bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring subtle Blood‐Brain Barrier permeability changes with reduced scan time in DCE‐MRI
Authors: Bae Jonghyun , Ge Yulin , Kim Sungheon Gene
Published: December 2022

Background

Increasing evidence suggests the subtle changes of Blood‐Brain Barrier (BBB) permeability in normal aging and in Alzheimer’s disease using Dynamic Contrast‐Enhanced MRI (DCE‐MRI). However, measuring this subtle change poses great challenge for accurate measurement, resulting in inconsistent results among previous studies. Two major challenges are long scan times, as suggested by previous studies and selection of the arterial input function (AIF). In this study, we aim to estimate the capillary level input function (CIF) using a deep learning network to overcome these two challenges.

Methods

Healthy volunteers (n= 8, ages: 21‐76) were recruited for DCE‐MRI scan for 28min. Golden‐angle RAdial Sampling Parallel (GRASP) sequence was used to obtain the dynamic images at ∼5s/frame. Individual AIF was sampled from the superior sagittal sinus of the brain (Fig.1a). FSL was used to segment the gray and white matters (Fig.1b). Each voxel was fitted using the graphical Patlak model (Fig.2a) to assess the vascular permeability‐surface area product (PS) for both 28‐min data and 10‐min truncated data. We used a 3x3 kernel sliding through the images (Fig.3) and feed each voxel’s dynamic as the input to our vision‐transformer. Training data were generated using individual AIFs with a mathematical model, consisting of two Gaussian and one exponential function, and used to simulate dynamic patches using the Extended Patlak model (Fig.2b).

Result

When the 10‐min data are used, the conventional approach with AIF results in overestimation of PS when the scan‐time is reduced, while the network‐predicted CIF allows more accurate estimation, with refence to the results using the 28‐min data, as illustrated by an example in Figure 4. Figure 5 shows the regional permeability differences between young and old subjects, where the conventional approach with AIF does not show the difference, while the approach with CIF shows subtle increases in PS with aging.

Conclusion

Our proposed CIF‐based approach provides an appropriate input‐function for DCE analysis, allowing assessment of subtle permeability changes in the BBB.
Longitudinal changes in plasma p‐tau181 as a surrogate variable to populational interventions
Authors: Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Benedet Andréa Lessa , Ashton Nicholas J. , Tissot Cécile , Bellaver Bruna , Leffa Douglas Teixeira , Brum Wagner S. , Therriault Joseph , Chamoun Mira , Lussier Firoza Z , Kang Min Su , Stevenson Jenna , Soucy Jean‐Paul , Gauthier Serge , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Rosa‐Neto Pedro , Pascoal Tharick A
Published: December 2022

Background

It has already been shown that longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) correlate with longitudinal Alzheimer’s disease (AD) progression. However, it is unclear whether longitudinal plasma p‐tau181 is a suitable measure to be used as a surrogate variable in clinical trials. This study aims to evaluate the utility of using longitudinal changes in plasma p‐tau181 to monitor drug effects in AD clinical trials.

Method

We evaluated 715 individuals (227 cognitively unimpaired (CU) amyloid‐beta (Aβ ) negative, 103 CU Aβ positive, 265 mild cognitive impairment (MCI) Aβ positive, and 120 Alzheimer’s disease (AD) dementia Aβ positive) from the Alzheimer’s Disease Neuroimaging Initiative. Individuals diagnosed with AD or MCI were classified as cognitive impaired (CI). The subjects had [18F]florbetapir Aβ PET at baseline and longitudinal plasma p‐tau181 (up to 4‐year follow‐up duration). We determined the longitudinal rates of change in plasma p‐tau181 concentrations and its effect sizes, calculated as mean change divided by the standard deviation. Logistic regression tested whether the longitudinal change in p‐tau181 status was associated with individuals’ clinical deterioration.

Result

Plasma p‐tau181 slope of change was positively associated with baseline plasma p‐tau concentrations (Fig 1). Longitudinal increase in plasma p‐tau181 was correlated with longitudinal worsening in cognition. Long‐term increase in plasma p‐tau181 values was more consistent in CU Aβ negative (48‐month effects size=0.4) and CU Aβ positive (48‐month effects size=0.6) than in CI Aβ positive (48‐month effects size=0.2) individuals (Fig 2).

Conclusion

Monitoring change in plasma p‐tau181 status from negative to positive can be helpful to identify individuals on the verge of cognitive deterioration in clinical practice. Longitudinal changes in plasma p‐tau181 values can open a new frontier in AD research offering a cost‐effective and scalable alternative to be used as a surrogate variable in large‐scale trials designed to test the effects of population interventions on the natural history of tau pathology in elderly populations.
Extracellular Tau Oligomers Rapidly Induce Nuclear Invagination in Neurons
Authors: Sun Xuehan , Shi Yu , Saibaba Subhi , Mandell James W , Bloom George S
Published: December 2022

Background

Neuronal nuclei are normally spheroidal with a smoothly contoured surface. In Alzheimer’s disease (AD) and other tauopathies, however, neuronal nuclei often develop deep invaginations that include the nuclear lamina, a meshwork of intermediate filaments on the inner face of the inner nuclear membrane. The lamina is involved in numerous nuclear activities that might be adversely affected by invagination, including chromatin organization, nucleocytoplasmic trafficking of macromolecules, cell cycle regulation and apoptosis. Previous work showed that in vivo expression of pathogenically mutated human tau in Drosophila melanogaster neurons causes nuclear lamina invagination and that invaginated neuronal nuclei are found in human AD brain (Frost, et al. 2016. Current Biology 26; 129‐136). In light of this background we sought to shed further light on the mechanism of pathological nuclear invagination in mammalian neurons.

Method

Lamina invagination was assessed by immunofluorescence microscopy in human and mouse brain tissue, and in cultured mouse neurons using an antibody against lamin B1, a major subunit protein of the nuclear lamina. To ensure thorough neuroanatomical coverage in mouse brain, we stained lateral, medial, and middle sections from each brain, and imaged across the cortical region. To seek stimuli that would cause neuronal nuclear invagination, cultured mouse neurons were exposed to extracellular tau oligomers (xcTauOs).

Result

We detected nuclear invagination in neurons in brains of AD patients and CVN (APPSwDI;NOS2−/−) mice, in the latter of which nuclear invagination in cortical neurons was more frequent than in age‐matched wild type control neurons. In cultured mouse neurons, lamina invagination was induced by xcTauOs within one hour of exposure. This effect of xcTauOs was found to depend on intracellular tau, because nuclear invagination was not detected in neurons derived from tau knockout mice unless they expressed human tau by lentiviral transduction.

Conclusion

Our data confirm that nuclear invagination is common in both naturally occurring human AD and a transgenic mouse model of AD, and implicate xcTauOs as likely triggers of this phenomenon by a mechanism that also requires intracellular tau.
Differential effects of comorbid Lewy body and Alzheimer’s disease pathology on regional FDG‐PET patterns
Authors: Silva‐Rodríguez Jesús , Labrador‐Espinosa Miguel , Moscoso Alexis , Schöll Michael , Mir Pablo , Grothe Michel J.
Published: December 2022

Background

In differential dementia diagnosis, an FDG‐PET pattern of pronounced posterior‐occipital hypometabolism with relative sparing of the posterior cingulate cortex (PCC) and medial temporal lobe (MTL) is indicative of an underlying Lewy body (LB) vs Alzheimer’s disease (AD) pathology. However, LB and AD pathology are often comorbid, and in patients with LB dementia the presence of AD co‐pathology correlates with a more AD‐like neurodegeneration pattern. Here we studied how concomitant LB and AD pathology affects regional FDG‐PET patterns in patients with AD dementia.

Method

The study included 52 patients from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had a final diagnosis of AD dementia (N=46) or amnestic mild cognitive impairment (N=6) and had an ante‐mortem FDG‐PET scan available (FDG‐PET to death interval: 3.4±2.4 years). Twenty‐one patients had autopsy‐confirmed AD without comorbid LB (‘pure‐AD’), 24 had AD with LB co‐pathology (‘AD‐LB’), and 7 had LB with no or low evidence of AD pathology (‘pure‐LB’). Pathologic groups were compared on regional FDG‐PET SUVRs, the “cingulate island sign” ratio (CISr; PCC/(precuneus+cuneus) SUVR), as well as neuropathologic ratings of substantia nigra neuron loss (SNnl). A complementary analysis assessed continuous associations of AD co‐pathology (Braak tau stage) with regional FDG‐PET SUVR and the CISr across cases with LB pathology (pure‐LB+AD‐LB).

Result

Compared to healthy controls (N=179), both pure‐AD and AD‐LB showed highly similar patterns of AD‐typical temporo‐parietal hypometabolism (Fig. 1), and neither regional FDG‐PET SUVRs, CISr, nor SNnl differed between the groups. By contrast, pure‐LB showed the expected pattern of pronounced occipital hypometabolism with relative sparing of the MTL, and CISr and SNnl were significantly higher compared to both pure‐AD and AD‐LB (p<0.05). Across cases with LB pathology, higher Braak tau stage was significantly correlated with a lower CISr (Spearman’s ρ=‐0.53, p=0.002), less occipital (ρ=‐0.37, p=0.043), and more MTL (ρ=0.36, p=0.047) hypometabolism.

Conclusion

In autopsy‐confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG‐PET pattern, which may complicate in‐vivo detection of this comorbid condition. By contrast, we confirm and extend previous findings that AD co‐pathology associates with a more AD‐like neurodegeneration pattern in cases with LB pathology.
Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease
Authors: Guimaraes Fernanda Burle dos Santos , Balthazar Marcio Luiz Figueredo , de Campos Brunno
Published: December 2022

Background

There is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease.

Method

We analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p<0.05 FWE corrected, with subsequent cluster‐level FDR correction p<0.05. In addition, only anatomical regions with more than 10 voxels were described.

Result

Significant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance.

Conclusion

Hyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.
Identifying Subtypes of Alzheimer’s Disease: An analysis of possible cognitive subgroups through the life span
Authors: Lima Bruna Seixas , Freedman Morris , Binns Malcolm , Tang‐Wai David F. , Black Sandra E. , Leach Larry , Tartaglia Carmela , Stokes Kathryn A. , Goldberg Yael , Chertkow Howard
Published: December 2022

Background

Typical Alzheimer’s disease (AD) is linked to memory impairment and medial temporal lobe atrophy. However, different patterns of cognitive decline in individuals with AD have been described in the literature (e.g., Murray et al., 2011; Lam et al., 2013; Scheltens et al., 2015). The variability of AD is also observed throughout the life span, as aging processes develop (Ferreira et al., 2017), which highlights the importance of investigating changes over time and establishing possible stages and therapeutic windows.

Method

The Toronto Cognitive Assessment (TorCA) was used to provide a characterization of cognitive profiles including orientation, immediate recall, delayed recall, delayed recognition, visuospatial function, executive control and language in 609 individuals with possible AD. Normative data for the TorCA (Freedman et al., 2018) suggest different levels of impairment can be identified depending on age groups. The present study investigated 27 neuropsychological subtests within the TorCA. Scores were summed based on cognitive domains and transformed into z‐scores. Further, the dataset was split into 4 age groups (Group 1 = less than 59; Group 2 = 60 to 69; Group 3 = 70 to 79; and Group 4 = over 80 years of age). The scores were analyzed with latent profile analyses (LPA) to identify cluster memberships among subjects.

Result

Different AD subtypes were identified in each age group characterized by patterns of cognitive impairment as follows:

a) Group 1:

1. Cluster 1: mild;

2. Cluster 2: amnestic;

3. Cluster 3: executive;

4. Cluster 4: moderate diffuse.

b) Group 2:

1. Cluster 1: mild diffuse;

2. Cluster 2: executive / visuospatial;

3. Cluster 3: moderate with preserved orientation and visuospatial

c) Group 3:

1. Cluster 1: moderate executive;

2. Cluster 2: mild diffuse;

3. Cluster 3: amnestic;

4. Cluster 4: moderate diffuse.

d) Group 4:

1. Cluster 1: severe diffuse;

2. Cluster 2: mild diffuse.

Conclusion

These findings suggest that different subtypes of AD can be identified throughout the life span. Further investigation of these differences will aid in the development of clinical tools to diagnose and treat subgroups, in the development of protocols that stratify this population for better research recruitment, and establishing relevant neuropsychological and clinical tools.
Neuropsychiatric symptoms and functional connectivity of neurotransmitter producing nuclei in MCI and mild dementia in Alzheimer’s disease
Authors: Burle Fernanda , Guimaraes Santos , Balthazar Marcio Luiz Figueredo , de Campos Brunno
Published: December 2022

Background

There is evidence that neurotransmitter producing nuclei are impaired in Alzheimer's disease (AD). Recent studies suggest that locus coeruleus and ventral tegmental area, main producers of noradrenaline and dopamine, respectively, are affected before the onset of amyloid‐beta deposition in the entorhinal cortex. Dysfunction of these nuclei seem to contribute especially to the manifestation of neuropsychiatric symptoms (NPS), which tend to aggravate as the disease progresses. As such, we aimed to correlate the functional connectivity (FC) maps of basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) to NPS in patients with mild cognitive impairment (MCI) and mild dementia in Alzheimer’s disease.

Method

We analyzed data from 43 subjects with altered amyloid‐beta in the cerebrospinal fluid (23 MCI; 20 mild dementia). Participants underwent rs‐fMRI and full neuropsychological evaluation, including Neuropsychiatric Inventory (NPI). FC maps were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. We correlated the NPI syndromes (apathy, hyperactivity, affective syndrome and psychosis) scores with the individual FC maps generated with each seed and group regressing for age and years of education variables (SPM12‐toolbox). The significance level was defined as p<0.05 FWE corrected, with subsequent cluster‐level FDR correction p<0.05. In addition, only anatomical regions with more than 10 voxels were described.

Result

Significant correlations were found exclusively with scores from hyperactivity subsyndrome (agitation, irritability, aberrant motor behavior, euphoria and disinhibition). Regarding right VTA we noticed an increased FC mainly with right and left subcallosal area (volumes 177.92 and 211.68mm³, respectively, Figure 1) and left medial orbital gyrus (volume 162.88). We found a similar pattern in the left VTA (Figure 2) and the right LC (Figure 3), showing increased FC predominantly with right subcallosal area (volumes 151.2 and 91.04mm³, respectively) and left subcallosal area (volumes 110.72 and 97.52mm³, respectively). When looking at BNM FC, there were no between‐group changes that reached statistical significance.

Conclusion

Hyperactivity symptoms in AD correlate to changes in noradrenergic and dopaminergic‐producing nuclei‐FC to subcallosal area/left medial orbital gyrus. These findings may support new research for NPS therapies.
Intact olfactory and cognitive abilities predict lack of transition to dementia in a biracial sample of older adults
Authors: Motter Jeffrey N , Choi Jongwoo , Lee Seonjoo , Goldberg Terry E. , Devanand Davangere P.
Published: December 2022

Background

Odor identification deficits predict transition to dementia, whereas intact odor identification and global cognition may identify lack of transition. The purpose of this study is to examine intact odor identification and global cognitive functioning as prognostic indicators of lack of transition to dementia in a well‐characterized biracial (Black and White) cohort.

Method

In a community‐dwelling sample of 2,270 older adults without dementia participating in the Health, Aging, and Body Composition (Health ABC) study, odor identification was measured using the Cross‐Cultural Smell Identification Test (BSIT) and global cognition was measured using the Teng Modified Mini‐Mental Status Examination (3MS), both in Year 3. Incident dementia was defined by diagnosis in medical/hospital records or prescription of anti‐Alzheimer’s disease medications. Survival analyses for dementia transition over 4 years and 8 years were conducted using Cox proportional‐hazards models.

Result

Survival analyses adjusted for demographic and medical covariates indicated that impaired odor identification (hazard ratio [HR] = 2.17, 95% confidence interval [CI] = 1.5‐3.1) and global cognition (HR = 2.75, 95% CI = 1.8‐4.3) each independently predicted transition to dementia (n = 287). Odor identification interacted with ApoE genotype, such that the effect of impaired odor identification on dementia transition risk was significantly greater in ApoE e4 carriers (HR = 4.0) than noncarriers (HR = 1.6). This interaction was significant for White participants, though not for Black participants. Among participants with intact odor identification (BSIT ≥ 11/12 correct) and global cognition (3MS ≥ 77/100 correct), 6.4% (49/765) transitioned to dementia over 8 years of follow‐up. Only 0.9% (4/451) of participants aged 70–75 with intact performance on both measures transitioned to dementia over 4 years of follow‐up.

Conclusion

Odor identification testing paired with global cognitive screening identified individuals at low risk for transition to dementia in a biracial community cohort with this decrease in risk being pronounced in the seventh to eighth decade of life. Identification of such individuals can obviate the need for extensive investigation to establish a diagnosis and has potential for screening participants for clinical trials.
Gene‐based polygenic score analysis identifies novel immune genes with deleterious variants that associate with Alzheimer’s disease
Authors: Reddy Joseph S. , Wang Xue , Allen Mariet , Carrasquillo Minerva M. , Biernacka Joanna M , Gregory Jenkins D. , Coombes Brandon J , Ertekin‐Taner Nilufer , Younkin Steven G.
Published: December 2022

Background

In the Alzheimer’s disease sequencing project (ADSP) whole exome dataset, only the well‐known TREM2.pR47H variant shows genome‐wide significance by conventional single variant analysis. To identify novel AD genes related to TREM2, we used gene‐based polygenic score analysis (PGSA) to evaluate an immune, temporal cortical co‐expression network with 229 genes including TREM2.

Method

The most recent whole exome variant call files from the ADSP (NG00067.v7) were subjected to stringent quality control. Post‐QC samples were divided into discovery (4174 samples sequenced at Broad), test (3299 samples sequenced at WashU), and follow‐up (2273 samples sequenced at Baylor) sets. The pruned variants (r2 < 0.2) with a minor allele count over 20 in each gene were analyzed by Broad/WashU PGSA thereby obtaining P‐values (gPbr.wa) for each gene in WashU samples. To assess significance in independent Baylor samples, cumulative Broad/Baylor PGSA was performed using a novel approach in which variants were stratified by both gene (gPbr.wa) and variant (Broad.P).

Result

After excluding TREM2, the five variants with gPbr.wa ≤ 0.08 and Broad.P ≤ 0.03 showed significant association in Broad/Baylor PGSA. One of these variants showed no evidence of association with AD in the combined dataset. Polygenic scores for the other four variants, which were in three genes, showed significant association in Baylor samples, and significant, essentially identical association in WashU samples. Polygenic scores for nine additional variants in these genes (0.03> Broad.P ≤ 0.13) also showed significant, essentially identical association in Baylor and WashU samples. The association of these 13 variants with AD was driven primarily by six deleterious, protein‐altering variants with minor allele frequencies less than 1%, but the other 7 variants also contributed.

Conclusion

Using gene‐based polygenic score analysis to analyze an immune co‐expression network, we identify three novel immune genes with actionable nonsynonymous and stopgain variants that show significant, replicable association with AD in the most recent release of the ADSP whole exome dataset.
Exploring Care Service Use Among Latino LGBTQ+ Caregivers of Persons Living with Alzheimer’s Disease and Related Dementias
Authors: Kittle Krystal R. , Flatt Jason D. , Perales Jaime , Anderson Joel G
Published: December 2022

Background

Latino and lesbian, gay, bisexual, transgender or queer (LGBTQ+) adults are both growing populations at increased risk of Alzheimer’s disease and related dementias (ADRD). The increased prevalence in ADRD among these populations requires caregiving that is often met by informal caregivers. Yet, very little is known about the experiences of informal ADRD caregivers who identify as both Latino and LGBTQ+.

Method

We examined differences in sociodemographic characteristics, caregiving characteristics, and use of caregiver support services between English‐proficient Latino and non‐Latino LGBTQ+ ADRD caregivers recruited via social media (n = 286; Latino n = 103).

Result

Latino caregivers identified as gay (45%), lesbian (24%), bisexual (20%), and queer/other (11%). Sixty‐one percent identified as cisgender (not transgender) women, 39% cisgender men, and 19% identified as transgender. On average, Latino caregivers were younger (36 vs. 38 years old), reported a lower percentage of individuals who completed a college degree (36% vs. 51%), a higher income (64% vs. 50%), and a lower percentage of being married or partnered (44% vs 63%). Latino caregivers were in their caregiving roles for seven months less than non‐Latino caregivers, and reported a greater (8% vs. 6%) presence and severity of behavioral symptoms of distress (e.g., agitation, disrupted sleep) among their care recipients living with ADRD. Latino caregivers indicated their care recipients had less dependence in activities of daily living (1.3 vs. 1.8) and more independence in instrumental activities of daily living (5.1 vs. 4.2). Latino caregivers also reported lower use of respite services (38% vs. 51%), transportation services (37% vs. 53%), and making home modifications (34% vs. 71%) for their care recipients living with ADRD.

Conclusion

Findings indicate Latino and non‐Latino LGBTQ+ ADRD informal caregivers differed in sociodemographic characteristics, length of time caregiving, and the presence and severity of behaviors and functioning levels of their care recipients living with ADRD. Latino caregivers utilized caregiver support services to a lesser degree than non‐Latino caregivers. More research is needed to understand ways to address the needs and better serve this growing population.
Exploring Cognitive Impairment in a Community‐Based Sample of LGBTQ+ Older Adults
Authors: Flatt Jason D. , Evans Alexandria , John Samantha E , Correro Anthony N , Kittle Krystal R. , Cicero Ethan C. , Wharton Whitney , Anderson Joel G
Published: December 2022

Background

Over three million adults aged 60+ in the U.S. identify as lesbian, gay, bisexual, transgender, queer, or another sexual and/or gender minority identity (LGBTQ+). Population‐based studies have found a higher prevalence of subjective cognitive decline among LGBTQ+ adults compared to non‐LGBTQ+ adults. Less is known about objective cognitive impairment in LGBTQ+ older adults.

Method

We recruited a community‐based sample of LGBTQ+ older adults (n = 61) from low‐income housing registries. The Telephone Interview for Cognitive Status (TICS; Brandt et al., 1988), an 11‐item screening test of global cognition. Descriptive statistics were used to summarize demographic characteristics, TICS scores, and the prevalence of cognitive impairment. We also examined associations between TICS score (adjusted for age and education) and self‐reported physical and mental health limitations.

Result

Mean age was 70.8 (SD = 5.8, range = 58‐84). Most reported their sex assigned at birth as male (67%), and 5% identified their gender as transgender or non‐binary. Most participants identified as lesbian or gay (85%), with 7% identifying as bisexual, and 8% queer or another sexual orientation. The majority (90%) identified as White, 7% Black, and 3% Latino. Over 62% of participants had a four‐year college degree or higher. Nearly 80% reported an annual income ≤$30,000. Common chronic health conditions included depression (57%), anxiety (48%), hypertension (46%), post‐traumatic stress disorder (26%), and human immunodeficiency virus infection (21%). About 40% (n = 24) reported problems with their memory. TICS median score was 33.0 (SD = 3.55, range = 21‐39). Nearly 43% (n = 26) may have cognitive impairment (i.e., TICS score of ≤32). A lower TICS score was associated with reporting limitations in daily activities (p = 0.02) and social activities with family and friends (p = 0.04) over the past four weeks.

Conclusion

Over 40% of LGBTQ+ older adults scored in the impaired range on a screening measure of global cognition. Clinically, more comprehensive evaluations would clarify the extent of decline present among the current sample. Follow‐up studies are needed to better understand the cognitive functioning of LGBTQ+ older adults as some subgroups report more memory problems relative to non‐LGBTQ+ groups. Moreover, inclusive recruitment and outreach efforts are essential so the voices of all LGBTQ+ subgroups can be accurately portrayed in clinical research.
Cognition research in LGBTQIA+ groups: What’s it mean for Alzheimer’s research?
Authors: Stites Shana D. , Bonsu Edna , Harkins Kristin , James Richard
Published: December 2022

Background

Older adults who are members of sexual and gender minoritized (SGM) communities, including lesbian, gay, bisexual, transgender, queer, intersex, asexual and other identity (LGBTQIA+) groups, are at high risk of cognitive problems and caregiving deficits. Sexual orientation is a social and structural determinant of health (SSDOH), impacting cognitive health and medical management as members of SGM groups encounter social and structural barriers that could be impacting cognition directly and indirectly, and research is needed to understand pathways that lead to those elevated risks. So, what type of cognition research is being conducted with LGBTQIA+ groups and how does it herald inclusion of these groups in Alzheimer’s studies?

Methods

We conducted a broad search of Pubmed, Embase, and PsychINFO (ProQuest platform) databases for January 2000 to December 2020 using search key terms for constructed related to: LGBTQIA, cognition, and Alzheimer’s disease and related dementias (AD/ADRD). Abstracts were analyzed to identify studies reporting on medical conditions. We report summary statistics to describe the topics, conceptual frameworks, sample characteristics, and methods in those studies with a focus toward the relevance of that information in Alzheimer’s research.

Results

In the past 20 years, 173 publications reported results from studies with samples identified as LGBTQIA+, suggesting about six studies per year are published on cognition topic‐related biomedical literature on these populations. The bulk of the empirical articles focused on sexual risk‐taking (n = 56) with a few addressing specific medical conditions: HIV (n = 37), AD/ADRD (n = 3), and cervical cancer (n = 1). Eight articles discussed cognition, with 5 of them reporting on cognitive measures.

Conclusions

Biomedical research on cognition with LGBTQIA+ populations remains focused on sexual behavior. Understanding how sexual orientation influences cognitive health and medical management requires advancing a conceptual framework of how other social and structural determinants of health operate on LGBTQIA+ identities. Investigations, for example, that help advance what is known about cognition – risks, resilience, and function, in members of SGM groups that are impacted by barriers to quality healthcare, employment instability, and experience daily discrimination. This type of framework may facilitate LGBTQIA+ inclusion in cognition studies and research priorities.
Urinary cadmium concentration and incident cognitive impairment: the REGARDS study
Authors: Zhang Yijia , Lu Liping , Bejerano Shai , Angley Meghan , Kahe Ka
Published: December 2022

Background

Studies have indicated neurotoxicity of cadmium (Cd) exposure. However, little is known about Cd exposure in relation to cognitive impairment.

Method

A total of 2,172 participants (mean age: 64.1±9.0 years old; female: 54.8%; Black: 38.7%), without cognitive impairment or stroke at baseline (2003‐2007), from a random sub‐cohort (n = 2,666) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, were included in this study. Urinary creatinine‐corrected Cd concentrations were measured at baseline. The Enhanced Cognitive Battery (ECB) and Six Item Screener (SIS) were performed every two years (ECB) or annually (SIS) during an average of 10 years of follow‐up. The ECB consisted of 4 tests: Word list learning (WLL), Delayed Recall (WLD), Animal Fluency, and Letter F Fluency, and its composite score was used to determine our first outcome: cognitive impairment by ECB. Because of missing data on ECB scores (n = 482), we also defined a second outcome for cognitive impairment by assigning them a cognitive impairment status based on SIS. Therefore, in the secondary analysis, the outcomes consisted of three levels: ECB, SIS, and control. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were examined using multivariable‐adjusted logistic regression for the ECB‐defined cognitive impairment or using multinomial logistic regression for the second outcome.

Result

During the follow‐up, 53 participants developed cognitive impairment as assessed by the ECB and 36 cases were determined by the SIS. After adjustment for potential confounders, no significant association was observed between the urinary Cd concentration and incident cognitive impairment. Comparing the highest tertile of Cd concentration to the lowest, the OR (95% CI) of incident cognitive impairment was 1.07 (95% CI: 0.43, 2.67; P
for trend = 0.87) for the cases measured by ECB (Table 1). In the analysis of multinomial logistic regression, the OR (95% CI) was 1.15 (95% CI: 0.47, 2.81; P
for trend = 0.97) for ECB and 1.04 (95% CI: 0.34, 3.22; P
for trend = 0.32) for SIS (tertile 3 vs. tertile 1) (Table 2).

Conclusion

Findings from this US cohort do not support the hypothesis that Cd exposure is associated with the risk of cognitive impairment.
Phenotypic characterization of UCI MODEL‐AD mice using RNA‐seq
Authors: Gantuz Magdalena , Liang Heidi Yahan , Rezaie Narges , AD MODEL , Mortazavi Ali
Published: December 2022

Background

The development and characterization of new mouse models late‐onset Alzheimer’s Disease (LOAD) are critical for understanding the progression of the pathology and as a platform for theevaluation of new drugs. The UCI MODEL‐AD project focuses on the development of LOAD mouse models based on human GWAS data.

Method

We evaluate each new modeldeveloped in our group by performing a comparative network analysis of hippocampal transcriptomes in order to relate changes in expression to other phenotypic changes. As part of our standard pipeline, we test each new GWAS variant model at the ages of 4 and 12 months crossed with 5XFAD mice to regular 5XFAD mice and GWAS variant‐only mice.

Result

Differential gene expression analysis allows us to quantify the impact of the ABI3, ABCA7, PICALM and TREM2 variants on the pathology. Each model that we have analyzed have both shared as well as unique gene modules. Several variants showed less transcriptional differences compared to wild type than 5xFAD at 4 months but increase inflammation at 12 months.

Conclusion

RNA transcriptome analysis combined with phenotypic characterization is essential to the characterization and identification of the most appropriate LOAD mouse model.
Retention of American Indian and Alaskan Native Patients in National Alzheimer’s Coordinating Center Data
Authors: Conniff Kyle R , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

In 2016, the Administration on Community Living noted that 258,616 American Indian and Alaskan Natives (AI/AN) were over 65 years old. That number is projected to be 648,000 by 2060. This change highlights the need to better understand Alzheimer’s disease and related dementias (ADRD) in these communities through research. Retaining AI/AN populations in research will be key to avoiding bias and maximizing value.

Method

We used logistic regression to compare participant retention at the first follow‐up visit in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set, using self‐identified White participants as a reference group. We defined retention as attending the first follow‐up visit within 18 months of the initial visit. Secondary analyses assessed potential variables related to the retention of AI/AN patients using stepwise logistic regression to identify a model that minimizes Akaike Information Criteria (AIC). Potential covariates considered include cognitive status, age, independence level, sex, education, marital status, co‐participant sex, smoking status, and body mass index.

Results

AI/AN populations had significantly lower retention than the White patients, and also had the lowest point estimate for odds of retention (OR: 0.65, 95% (0.51, 0.83)) among black (0.71 (0.67, 0.76)) and Asian (0.72 (0.64, 0.81)) populations when controlling for cognitive status, age, sex, and education. Among covariates considered for the prediction model, age (x5 years; OR: 1.13 (0.99, 1.29)) and education (more retention with high education) were found to be most predictive of retention among AI/AN participants.

Conclusion

Retention among AI/AN individuals was significantly lower than retention among White individuals. The stepwise‐selected logistic regression model indicated that older age at baseline and greater educational attainment may be associated with better retention. While all confidence intervals include 1, that may be a precision issue with only 224 AI/AN patients not missing information for the covariates considered for the models. Regardless, improved education in AI/AN communities may improve retention of AI/AN in research. Future research will investigate retention of AI/AN populations using different definitions of race and comparing different factors across races.
Longitudinal genetic and environmental relationships between structural‐ and diffusion‐based Alzheimer’s disease neuroimaging signatures
Authors: Williams McKenna E. , Gillespie Nathan A. , Bell Tyler Reed , Dale Anders M. , Elman Jeremy A. , Eyler Lisa T. , Fennema‐Notestine Christine , Franz Carol E , Hagler Donald J. , Lyons Michael J. , McEvoy Linda K. , Neale Michael C. , Panizzon Matthew S. , Reynolds Chandra A. , Sanderson‐Cimino Mark E. , Kremen William S.
Published: December 2022

Background

Composite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures’, are tools developed to identify brain changes specific to mild AD. We found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year progression to MCI beyond age and polygenic risk for AD (Williams et al., Brain Communications, 2021). Results held up after accounting for general brain age. In contrast, a cortical thickness/hippocampal volume‐based signature did not improve prediction. Given the importance of genetic influences on brain structure and AD, we examined the phenotypic and genetic relationships among diffusion and structural AD signatures and brain age, and how those relationships change across midlife and early old age.

Method

Our validated thickness/volume signature, novel MD signature, and a validated brain age measure were used in biometrical twin analyses to examine phenotypic, genetic, and environmental relationships both cross‐sectionally and longitudinally across 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1‐60.2). Subsequent waves were at approximately 5.7‐year intervals.

Result

Both AD signatures and brain age are heritable (56%‐72%), but each signature captured unique phenotypic and genetic variance that is also not explained by general brain aging. Genetic correlations across time within each signature were high (0.77‐0.98). Baseline MD signatures (age=56 years) predicted thickness/volume signatures over a decade later (r= ‐0.53, 95% CI: ‐0.62, ‐0.42), but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures (r= ‐0.13, 95% CI: ‐0.24, ‐0.01). Interestingly, by wave 2 (average age=62 years), the thickness/volume signature appears to have caught up with the MD signature in terms of predictive ability.

Conclusion

Findings lend further support to the idea that a signature based on brain microstructure captures very early AD‐related changes that are later reflected in the macrostructural signature. This MD signature explains substantial genetic variance that is consistent throughout midlife and into early old age, supporting the utility of the MD signature as a very early AD‐related neuroimaging biomarker and its potential role in clinical trials.
Identifying complement‐related proteins expression pattern of different APOE genotypes in patients with Alzheimer’s disease
Authors: Chen Guangxin
Published: December 2022

Background

Apolipoprotein E (APOE) gene is one of the strongest risk factors found for late‐onset Alzheimer’s disease (AD). Complement pathways are implicated in AD. The objective of this project was to examine the difference of complement related proteins expression and networks between AD and healthy control of the same genotype.

Method

Two publicly available label free quantification (LFQ) mass spectrometry brain proteomics datasets were used. The Emory cohort consisted of 4,774 protein groups for 10 controls (E3/E3) and 24 autopsy‐confirmed AD (8 of each genotype of E2/E3, E3/E3, and E3/E4); the Banner cohort of 5,711 protein groups for 77 controls (18 E2/E3 and 59 E3/E3) and 44 autopsy‐confirmed AD (6 E2/E3, 30 E3/E3, and 8 E4/E4). Each proteomics dataset was screened by a list of complement‐related proteins identified in Uniprot database using “Complement protein” as the keyword. Differential analyses were conducted using R package DEP for AD compared to control (non‐AD) group with the same genotype. Correlation analysis using R package WGCNA (Weighted correlation network analysis) was performed to cluster similar proteins into modules. The identified modules are then correlated with APOE genotypes, tau tangle burden and neurotic amyloid plaque burden. Finally, protein functional enrichment analysis was conducted using DAVID (DAVID Bioinformatics Resources 6.8).

Result

Complement proteins are highly expressed in AD (n = 36) than controls (n = 64) in genotype of E3/E3 and in AD (n = 17) than controls (n = 49) in genotype of E3/E4 in the Banner cohort (p‐value < 0.05, log‐fold‐change > log[1.5]). For both cohorts, one module is identified to have a positive correlation with APOE genotypes, tau tangle burden and neurotic amyloid plaque burden (p‐value < 0.05, correlation coefficient > 0.35). Proteins in those modules were involved in classical complement pathway and immunity innate, mitochondrial ribosomal proteins, and proteins related to Alpha‐2‐macroglobulin and extracellular exosome.

Conclusion

Our results suggest significant differential expressions of complement‐related proteins in AD, independent of APOE genotypes. This may provide potential biomarkers and therapeutic target related to complement pathways for AD.
Baseline blood amylin levels predict longitudinal cognitive decline in participants at risk for or with mild cognitive impairment and dementia
Authors: Jicha Gregory A , Goldstein Larry B , Wilcock Donna M , Despa Florin
Published: December 2022

Background

Amylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells that co‐aggregates with parenchymal and vascular b‐amyloid in the CNS. Cross‐sectional data shows that higher CSF and blood amylin levels are associated with increased frequency of cognitive impairment and dementia. The present study sought to determine whether baseline blood amylin levels are associated with longitudinal cognitive decline.

Method

Whole blood amylin levels were ascertained from 83 participants in a longitudinal cohort spanning the cognitive continuum from normal to MCI and dementia who were evaluated initially in 2017 and followed to present. Cognitive change data including MMSE, MoCA, CDR global and sum‐of‐box scores at baseline and longitudinal follow‐up were analyzed in relation to baseline amylin levels.

Result

Participants were followed for a mean 2.0 ± 1.1 years. Baseline whole blood amylin levels varied widely (mean of 8.8 ± 12.2 pg/ml). Seventy‐one participants had complete baseline and follow‐up data were included in this analysis. Of these, 20 had objective evidence for longitudinal decline. Participants with above vs below modal baseline amylin levels scored lower on baseline and follow‐up assessment scores including MMSE, MoCA, CDR global and CDR sum‐of box scores (p‐values all < 0.05). Annualized cognitive change scores (loss) for the MMSE (1.4 ± 2.4 vs. 0.3 ± 1.3; p < 0.05) and MoCA (1.5 ± 2.5 vs. 0.4 ± 1.8; p < 0.05) were greater in the above median baseline amylin level vs below median groups.

Conclusion

Baseline amylin whole blood levels are predictive of objective decline in MMSE and MoCA scores over periods as short as 2 years. These data suggest that the higher pancreatic hormone amylin may accelerate disease pathogenesis and cognitive decline as a result of altered pancreatic β‐cell function, potentially explaining, at least in part, the strong epidemiologic link between diabetes and dementia found across global observational cohorts. These data further suggest that the use of amylin biomarkers may serve as a useful tool for identifying subjects at high risk for short term cognitive decline. Additional work elucidating the role of amylin in degenerative disease cascades is warranted.
Bulk and single‐cell gene expression network analysis in mouse models of AD using PyWGCNA
Authors: Rezaie Narges , AD MODEL , Mortazavi Ali
Published: December 2022

Background

Mouse models of human diseases such as Alzheimer disease (AD) are one of the most important tools for studying pathogenic mechanisms and testing interventions and therapeutics. While much of the characterization of gene expression changes to date has been done with “bulk” RNA‐seq in tissues such as hippocampus and cortex, the advent of single‐cell and single nucleus functional genomics assays allow us to analyze those changes at the level of individual cell subtypes. However, we would like to compare the relatively sparse and noisy single‐cell assays to bulk RNA‐seq to deconvolve which cells are driving the changes observed in the previously collected bulk datasets.

Method

Here we develop a python package called PyWGCNA that is designed to identify and compare gene expression modules in bulk RNA‐seq data as well as compare them to scRNA‐seq data and snRNA‐seq clusters.

Result

As a proof of concept, we apply this to bulk RNA‐seq of the cortex and hippocampus from 5xFAD as well as matching control mice from MODEL‐AD to identify gene modules associated with the genotype and phenotypes. Comparisons of these modules to single‐nuclei reveal the specific cell‐types driving specific modules in a region‐specific manner.

Conclusion

This deconvolution approach allows us to interrogate existing bulk datasets using single‐cell data to look for the signature of cell‐type specific changes in gene expression.