 9 from ALFA+ and 82 from EMIF‐AD (Figure 1). To date, 329 subjects have been scanned with [18F]flutemetamol or [18F]florbetaben, and 108 PET scans have been analyzed with IXICO’s LEAP pipeline. The primary variable is the Centiloid value (CL) using the whole cerebellum as reference region. Scans were categorized as negative (CL<12); gray‐zone (12<CL<50) or positive (CL>50) for amyloid burden, and associations between CL values and age, CDR and RBANS were assessed.ResultSite activation is almost complete, with two remaining sites to be activated by February 2020. In addition to current recruitment sources, two additional cohorts (FACEHBI and FPACK) have started recruitment, and at least one more is expected in February. Current AMYPAD PNHS participants have a mean age of 67.08 ± 7.71 years and 59% of them are female. The distribution of CL values ranged from ‐12.75 to 141.79 (Figure 2), and showed a positive association with age (p<0.001) as expected, with similar behavior for the each radiotracer (Figure 3). Forty‐five scans (42%) were classified as negative, 40 (37%) gray‐zone, and 23 (21%) positive. Within EPAD LCS participants, increasing amyloid burden was related to lower global scores on RBANS (ANOVA, F=3.6, p<0.05), and CDR=0.5 was most frequently observed in the gray‐zone (9.5%) and positive (12.0%) groups compared to amyloid‐negative subjects (2.1%).ConclusionThe AMYPAD Prognostic and Natural History Study is currently ongoing and a total of 17 sites will be actively recruiting by February 2020. Preliminary quantitative results indicate that the trial is effectively recruiting the intended target population.