bluuebunny/crossref_metadata_2025 huggingface dataset:
Tau pathology in posterior DMN is related to aberrant SN‐DMN network connectivity in atypical Alzheimer’s disease
Authors: Putcha Deepti , Eckbo Ryan , Touroutoglou Alexandra , Dickerson Brad C. , Collins Jessica A.
Published: December 2020

Background

Circumscribed patterns of pathological tau propagation along functional networks have been observed in normal aging and amnestic Alzheimer’s disease (AD), including in two cognition‐relevant networks: the default mode network (DMN) and the salience network (SN). It remains unclear if atypical phenotypes of AD demonstrate a direct relationship between tau and functional connectivity within and between these networks.

Method

Twenty‐six amyloid‐positive patients diagnosed with atypical phenotypes of AD (12 PCA, 10 lvPPA, and 4 dysexecutive; mean age = 66 years, 9M/17F) were examined with tau (18F‐AV‐1451) PET and resting state functional MRI (rs‐fMRI). Hub regions within the DMN and SN were defined from the literature within the bilateral posterior cingulate cortex (PCC) and anterior insula (aI), respectively. ROI‐to‐ROI connectivity was calculated to determine within‐ and between‐network connectivity. Bivariate correlation analyses were conducted to determine if the magnitude of partial volume corrected tau PET signal in each network’s hub region was related to the within‐network functional connectivity of the DMN and SN, as well as between the hub regions of the DMN and SN.

Result

We found that higher tau signal in bilateral PCC was associated with diminished DMN connectivity (PCC to posterior angular gyrus) in both hemispheres (left: r = ‐0.50, p = 0.009; right: r = ‐0.47, p = 0.01). We did not observe any relationship between tau and functional connectivity within the SN. Our novel observation was that higher tau signal in the PCC was associated with increased connectivity between the DMN and SN within both hemispheres (left: r = 0.55, p = 0.004; right: r = 0.47, p = 0.02), with some patients demonstrating pathologically positive functional connectivity between the DMN and SN.

Conclusion

Our findings support the posited relationship between tau pathology and aberrant functional network connectivity reported in aging and amnestic AD by demonstrating that higher tau burden within the PCC is related to fractured DMN connectivity and pathologically increased DMN‐SN connectivity in a group of non‐amnestic AD patients. These findings may help explain how tau deposition in key hub regions of the DMN bring about dysfunctional inter‐network connectivity with the SN, likely contributing to the cognitive and affective dysfunction observed across the clinical spectrum of AD.
Predicting future rates of tau accumulation on PET
Authors: Jack Clifford R.
Published: December 2020

Background

Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired.

Method

All 337 participants in this study were enrolled in one of the three longitudinal cohort studies at the Mayo Clinic that include serial tau PET scanning. For inclusion a person must have had a baseline study visit with MRI, amyloid PET, and tau PET exams, had at least one follow‐up tau PET exam, and have met clinical criteria for membership in one of two clinical diagnostic groups ‐ cognitively unimpaired (n=203) or cognitively impaired (n=134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer clinical syndrome). A temporal lobe tau PET meta‐region of interest (ROI) was used in our primary analysis but we also examined four additional tau PET ROIs. Linear mixed effects models where used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET SUVR, cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log‐transformed tau PET SUVR was used as the response and rates were summarized as annual percent change.

Result

In the cognitively unimpaired group only higher baseline amyloid PET was a significant independent predictor (i.e. in a multivariable model) of higher tau accumulation rates in the temporal meta‐ROI (p<0.001). In the cognitively impaired group, younger age (p=0.02), higher baseline amyloid PET (p=0.05), APOE ε4 (p=0.05), and better cognitive performance (p=0.05) were significant independent predictors of higher tau accumulation rates in the temporal meta‐ROI.

Conclusion

While we examined many possible predictor variables, the main independent predictor of high tau PET accumulation rates in cognitively unimpaired persons was amyloidosis. In contrast, in cognitively impaired individuals imaging and clinical variables that are consistent with early onset Alzheimer’s disease phenotype (younger age, amyloidosis, higher tau, APOE, less severe cognitive impairment) were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct clinical trials that target tau‐related mechanisms.
Optimizing the memory binding test for detection of aMCI and dementia
Authors: Mowrey Wenzhu , Lipton Richard B. , Katz Mindy J. , Ramratan Wendy S. , Loewenstein David A. , Buschke Herman
Published: December 2020

Background

The Memory Binding Test (MBT) Version 1 demonstrated good discriminative validity for distinguishing persons with dementia and amnestic mild cognitive impairment (aMCI) from cognitively normal elder controls (CN). Version 2 of the MBT test was developed to improve brevity, which is essential for screening. We aimed to compare these two versions in terms of cross‐sectional discriminative validity to distinguish A. aMCI vs. CN, B. aMCI and dementia vs. CN, and C. dementia vs. CN and aMCI.

Method

Version 1 and Version 2 (for differences see Table 1) of the MBT were administered to independent and systematically recruited samples between May 2003 and December 2007 (Age: 70+; Version 1: 20 dementia cases, 31 aMCI, 246 CN; Version 2: 13 dementia cases, 29 aMCI, 236 CN). Scores on the MBT indices were compared between the versions. The partial area under the receiver operating characteristic curve (ROC AUC) for specificities ≥ 0.70 was compared between indices and versions (Table 1). Specificities were compared between versions when the sensitivity values were comparable.

Result

The MBT indices were not significantly different between versions for the diagnosis groups of aMCI and dementia. In CN, Version 2 yielded higher scores on number of items Cued Recall for List 1 (CR‐L1), number of Pairs In the Paired condition (PIP), and number of Total Items recalled in the Paired condition (TIP) (14.8±1.5 vs. 14.4±1.7, 11.0±3.2 vs. 9.9±3.8, 26.3±4.0 vs. 24.9±5.0, respectively, p=0.005) and PIP and TIP remained higher (p=0.02) when adjusting for potential confounders of age, gender, education and global cognitive function. Partial AUC comparison shows that TIP was the optimal index for Version 1 and TIP partial AUCs were not significantly different between two versions (Figure 1, Table 2). The specificities were higher in Version 1 vs. Version 2 in Comparisons A and B, while the specificities were comparable in Comparison C (Table 3).

Conclusion

MBT Version 1 is better at distinguishing aMCI, or aMCI and dementia combined, from cognitively normal elderly. To distinguish dementia vs. cognitively normal elder controls and aMCI, Version 1 and Version 2 are comparable. We recommend using Version 1 for future studies.
Perceptions of research burden reported by study partners of longitudinal ADC cohort participants
Authors: Edwards Dorothy Farrar , Lingler Jennifer , Chin Erin , Gabel Matthew , Coble Dean W , Grill Josh D , Stark Susan
Published: December 2020

Background

Study partners are required for all ADC Clinical Core participants, they provide valuable information about cognitive and functional status of enrolled participants, which is essential for CDR ratings and documentation of perceived cognitive changes over time. Retention of participants and their SPs is essential for unbiased longitudinal data, yet little is known of SP attitudes and beliefs and how these attitudes influence missed visits or overall attrition. This mixed methods study identified SPs perceived barriers and facilitators related to participant retention in longitudinal ADC studies

Method

Methods: A 57 item survey with 2 open ended questions was administered by telephone to randomly selected study partners (N=210) from four NIA funded Alzheimer’s disease Centers. The Perceived Research Burden Assessment (PeRBA) was included in the survey. Respondents were 51% female, mean age was 72±8.6 ( 52‐92yrs), 92% were spouses. Response frequencies were computed for each item, open ended responses were transcribed, and thematically coded.

Result

Study partners report high levels of trust in medical researchers (88%), high levels of altruism they believe their participation is valuable (96%) and society benefits from their research participation (98%). Low levels of overall burden were associated with ADC participation. Most negative attitudes were associated with travel (14%), inconvenience reaching the research center (15%) and length of study visits (17%). They also reported that their last LP (18%) and memory testing (19%) visits were difficult, with physical pain (13%) and fatigue (16%) as most common post‐assessment problems. A substantial number (83%) had difficulty keeping track of different study procedures. Only 37% reported being invited to participate in additional ADC‐sponsored studies. Thematic analyses identified common concerns/suggestions across ADC sites including: more frequent feedback and information about study results, evidence‐based caregiving advice, more complete disclosure of individual findings, better coordination and communication around multiple study visits and high praise for research staff.

Conclusion

Study partners are critical to longitudinal retention of ADC participants. SP loss accounts for a significant proportion of missed visits or outright attrition. Changing study partners contributes to greater variability in longitudinal data. Our findings emphasize the importance of attending to the concerns of study partners in retention programs.
Perceptions of research burden among participants in ADC cohorts
Authors: Lingler Jennifer , Coble Dean W , Bollinger Rebecca , Edwards Dorothy Farrar , Gabel Matthew , Grill Josh D , Knox Melissa , Stark Susan
Published: December 2020

Background

The burden of participating in research on Alzheimer’s disease and related disorders (ADRD) has been described as extending beyond the direct risks associated with research procedures to encompass the overall hassle of getting to and through study visits. The Perceived Research Burden Assessment (PeRBA) was designed to measure participants’ perceptions of the logistical (e.g., time commitment), psychological (e.g., intrusiveness of interview questions), and physical burden (e.g., perceived risk of injury) associated with enrollment in ADRD research. Initially validated using a pre‐enrollment version of PeRBA to assess the anticipated burden of a hypothetical research study, our team administered a post‐enrollment version of PeRBA to assess research burden as experienced by participants in longitudinal cohort studies of ADRD.

Method

PeRBA interviews were administered by telephone to a random sample of 443 participants from the active cohorts at four NIA‐funded Alzheimer’s Disease Centers (ADCs; n=∼110 per site). Survey respondents were on average 73 years old, primarily Caucasian (79%), female (59%), and had been participating in UDS study visits for 5 years. Respondents were instructed to reflect on their most recent UDS study visit as they considered each of the 22 PeRBA items. Principal component (unrotated) factor analysis was performed using STATA 15.0 to estimate the factor structure and confirm the PeRBA burden dimension based on eigenvalues and the pattern of factor loadings.

Result

The factor analysis suggests a single factor solution, with PeRBA items loading constituent with a general perception of burden. Factor structure and fit were consistent across sites.

Conclusion

These findings provide cross‐validation for prior research suggesting that the PeRBA is psychometrically valid measure of perceived research burden. Our finding of a single factor solution suggests that perceived research burden is a unidimensional construct and that use of the total PeRBA score is appropriate.
Perceived facilitators and barriers to continued enrollment in longitudinal studies of Alzheimer disease
Authors: Gabel Matthew , Coble Dean W , Bollinger Rebecca , Edwards Dorothy Farrar , Lingler Jennifer , Chin Erin , Grill Josh D , Stark Susan
Published: December 2020

Background

Retention of study participants is critical to the success of longitudinal studies of Alzheimer Disease (AD). A comprehensive understanding of the factors that influence retention requires knowledge of what motivates study participants to continue to participate and of the perceived challenges of participation. We conducted a survey of current participants in Alzheimer Disease Centers (ADCs) to characterize their perceived facilitators and burdens of participating in longitudinal studies of AD.

Method

A 57‐item interview battery with 2 open ended questions was administered by telephone to 443 randomly selected study participants from four NIA funded ADCs. Respondents were 59% female, mean age was 73±8.5 ( 49‐95 yrs), and the mean number of years enrolled was 5.1±3.5 ( 0‐13.5 yrs).

Result

Survey respondents showed strong altruistic motivation for participation. Almost all respondents (>90%) indicated they were motivated by a desire to advance AD research, to benefit society, and to benefit future generations of their families. In contrast, 5% of respondents identified money or gift cards as the reason they participate. Only a small minority of respondents registered complaints about study participation. The most common problems involved fatigue (12%) and the distance/inconvenience of travel to the study visit (11%). These response patterns were broadly consistent across gender, race, and age cohorts. Women and younger respondents were slightly more altruistic in motivation than men and older respondents. Also, African American respondents were more strongly motivated by personal benefit from the study and expressed greater concern about privacy of their personal information than other respondents. They also had lower trust in medical research.

Conclusion

Retention of participants and their consistent attendance at regular visits is vital to the quality of longitudinal studies of AD. Our results indicate that, while most participants surveyed indicate an altruistic commitment to the study of AD, the organization of study visits could be improved to facilitate participation. In particular, increasing the convenience of both attending and executing the study visit would address the most common complaints. Furthermore, the retention of African Americans requires sensitivity to their relatively low trust in medical research.
Resting state functional connectivity of financial capacity in mild cognitive impairment
Authors: Nowrangi Milap , Naaz Farah , Chen Liuyi , Outen John D. , Bakker Arnold , Rosenberg Paul B.
Published: December 2020

Background

Financial capacity (FC) is a complex, multi‐dimensional neurocognitive construct that is commonly impaired and disables older individuals with cognitive impairment but the underlying mechanisms are not well understood. Resting state functional connectivity was measured in individuals with mild cognitive impairment (MCI) and impaired FC compared to cognitively normal controls (NC) in order to identify relevant network components that may help drive future interventions.

Method

Resting state functional MRI scans were obtained from individuals with MCI (N = 17) and age, gender, and education matched NC (N = 15). Table 1. All participants completed the Financial Capacity Instrument (FCI) and neuropsychological assessment. Based on previously reported imaging findings in this population, the left Angular Gyrus (lAG) was used as the seed region in functional connectivity measurements. Connectivity beta values (Fisher transformed correlation coefficients) were calculated for each connection that showed significantly altered connectivity between control and MCI cases. A Pearson’s correlation was calculated between the connectivity beta values from relevant regions and cognitive measures.

Result

A total of 26 brain regions showed significant increased functional connectivity (p <0.05 uncorrected) with the lAG in NC compared to MCI. Of these regions 14 were identified as relevant to higher‐level cognitive function and carried forward in the correlation analysis (Figure 1). Pearson’s correlation showed significant negative association between the FCI and increased connectivity with the right temporal fusiform cortex (rTFC, r = ‐0.455, p = 0.009); negative correlation between Clock drawing and increased connectivity with the intraparietal sulcus (r = ‐0.38, p = 0.03); positive correlation between Trails B and increased connectivity with postcentral gyrus (r = 0.39, p = 0.03) and left central operculum (r = 0.36, p = 0.04). Table 2.

Conclusion

There is a significant correlation between a well‐validated measure of FC and increased functional connectivity between the lAG and the rTFC in controls compared to MCI. This novel finding suggests that integration of visuoperception, memory, and mathematical function is critical for FC. No other significant correlation between the lAG and rTFC was found with other tests of executive function or visuospatial cognition.
Cognitive symptoms in early postmenopausal women: Impact on estrogen‐sensitive cholinergic function
Authors: Newhouse Paul A. , Conley Alexander C. , Albert Kimberly , McDonald Brenna C. , Saykin Andrew J. , Dumas Julie
Published: December 2020

Background

Menopause 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. Estradiol (E2) has been shown to be important for brain cholinergic functioning, the decline of which is linked to AD and cognitive decline. We have previously shown that E2 can attenuate the impact of cholinergic blockade on cognitive performance in normal postmenopausal women. To further explore these relationships, we examined the relationship of menopausal‐associated subjective cognitive complaints (mCC) with E2 effects on cholinergic functioning in postmenopausal women.

Method

56 early postmenopausal women (aged 50‐60 years) with differing levels of mCC completed subjective measures of cognitive complaints and postmenopausal symptoms as well as objective cognitive tests of verbal episodic and working memory and completed a 3‐month treatment regimen of either 1 mg oral 17β‐estradiol or placebo. Participants then completed four cholinergic antagonist drug challenges (mecamylamine, scopolamine, combined mecamylamine+scopolamine, or placebo) and completed cognitive performance tasks including working memory (N‐Back), episodic memory (selective reminding), attention (critical flicker fusion, spatial selective attention), and psychomotor tasks (choice reaction time).

Result

All participants performed worse under cholinergic challenge compared to placebo. Higher mCC was associated with greater anticholinergic‐induced impairment on working memory performance and reaction time, but not other measures. E2 treatment did not blunt anticholinergic blockade effects on performance compared to participants who received placebo. On both the CFF and CRT tasks, the performance‐impairing effects of anticholinergic drugs were increased in E2 treated participants compared to placebo treatment.

Conclusion

mCC was associated with greater negative effects of anticholinergic drugs on some cognitive domains. In this sample recruited for mCC, E2 treatment did not enhance cholinergic functioning as evidenced by the failure to blunt the effects of cholinergic blockade in contrast to our prior work in normal postmenopausal women. The development of significant menopause‐related cognitive symptoms may represent early brain functional and/or cholinergic changes that may indicate increased risk for cognitive decline and is not modifiable by E2 treatment.
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

Background

Menopause 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.

Method

44 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.

Result

Cognitive 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.

Conclusion

The 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

Background

Several 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.

Methods

Primary 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.

Results

We 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.

Conclusion

This 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

Background

EXERT 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.

Method

EXERT 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.

Result

EXERT 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.

Conclusion

Age 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

Background

Nearly 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.

Method

DTI 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).

Result

Adjusting 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.

Conclusion

Our 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

Background

Sleep 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.

Method

We 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.

Result

Both 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.

Conclusion

Our 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

Background

The 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.

Method

Tau 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.

Result

Exemplar 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).

Conclusion

MK‐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

Background

Although 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.

Method

A 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.

Result

Although 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).

Conclusion

With 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

Background

Understanding 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.

Method

As 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.

Result

Site 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%).

Conclusion

The 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.
Multimodal neuroimaging correlates of NREM and REM sleep: EEG spectral power in aging
Authors: Andre Claire , Rehel Stéphane , Kuhn Elizabeth , Touron Edelweiss , Mézenge Florence , De la Sayette Vincent , Vivien Denis , Chetelat Gael , Rauchs Géraldine , Group Medit‐Ageing Research
Published: December 2020

Background

Sleep disturbances have been associated with cognitive decline and Alzheimer’s disease (AD), with growing efforts to understand how these changes may relate to AD pathophysiology. However, we lack a comprehensive overview of the associations between objectively‐measured sleep oscillations and brain changes in aging so that efficient treatment strategies could be developed. Using an unbiased, fast, and powerful quantitative (spectral) analysis of sleep EEG rhythms, we assessed the relationships between both non‐rapid eye movement (NREM) and REM sleep oscillations, and amyloid burden, gray matter (GM) volume and perfusion in cognitively unimpaired older adults (CUOA).

Method

125 CUOA from the Age‐Well randomized controlled trial underwent a neuropsychological assessment, an ambulatory polysomnography recording and a structural MRI. A Florbetapir‐PET scan was also performed with early and late acquisitions to measure brain perfusion and amyloid burden respectively. Normalized EEG spectral power values were obtained using the ASEEGA® algorithm for delta (0.1‐4 Hz), theta (4‐8 Hz), alpha (8‐12 Hz) and beta (16‐50 Hz) EEG frequency bands, over the Cz‐Pz derivation (Berthomier et al., 2007). Voxel‐wise multiple regressions were then conducted between EEG spectral power values and neuroimaging data (i.e., GM volume, perfusion and amyloid burden), separately for NREM and REM sleep, controlling for age, gender, education, the apnea‐hypopnea index, sleep medication use, and the ApoE4 status.

Result

Lower NREM sleep delta power, reflecting a decrease in slow wave activity, was related to decreased GM volume and perfusion in fronto‐cingulate areas, but not to amyloid deposition. By contrast, decreased REM sleep theta power was associated with i) greater amyloid deposition in frontal, cingulate, parietal and temporal areas; ii) lower GM volume in frontal, temporal, occipital and insular cortices, and iii) increased perfusion in frontal and parietal regions.

Conclusion

Both NREM and REM sleep alterations were associated with structural and functional changes in regions sensitive to aging and AD pathophysiology. Importantly, REM sleep changes were associated with greater amyloid deposition. This may be due to early changes in cholinergic structures, acetylcholine playing a neuroprotective role against amyloid. Thus older individuals with REM sleep alterations may be more at risk of belonging to the Alzheimer’s continuum.
Using spatial filters to study regional reorganization of brain connectivity in familial early onset AD (PSEN1 E280A)
Authors: Quintero Carlos Andrés Tobón , Ochoa John F. , Aguillon David , García Francisco
Published: December 2020

Background

The most common cause of familial early onset Alzheimer Disease (AD) are the PSEN1 mutations. One of the largest family carriers of the mutation lives in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to characterize the preclinical changes and the brain reorganization strategies associated with predisposition to AD. The Electroencephalography (EEG) has an enormous potential to study the neurophysiological changes in neurodegenerative processes with promising clinical applications. During the 2012 – 2019 period different studies on a large database of high‐density EEG from PSEN1 E280A carriers were done trying to identify early changes that could be preclinical biomarkers of AD

Method

A sample of 83 participants, belonging to families with genetic risk for AD by PSEN1 E280A mutation was included. They were distributed in three groups; asymptomatic carriers (AC, n=27), asymptomatic non‐carriers (ANC, n=33) and a symptomatic group with Mild Cognitive Impairment (SYMP, n=23). We used a 60 channel EEG for recording the brain electrical activity. The relative power values were obtained using Matlab’s chronux toolbox. The results obtained using a workflow based on Independent Component Analysis (ICA), introduced to improve the spatial resolution given by EEG, are discussed. A two‐parameter non‐parametric T‐test was used to calculate the statistical significance of the relative power among the populations analyzed.

Result

The comparison of carriers of PSEN1 E280A mutation and non‐carriers, show altered brain function even in asymptomatic stage complementing previous findings using functional Magnetic Resonance Imaging or Positron Emission Tomography. Regions, like the Precuneus, can be screened across the neurodegenerative process, offering new potential biomarkers of AD. The multivariate analysis of brain sources show generalized impairment in the brain connectivity for asymptomatic subjects. The results found using the workflow were compared with alternatives approaches of analysis, based on scalp EEG or data obtained through inverse solution methods, corroborating the findings.

Conclusion

The neurophysiological correlates found opens the possibility of studying new biomarkers in AD based in EEG. The workflow proposed could be used in other neurodegenerative diseases or other brain mapping problems based in EEG.