bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association of Pain and Dementia among Mexicans aged 50 and older from 2001 to 2018
Authors: Milani Sadaf Arefi , Samper‐Ternent Rafael , Downer Brian
Published: December 2022

Background

Findings on pain and dementia are mixed. While some studies document an increased odds of dementia among those with pain, others have found that pain that limits a person’s ability to do daily activities (i.e., pain interference) is a stronger risk factor for dementia, rather than pain presence or severity.

Method

We used data from five waves of the Mexican Health and Aging Study (2001 to 2018), a nationally representative survey of Mexican adults aged 50+. Pain and dementia status were measured at each wave. Pain was defined as frequent pain (yes/no), pain severity (none, mild, moderate, severe), and pain interference (none/non‐interfering, interfering), defined as pain that limits daily activities. Dementia was defined as impairment on two or more cognitive domains and limitation with one or more instrumental activities of daily living. Multilevel mixed logistic regression was used to model the association between pain and dementia among those without dementia at baseline, adjusting for sociodemographic and health characteristics.

Results

Our analytic sample (n = 10,819) was 54.4% female with a mean age of 61.6 [standard deviation (SD): 9.1]. At baseline, 40.5% of participants reported frequent pain, 11.6% reported mild pain, 16.8% reported moderate pain, 10.1% reported severe pain, and 18.4% reported pain interference. The proportion of participants with dementia ranged from 3.5% in 2003 to 12.9% in 2018. Those with frequent pain had higher odds of dementia [odds ratio (OR): 1.59; 95% confidence interval (CI): 1.21, 2.09], compared to those without. Compared to those with no pain, those with moderate (OR: 1.45; 95% CI: 1.04, 2.02) or severe (OR: 2.26; 95% CI: 1.55, 3.29) pain had higher odds of dementia. Those with pain interference had higher odds of dementia (OR: 2.35; 95% CI: 1.77, 3.11) compared to those without.

Conclusion

In our sample of community‐dwelling Mexicans, we found that those with frequent, moderate, and severe pain, as well as pain interference had higher odds of dementia, compared to those without pain. Further work is needed to establish the temporality of the pain and dementia relationship. This is particularly needed in Mexico, where many individuals requiring pain relief have their needs unmet.
APOE4 copy number‐dependent Complement Pathway Dysregulation
Authors: Berger Miles , Morshed Nader , Stevens Beth
Published: December 2022

Background

Complement has been implicated in the pathophysiology of AD based on human genetic studies, human post‐mortem pathology, and mouse genetic studies. However, the relationship between complement activation and other AD risk factors (such as the APOE4 allele) remains unclear.

Method

We used pathway analysis of the ADNI targeted proteomics dataset to identify protein clusters highly correlated with each other, including a complement pathway cluster. We then developed a hybrid proteomics platform, which allows for both discovery proteomics (via LC‐MS/MS) and precise quantitation of complement protein‐derived peptides via Stable Isotope Labelled (SIL) internal control peptides for the complement proteins. We then tested this hybrid proteomics platform on over 130 CSF samples from cognitively normal older adults (ages 60‐80), together with assays for CSF amyloid beta, tau and p‐tau‐181p. Spearman correlation tests were used to evaluate correlations between protein pathway expression and demographic variables, such as APOE4 allele number.

Result

Pathway analysis of the ADNI targeted proteomics dataset identified a cluster of complement proteins whose levels were highly correlated with each other in the CSF; this cluster included peptides from C1QB, C2, C3, C4A, C5, C6, C8B and CRP and several additional proteins. Across ∼300 individuals (including cognitively normal controls, MCI and AD patients), expression of this complement protein cluster was inversely correlated with APOE4 allele count and gender (with lower expression in females), and a positive correlation with age (P<0.05 for each). To further study complement protein levels in human CSF across the AD spectrum, we developed a hybrid proteomics platform for precise quantitation of complement proteins and for unbiased discovery proteomics. In 130 CSF samples from older adults, we were able to detect ∼9,000 different peptides from 884 different proteins, and to precisely quantitate all proteins in the classical, alternative and mannose binding lectin complement pathways using the SIL peptide internal controls. Here we report data on APOE4 copy number dependent changes in quantified CSF complement protein levels, and on APOE4 dependent changes across the human CSF proteome.

Conclusion

APOE4 is associated with a reduction in CSF complement protein levels, which may reflect increased complement pathway activation and ensuing degradation of these proteins.
Trusted Partnerships in the Faith Community Facilitate Awareness and Recruitment of African Americans for Alzheimer’s Disease Studies
Authors: Williams Kelvin , Henderson Shelby , Lloyd Shawnta' , Caban‐Holt Allison M , Starks Takiyah D. , Martin Patrick McPhail , Bozoki Andrea C. , Price Stephen Russ , Plassman Brenda L , Welsh‐Bohmer Kathleen A. , Byrd Goldie S.
Published: December 2022

Background

Historical mistrust in medical systems has resulted in low Alzheimer’s disease (AD) research participation among African Americans (AA). However, the faith community remains a trusted institution among many AAs and can be a major facilitator for increasing AA AD awareness and research. To better understand the health needs of AAs and build relationships with faith organizations in the Triad area of North Carolina, we conducted a community needs assessment (CNA) among local faith leaders.

Method

A mixed‐methods CNA was conducted. Quantitative data was collected from 44 pastors of AA churches via surveys that assessed resources, church demographics, and health topics of concern. Descriptive statistics were conducted for survey data. Qualitative data was collected during “listening tours” among pastors, with specific emphases on healthy aging, trust in medical systems, and research perceptions. Data from “listening tours” were analyzed using thematic analysis.

Result

Our CNA indicated that AD was a common health topic of concern among pastors and their congregations. This is likely influenced by the composition of the churches, given that more than half of the pastors reported that at least 30% of their congregation was 65 years of age or older. During 2021, collaborations between MACHE and faith leaders produced 3 webinars, 13 food distributions, and 4 community outreach events. Over 40,000 people were provided AD and brain health education; 1,961 community members expressed interest in AD research opportunities; and 580 AAs enrolled in the NC Registry for Brain Health over an 8‐month period in 2021, during the COVID‐19 pandemic.

Conclusion

Through a 3‐year partnership, the TPN and MACHE have significantly increased brain health awareness and AA participation in AD research through grassroots community engagement and outreach. Investments in trusting and sustained partnerships between an academic institution and faith communities demonstrated efficacy in increasing opportunities for providing service, access to research, and health education opportunities to communities that are typically underrepresented in research.
Socioeconomic Status Moderates the Effect of Inflammation on Whiter Matter Hyperintensity Burden and Neurodegeneration in Hispanic Older Adults: A Healthy Aging Brain Study‐Health Disparities
Authors: Clark Alexandra L , Haley Andreana , Evangelista Nicole D. , Ortega Nazareth , Dekhtyar Maria , Foret Janelle T
Published: December 2022

Background

Hispanic/Latino (H/L) older adults are at increased risk for AD, demonstrate an earlier age of dementia onset, and are more likely to experience delays in AD diagnosis and treatment relative to Non‐Hispanic Whites. These racial/ethnic disparities are the consequence of structural inequities and socioeconomic disadvantages (e.g., income, education) that disproportionately affect H/Ls and promote pathologic inflammatory cascades. Although low socioeconomic status (SES) and inflammation have independently been linked to poor cognitive outcomes, their effects on neural markers of brain health in older adults have yet to be fully examined. Therefore, the present study examined the independent and interactive effects of inflammation and SES on brain markers of neurodegeneration in Hispanic older adults.

Method

Data from 524 H/L (428 = cognitively normal; 105 = mild cognitive impairment) older adults enrolled in the Health Aging Brain Study‐Health Disparities were included. Z‐scores for income and years of education were averaged to estimate SES. A principal component analysis was used to create a composite measure of inflammation from serum markers (IL‐6, TNFα). MRI brain scans characterized intracranial volume, white matter hyperintensity (WMH) burden, and neurodegeneration of an AD‐signature meta‐ROI. Multiple linear regressions were used to examine (1) the independent effects of inflammation and SES and (2) inflammation x SES interactions on brain MRI markers.

Result

Regression analyses controlling for age, intracranial volume, sex, and vascular risk revealed that inflammation and SES were not significantly associated with WMH burden (ps >.15) or neurodegeneration (ps >.35). However, results revealed significant SES x inflammation interactions on WMH (p = .02) and neurodegeneration (p = .004); examination of simple main effects revealed that inflammation was associated with higher WMH burden and neurodegeneration in individuals from a lower SES, but not in those from a higher SES.

Conclusion

Inflammation negatively impacts brain health in H/Ls from a low SES. Results suggest that inflammation is a potentially modifiable point of prevention and intervention underlying poor brain health in H/L older adults from a lower SES. Importantly, results provide a foundation for further characterization of the contributions of systemic racism and barriers to brain health equity in minoritized and marginalized community members.
White Matter Correlates of Spoken Discourse in Cerebrovascular Disease
Authors: Broberg Dana N , Haddad Seyyed Mohammad Hassan , Aveni Katharine , Havens Alexander , Orange Joseph B , McLaughlin Paula , Binns Malcolm , Roberts Angela C , Bartha Robert ,   ONDRI Investigators
Published: December 2022

Background

Spoken discourse (language beyond single words or sentences) performance can be used to detect cognitive impairment in cerebrovascular disease (CVD) [Roberts A, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and indicators of white matter microstructural integrity provided by diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered spoken discourse.

Method

Spoken discourse and 3T DTI data (30‐32 directions, b=1000) were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n=133). Spoken discourse analyses were completed previously [Roberts, 2021]. A DTI analysis pipeline [Hassan SMH, et al. (2019) PLoS One 14(12):e0226715] was used to generate brain maps of fractional anisotropy (FA) and mean diffusivity (MD) and calculate mean FA and MD values for the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculi (UNC) in each hemisphere. Canonical correlation analyses examined associations between DTI metrics and 10 spoken discourse measures separately for FA in left hemisphere, MD in left hemisphere, FA in right hemisphere, MD in right hemisphere.

Result

Canonical correlations were significant in the left hemisphere (FA: r=0.47, p<0.05; MD: r=0.51, p<0.01) but not the right (FA: r=0.34, p=0.90; MD: r=0.40, p=0.15)(Figure 1). Among the white matter tracts, the strongest canonical loadings were seen for the SLFp (FA: 0.81; MD: ‐0.59) and SLFt (FA: 0.71; MD: ‐0.40) compared to the ILF (FA: 0.44; MD: 0.03) and UNC (FA: ‐0.34; MD: 0.10). Higher FA in the SLFp and SLFt was associated with better performance on measures of fluency and information content. Lower MD in these tracts was associated with better performance on measures of fluency, information content, and syntax.

Conclusion

Spoken discourse performance was associated with white matter microstructural integrity in the left hemisphere of the brain. Of the white matter tracts investigated in this study, impaired spoken discourse performance in CVD was most strongly linked to altered tissue microstructure in the parietal and temporal endings of the superior longitudinal fasciculus.
Characteristics of primary age‐related tauopathy defined by neuroimaging biomarkers
Authors: Jung Joon Hyung , Yi Dahyun , Byun Min Soo , Kim Min Jung , Kong Nayeong , Park Seo Hee , Jung Gijung , Lee Yun‐Sang , Lee Dong Young ,   for the KBASE Research Group
Published: December 2022

Background

Primary age‐related tauopathy (PART) is a neuropathological entity with neurofibrillary tangles (NFTs) in the absence of amyloid (Aβ) plaques in the brain. Recent advance of neuroimaging makes it possible to identify PART in living human brain. We tried to investigate the frequency and clinical characteristics including rate of cognitive decline of non‐demented older adults with PART defined by neuroimaging biomarkers.

Method

A total of 113 non‐demented older individuals recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included in the analysis. All participants underwent [11C] PiB PET and [18F] AV‐1451 PET with comprehensive clinical assessment. Global cognition was measured annually using MMSE, from 2 years before to 2 years after the PET scans. PART was defined when beta‐amyloid deposition is negative and tau burden corresponds to Braak stage I‐IV.

Result

Among 113 participants, 40 (35.4%) were classified as PART, 29 (25.7%) as no Alzheimer's disease (AD)‐ pathology (amyloid‐negative, Tau Braak stage 0), and 44 (38.9%) as AD (amyloid‐positive). Compared to PART and no‐AD associated pathology group, AD group had higher apolipoprotein E ε4 positivity (13.8%, 12.5%, and 59.1% for PART, no‐AD pathology, and AD, respectively). In regard of cognitive decline rate over 4 years, PART was similar to no‐AD pathology, but significantly slower than AD.

Conclusion

Our findings indicate that PART is relatively common in non‐demented older adults. In regard of genetic risk and progression rate, PART appears closer to no‐AD pathology condition rather than AD.
Cerebral Perfusion and Cortical Thickness Predict Cognitive Impairment in a Community‐dwelling Cohort
Authors: Okonmah‐Obazee Stephanie E. , Duran Tugce , Rundle Melissa M. , Williams Benjamin J. , Peavey Jeremy J. , Bateman James R. , Whitlow Christopher T. , Craft Suzanne , Lockhart Samuel N.
Published: December 2022

Background

Neurodegeneration and cerebral perfusion are key neuroimaging biomarkers in the Alzheimer’s Disease continuum. ASL (arterial spin labeling) explores cerebral blood flow (CBF) and has aided in elucidating cerebrovascular health amongst people at risk of cognitive decline. Reduced cortical thickness (CT) on MRI is a neurodegeneration biomarker that also implicated in cognitive impairment. The influence of cortical thickness and perfusion in AD‐related regions on cognitive status is poorly understood. We explored markers to investigate the roles they had in cognitive impairment.

Method

Participants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N= 535, Table 1) underwent baseline T1/ASL MRI. Participants were adjudicated as cognitively impaired (CI: mild cognitive impairment or AD) or cognitively unimpaired (CU) using NIA‐AA criteria by a consensus panel of experts. CT in an AD‐related temporal lobe meta‐ROI (region of interest) was calculated on T1 using FreeSurfer v5.3 and standardized. A homologous set of AD‐sensitive temporal lobe ROIs was used to extract mean CBF, which was log transformed for normality. A one‐way MANOVA (covariates: age, education, sex) assessed effects of CT and CBF on cognitive impairment. Bivariate models evaluated the associations of CT and CBF in relation to age, education, sex, and cognitive impairment. Linear regression was used to analyze whether cognitive impairment was predicted by CT and CBF (adjusted).

Result

We found both CBF and CT were associated with age (r2= ‐0.142, p<0.01; r2= ‐0.339; p<0.01) and cognitive status (r2= ‐0.188, p<0.01; r2= ‐0.264; p<0.01); respectively. CBF was also associated with sex (r2= 0.083; p=0.055) such that women had higher CBF. We also found that higher CBF was marginally associated with higher CT (r2= 0.083; p=0.055); this relationship was not significant when age, sex, and education were included in the model (r2= 0.886; p=0.376). Finally, we found both CT and CBF predicted cognitive impairment (p<0.01; both unadjusted and adjusted, in models where each MRI marker was used to predict cognition), such that CBF and CT were higher in CU; further, both CBF and CT independently predicted cognitive status when together in a model (p<0.008).

Conclusion

Cortical thickness and CBF are predictive of cognitive impairment.
Effect of APOE genotype on the Association between Sleep Disturbance and Cognition across Racial/Ethnic groups
Authors: Bubu Omonigho Michael M , Umasabor‐Bubu Ogie Queen , Mbah Alfred , Kaur Sonya , Turner Arlener D. , Williams Natasha , Jean‐Louis Girardin A , Osorio Ricardo
Published: December 2022

Background

APOE alleles are associated with cognitive‐decline and Alzheimer’s disease in Whites. We examined the effect of APOE‐genotype on the association between sleep disturbance (SD) and cognition across racial/ethnic groups.

Method

We conducted a cross‐sectional analysis of baseline data on 10,254 (i.e., 7900 non‐Hispanic Whites, 1428 Black/African‐Americans, 627 Hispanics and 299 Asians) cognitive‐normal subjects from the National Alzheimer’s Coordinating Center Uniform Dataset. We characterized SD using an item on the Neuropsychiatric Inventory‐Questionnaire. Generalized linear models examined SD‐group differences (i.e., SD vs. no SD) on psychometric tests performance between‐and‐within racial categories. The interactive associations of APOE genotype, SD, and race on psychometric tests performance was also examined. All models included age, sex, education, hypertension, and diabetes.

Result

Overall, the mean (sd) age was 71.1 (10.3) years and education was 15.7 (3.0) years. Prevalence of SD was 10% (Whites), 6.1% (Blacks), 18.2% (Hispanics), and 7.4% (Asians). SD subjects were at increased risk for worse psychometric scores in: executive, and language domains (p < 0.02 for all) among Whites; language domain (p = 0.001) among Blacks; memory, executive, and language domains (p ≤0.05 for all) among Hispanics; and visuospatial memory domain (p ≤0.001) among Asians. The interactive associations of APOE genotype, SD, and race on psychometric tests performance were significant (p ≤0.001 for all). Within racial groups, only Hispanic SD subjects with 1 or 2 APOE ε4 alleles were at increased risk for worse psychometric scores in memory, executive function, visuospatial, attention, processing speed and language domains (p ≤0.001 for all). Compared to Whites and Asians, Hispanic and Black SD subjects were at increased risk for worse psychometric scores across all domains (p ≤0.001 for all), regardless of APOE‐ε4 status.

Conclusion

In this sample of cognitive‐normal older‐adults, SD subjects were at increased risk for worse psychometric scores in specific cognitive domains that varied by race/ethnicity. Hispanic and Black SD subjects were at increased risk for worse psychometric scores regardless of APOE‐ε4 status. APOE‐ε4 effect on SD‐cognition association worsened psychometric scores and occurred only within Hispanics. These findings suggest that APOE‐ε4 interacts with sleep to effect varying cognitive domain outcomes within‐and‐between racial/ethnic groups.
Cerebrospinal fluid glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in Alzheimer’s Disease and Related Dementias (ADRD)
Authors: Jain Lavanya , Khrestian Maria , Tuason Elizabeth D. , Pillai Jagan A. , Rao Stephen M. , Leverenz James B. , Bekris Lynn M.
Published: December 2022

Background

Discerning Dementia with Lewy Bodies (DLB) from Alzheimer's disease (AD) can be a challenge for the clinician and represents a critical unmet medical need. Diagnosis of DLB is especially challenging in early stages due to variable core features and coexistent pathologies such as AD. A variable immune response has been implicated in AD/ADRD. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a myeloid cell activity marker, has been genetically linked to AD risk and glial fibrillary acidic protein (GFAP), an astrocyte activity marker, is liked to astrogliosis in a number of neurologic disorders. Our objective was to explore differences in cerebrospinal fluid (CSF) values of both sTREM2 and GFAP in AD/ADRD. This included individuals clinically diagnosed with AD, DLB, mild‐cognitive impairment (MCI), Parkinson’s Disease (PD), and cognitively normal controls (CN).

Method

Cohorts included participants from the Cleveland Clinic‐based Dementia with Lewy Body Consortium (DLBC), the Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease biobank (LRCBH‐biobank) and the Cleveland Alzheimer's Disease Research Center (CADRC). Patients were clinically characterized based on CSF biomarkers, clinical symptoms, and consensus review. Analytes measured included: CSF GFAP, CSF sTREM2, CSF a‐synuclein (aSyn) and plasma neurofilament light chain (NfL) using multiple platforms such as the Luminex/Millipore and Meso Scale Discovery systems.

Result

In this AD/ADRD cohort, CSF aSyn was higher in MCI than both PD and DLB, while lower in DLB than CN and AD. CSF sTREM2 was higher in MCI, AD and DLB than CN. GFAP was higher in MCI than either CN or DLB, while AD was higher than DLB. sTREM2/GFAP ratio was higher in DLB than CN, MCI, AD and PD.

Conclusion

These findings suggest that inflammatory factors, CSF sTREM2 and GFAP are altered in both AD and DLB. Future study of the relationship between CSF amyloid or tau and the immune response will help tease apart the potential influence of co‐existent AD‐related pathology on inflammatory factors in DLB. The findings will help inform possible immunotherapeutic strategies that seek to target the immune response in AD/ADRD.
Interplay of genetic and epigenetic factors in regulating immune‐related pathways in Alzheimer’s disease
Authors: Han Seonggyun , Nho Kwangsik , LEE YOUNGHEE
Published: December 2022

Background

Alzheimer’s disease (AD) is a major cause of dementia and among the most complex of diseases, featuring various heterogeneous molecular mechanisms. Not only genetic but also non‐genetic factors (i.e., epigenetics) contribute to progression in the human brain; dysregulation of gene expression by single nucleotide polymorphisms (SNPs) and altered DNA methylation is often observed in AD patients. Although genetic and epigenetic regulators have each independently received intensive study for their roles in AD progression, their interactive contributions to expression regulation are not yet fully understood. In this study, we aimed to elucidate the interplay of SNPs and DNA methylation in determining transcript‐level expression status in AD.

Method

We performed integrative analysis of whole‐genome sequencing (WGS), RNA‐seq, and methylation data from the dorsolateral prefrontal cortex in AD patients (n=495), obtained from the ROSMAP project. We tested a set of 160,126 SNPs having minor allele frequency (MAP) > 0.05 for interaction with 208,911 methylation loci within promoter regions (+3000 to ‐200 bp) related to expression status of 81,715 transcripts having transcripts per million (TPM) values. Likelihood ratio tests (LRTs) were used to determine the statistical significance of differences between linear models with and without the interaction term, with false discovery rate (FDR) < 0.05 for significance criteria.

Result

We identified 511 SNP‐methylation probe pairs as having interactions with statistically significant impacts on the expression of 76 transcripts (56 unique genes). Genes in the HLA family (e.g., HLA‐A, HLA‐B, HLA‐C, HLA‐DPA1, HLA‐DRB1, and HLA‐DMA) were found to be especially associated with the interplay of SNPs and methylation. For example, the SNP rs1126511 and DNA methylation locus cg13581859 interact in regulating expression of the HLA‐DPA1 transcript ENST0000419277: neither the SNP nor the methylation locus alone impacted its expression, but transcript levels tended to be significantly decreased under the combination of SNP allele T and low methylation. In addition, gene‐set enrichment analysis found that interaction‐regulated genes were significantly enriched in immune‐related pathways.

Conclusion

Our study provides a new molecular insight into the crosstalk between genetic and epigenetic elements that are involved in transcript expression status in AD and suggests that immune‐related pathways may especially be regulated by such interactions.
Neurotoxic mechanisms of glyphosate exposure
Authors: Limberger Christian , Roginski Ana Cristina , Amaral Alexandre U. , Venturin Gianina Teribele , Wajner Moacir , daCosta Jaderson Costa , Zimmer Eduardo R. , Souza Diogo O. , de Souza Débora Guerini
Published: December 2022

Background

Human exposure to pesticides is increasing, especially glyphosate‐based herbicides (GBH). Thus, it is of great interest to characterize whether glyphosate (Gly) exerts neurotoxic effects. Besides Gly, GBH formulations contain adjuvants, mainly POEA, a surfactant. We hypothesize adjuvants may enhance glyphosate neurotoxicity. Therefore, we aimed at investigating the neurotoxic properties of Gly and its adjuvants.

Method

Gly, POEA, Gly+POEA, and GBH were orally administered into male Wistar rats (90‐day‐old, n = 30) for 28 days (5 mg/kg/day). Controls received vehicle. Then, we assessed the working memory via Y‐maze test, glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), and glutamate transporter 1 (GLT‐1) immunocontent in cortex and hippocampus via Western blot, mitochondrial respiration via high‐resolution respirometry in cortex and brain metabolism via FDG‐PET (pons as reference region).

Result

GFAP and iNOS in the cortex were higher in Gly (p= 0.0053 and p=0.0012, respectively) compared to GBH (Figures A, B), whereas GLT‐1 was higher in the GBH (p=0.0004), compared to Gly (Figure C). Hippocampus showed no changes in GFAP, iNOS, and GLT‐1 expression in any group. The POEA group showed impaired working memory in the Y‐maze test (p=0.005) (Figure D). The respiratory control ratio was affected in the cortices of POEA (p=0.0212) and Gly+POEA (p=0.0281) groups (Figure E). Brain metabolism was not altered in cortical and hippocampal regions. However, the striatum presented hypermetabolism in POEA (p=0.0492) group (Figure F).

Conclusion

Environmental factors may contribute to the onset of neurodegenerative diseases in later life, including AD. Our preliminary results reveal individual toxic effects of Gly, POEA, and GBH, highlighting the overlooked role that adjuvants may have in herbicides toxicity. It seems that different subsets of reactive astrocytes result from each treatment. Mitochondrial uncoupling and striatum hypermetabolism may underlie working memory deficits. The study of potential pathways of neurotoxicity is fundamental for translational findings since the general population is chronically exposed to low doses of complex glyphosate formulations.
Sensory and Motor Differences in A Cognitive Aging Sample
Authors: Ho Emily , Mather Molly A , Weintraub Sandra , Gershon Richard C.
Published: December 2022

Background

Aging is associated with many different types of sensory, motor, and sensorimotor changes.

Recent evidence suggests such behavior may be able to predict the risk of developing Alzheimer’s Disease, potentially even before cognitive symptoms manifest. Existing studies have generally examined only particular facets of sensation and motor, rendering comprehensive comparisons of sensorimotor behavior in this sample difficult. To fill this gap, we use the NIH Toolbox® Motor and Sensation Batteries in three groups: normal controls (NC), Mild Cognitive Impairment (MCI), and dementia of the Alzheimer type (DAT).

Method

Participants (N = 336) were consensus diagnosed and grouped into either NC (N = 161), MCI (N = 104), and DAT (N = 71). Participants completed the NIH Toolbox Motor and Sensation Batteries. The motor battery included measures of Standing Balance, Grip Strength for both dominant and non‐dominant hands, Pegboard (dexterity) for both dominant and nondominant hands, the Walk 2 Minute, and the Walk 4 Meter. The sensation battery included measures of Odor, Visual Acuity (vision), Words‐in‐Noise, and Pain Interference. One‐way ANOVAs were conducted for each measure; effect sizes were also calculated.

Result

For all motor measures with the exception of Standing Balance, there were significant diffrences. For grip strength, NC exhibited higher strength than those in the DAT sample (medium effect). For Pegboard, DAT exhibited the weakest performance, followed by MCI (medium to large effect). In general, the DAT walked slower than MCI and NC (large effect), respectively. For sensation measures, there were no differences in visual acuity or pain interference across cognitive groups. DAT participants had decreased olfactory capacity compared with MCI and MCI to NC (large effect). The DAT group and MCI group had more difficulty distinguishing noise from words than the NC counterparts (large effect).

Conclusion

This represents one of the first studies to comprehensively characterize sensory and motor changes in a cross‐sectional sample of cognitive aging. Motor changes dominated; cognitive decline appeared more sensitive to both finer motor movements such as the pegboard task and gross movement such as walking. Sensation results were more mixed. We conclude with implications for sensorimotor changes and its relationship with cognitive performance in the latter life span.
Multi‐ethnic differences in brain and biopsychosocial risk factors for ADRD in UK immigrants from the Middle East and North Africa (MENA)
Authors: Jahanshad Neda , Haddad Elizabeth , Zhu Alyssa H , Nir Talia M , Bhatt Ravi R , Nourollahimoghadam Elnaz , Thompson Paul M , Salminen Lauren , Medland Sarah E , Gupta Arpana
Published: December 2022

Background

The populations of the Middle East and North Africa countries (MENA) are predicted to contribute to the world’s sharpest increases in rates of Alzheimer’s disease and related dementias (ADRD) in the coming years (GBD 2022), yet this group is underrepresented in health studies. The UK Biobank provides one of the largest and well‐characterized datasets on aging immigrants in the UK. We compare risk factors for ADRDs between UK immigrants from MENA countries to those of immigrants from other countries.

Method

Immigrants from MENA countries (N = 3557), India (N = 2959), Germany (N = 1103), and genetically‐determined British individuals (N = 1929) born outside of the UK in any of the three areas of interest were included in the study. There are multiple definitions of MENA: here, MENA was defined broadly to include the union of all included countries; Figure 1 highlights the distribution in this sample. We focused on variables associated with suboptimal brain aging and ADRD risk: APOE genotypes; education; an algorithmically defined diet quality score (Zhuang, 2021); BMI; incidence of parental death before 65 years; and the Townsend deprivation index (TDI) as a proxy of socioeconomic status (SES). Chi‐squared or Mann‐Whitney tests provided statistics on distribution discrepancies for categorical or continuous data, respectively. We also charted hippocampal volumes with age for the subset of each ethnic group who underwent neuroimaging.

Result

Figure 2 highlights group demographics and distributions. Compared to all other groups (Figure 3), MENA groups had higher TDI (lower SES), lowest diet quality, and highest BMIs; these differences remained even in college educated individuals. MENA also reported a greater incidence of maternal deaths before age 65. German immigrants were more highly educated than all other groups. ApoE4 alleles were significantly less prevalent in MENA and Indian countries than groups of European ancestry (Figure 4). Hippocampal volumes, adjusted for intracranial volume, had similar age‐trends across groups.

Conclusion

Many ADRD risk factors differ substantially across different ethnic groups, even when the proportion with a college education is not different. It is imperative to understand underlying lifestyle and sociological factors associated with immigration, to provide adequate healthcare for all aging individuals.
Validity of a remote supervised preclinical Alzheimer’s disease cognitive composite (PACC) score in preclinical and prodromal Alzheimer’s disease.
Authors: Maruff Paul , Lim Yen Ying , Masters Colin L. , Robertson Joanne
Published: December 2022

Background

Neuropsychological tests administered to individuals in locations different from the assessor (i.e., remote assessment) can provide substantial reductions in patient burden, study cost and barriers to access. However, such tests must be optimized and validated for use in remote settings. The preclinical cognitive composite score (PACC) is derived from neuropsychological tests of episodic memory, complex attention, and general mental status. This study determined whether a set of neuropsychological tests of these domains, which can provide a PACC score, can be given in a remote supervised setting and remain sensitive to AD related cognitive impairment.

Method

Older adults classified as cognitively unimpaired (CU, n = 30), preclinical AD (n = 30) or prodromal AD (n = 25), with conventional PACC scores known, completed three computerized tests; the International Shopping list Test (ISLT), Continuous Paired Associate Learning Test (CPAL) and the International Digit Symbol Substitution Test, while supervised by a neuropsychologist in in‐clinic and remote settings. All individuals then completed the remote assessments two more times 7days (+/‐4 days) apart

Result

Main performance measure from each test on each assessment was standardized using the mean and SD of the CU group, assessed under supervision, at baseline. Standardized scores for each assessment were then averaged to yield a PACC score. There was no difference in rates of missing data or group mean score on individual test scores or PACC score, between in‐clinic and remote settings. Compared to the CU group, impairment in performance on the digital PACC in the prodromal AD was substantial (z = ‐1.56) but equivalent between in clinic (9z = 1.57) and remote (z = ‐1.56) settings. Performance on the digital PACC was slightly worse in the preclinical AD group (z = –0.42) but did not differ for settings. The reliability of the digital PACC score was very high (r = 0.87).

Conclusion

The digital PACC derived from neuropsychological tests given in remote supervised contexts is acceptable, valid, reliable and sensitive to AD related cognitive impairment when given in‐clinic or remotely.
Multi‐modal sequencing analysis of astrocytes in human and mouse reveals strategically positioned novel reactive sub‐states
Authors: Hasel Philip , O'Dea Michael , Sadick Jessica S , Liddelow Shane A.
Published: December 2022

Background

Astrocytes can have helpful or harmful effects on neuron health and brain function in disease. While they normally provide trophic support to neurons during development and normal functioning, in response to many stimuli their heterogeneous ‘reactive’ responses can alter these functions drastically. Changes in astrocyte function depends on their ‘reactive’ sub‐state. Understanding when and where sub‐states of reactive astrocytes occur, and how these altered functions contribute to disease will pave the way for novel strategies to protect neurons.

Method

We performed combined 10x genomics single cell and spatial transcriptomics in wildtype and Alzheimer’s disease (AD) model mice, combined with single nuclei RNA sequencing of human postmortem non‐symptomatic and AD patient brains.

Results

With improved capture rates and subsequent powering of astrocyte sequencing we highlight lowly abundant, biologically important, reactive astrocyte sub‐states that are positioned in strategic locations throughout the brain – namely at sites of entry for peripheral immune cells (e.g. adjacent to penetrating vessels in layer I of the cortex, and around the ventricles). Further, we integrate our datasets with previously published scRNAseq and snRNAseq datasets to confirm these small populations exist in other patient populations. Most surprising was that interferon‐responsive reactive astrocytes were present early progression of pathology in the 5xFAD mouse AD model, but not at later time points – suggesting important early (possibly protective) roles for astrocytes early in AD. Additionally, when comparing mouse and human datasets we find most disease pathology‐associated reactive astrocytes are located around strategic points of entry to the brain, and express many inflammation‐responsive transcripts. Probing for ‘modules’ of genes associated with inflammation‐response and reactive sub‐states of microglia and other immune cells highlights putative interactions likely integral for feedback between these two cell types.

Conclusion

Optimization of astrocyte capture for single cell/nuclei sequencing combined with integration of previously published datasets increased the size of datasets for analysis and power of our analysis. Our data highlight several novel reactive astrocyte sub‐states that warrant additional functional characterization and further investigation.
Astrocytes mediate neuronal network hyperactivity in early AD
Authors: Shah Disha , Gsell Willy , Wahis Jérôme , Luckett Emma S. , Jamoulle Tarik , Preman Pranav , Moechars Daan , Craessaerts Katleen , Horré Katrien , Hendrickx Véronique , Jaspers Tom , Wolfs Leen , Vermaercke Ben , Fiers Mark , Holt Matthew , Vegh Zsuzsanna , Thal Dietmar Rudolf , D'Hooge Rudi , Vandenberghe Rik , Himmelreich Uwe , Bonin Vincent , de Strooper Bart
Published: December 2022

Background

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown.

Method

We analyzed resting‐state functional MRI data from a prospective cohort of patients and from the APP NLF knock‐in mouse model, with the aim to define which regions show early disruptions of functional connectivity (FC) before the presence of amyloid plaques. Next we used in‐vivo two photon calcium imaging to assess activity of astrocytes and neurons. Finally, we modulated calcium activity in astrocytes and assessed the effects on neuronal activity, FC and clinically relevant behavior readouts, i.e. seizure susceptibility and day/night activity.

Result

We found that, prior to amyloid accumulation, the human brain shows increased functional connectivity (FC) of the anterior cingulate cortex. Moreover, early increases of cingulate FC showed a positive correlation to amyloid load several years later in the human brain. Interestingly, we found the same FC deficit in the cingulate cortex of the APP NLF knock‐in mouse model, before amyloid deposition. We demonstrate that these FC deficits coincide with decreased calcium activity of astrocytes and increased neuronal activity. Recovery of the early astrocyte calcium deficits resulted in normalization of neuronal hyperactivity, increased FC as well as seizure susceptibility and day/night behavior disruptions.

Conclusion

In conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.
Identification of cis‐regulatory elements associated with MAPT expression in human induced pluripotent stem cell derived neural cells.
Authors: Rogers Brianne B. , Lauzon Shelby N. , Davis M. Natalie , Anderson Ashlyn G , Rizzardi Lindsay F. , Cooper Sara J. , Myers Richard M. , Cochran J. Nicholas
Published: December 2022

Background

Tau is encoded by MAPT and abnormal aggregates of tau are a hallmark of many neurodegenerative diseases. MAPT is highly expressed in neurons but much more lowly expressed in other cell types, including neural precursor cells (NPCs), suggesting that its expression may be controlled by neuron‐specific transcription factors and cis‐regulatory elements. Tau reduction, even of endogenous tau, is a current therapeutic strategy in both model systems and humans; therefore, understanding MAPT regulation may point to new strategies to achieve tau reduction. Additionally, genome sequencing studies continue to identify disease‐associated variants in non‐coding regions of the genome. These variants are likely located in regulatory regions and affect the expression of target genes whose function contributes to neurodegeneration. Therefore, an additional benefit of this study is that high confidence regulatory regions for MAPT may provide a way to identify important non‐coding variants associated with disease.

Methods

Three‐dimensional chromatin conformation capture (Capture‐C), single‐cell multiomics (RNAseq + ATACseq), and chromatin marks including H3K27ac, H3K4me1, and DNase hypersensitivity were used to identify candidate enhancers of MAPT in human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures (all lines were H1/H1). Approaches included nomination of elements with signals specific to neurons or neuronal subtypes. The nominated regions were then assessed using luciferase assays to test sufficiency for regulatory activity as well as CRISPR‐dCas9‐KRAB to assess the effect of nominated elements on MAPT expression.

Results

We identified both proximal and distal regulatory elements for MAPT with function confirmed by up to four orthogonal approaches (chromatin capture, single cell multiomics, a reporter assay, and element inhibition using dCas9‐KRAB). Several of these elements were specific to neurons. One particularly important region was centromeric to MAPT beyond the H2 inversion breakpoint.

Conclusions

Overall, these results indicate that MAPT regulation is likely controlled by neuron‐specific cis‐regulatory elements, including both proximal and distal elements. Next steps include study of the effect of trans‐regulatory elements (i.e., transcription factors) that may control recruitment of these cis‐regulatory elements for expression of MAPT and assessment of the effects of the disease‐associated genetic variation on cis‐regulatory element function and expression of MAPT.
Possible role for blood‐brain barrier disruption in patients with Alzheimer’s disease spectrum and non‐Alzheimer’s disease pathological changes
Authors: Moon Yeonsil , Jeon Hong Jun , Han Seol‐Heui , Noh Min‐Young , Kim Hee‐Jin , Kwon Kyoung JA , Moon Won‐Jin , Kim Seung Hyun
Published: December 2022

Background

The blood‐brain barrier (BBB) breakdown has been suggested as an early marker for Alzheimer’s disease (AD); yet the relationship between BBB breakdown and AD‐specific biomarkers based on the amyloid/tau/neurodegeneration (ATN) framework, is not clear. This study aimed to investigate the relationship between BBB permeability, AD‐specific biomarkers, and cognition in patients with cognitive decline.

Method

In this prospective observational study, we enrolled 62 participants with mild cognitive impairment or dementia between January 2019 and October 2020. All participants were assessed cognitive tests, amyloid PET, dynamic contrast enhanced MRI for BBB permeability (Ktrans), CSF studies for Aβ42/40 ratio, CSF phosphorylated tau Thr181 protein (p‐tau), CSF total tau protein (t‐tau), and structural MRI for neurodegeneration.

Result

Compared with the Aβ‐G, the Aβ+G had a higher median Ktrans in the frontal cortices (P = 0.049). In Aβ‐G, Ktrans was positively correlated with CSF p‐tau level in the cerebral cortex (all p < 0.05 except for the occipital cortex). In Aβ+G, Ktrans of occipital cortices was related with CSF Aβ42/40 (rho = 0.403, p = 0.027), and CSF t‐tau level (rho = ‐0.404, p = 0.027), whereas, Ktrans of frontal (rho = ‐0.610, p<0.001), insular (r = ‐0.400, p = 0.028), parietal (rho = ‐0.446, p = 0.013) and temporal cortices (rho = ‐ 0.435, p = 0.016) was negatively related with hippocampal volume. When adjusting age and education, neither BBB permeability nor CSF biomarkers predict cognition.

Conclusion

Our results suggest that the relationship between BBB permeability and ATN biomarkers is evident, more interestingly, this relationship varies with the presence of Aβ plaque accumulation.
Treatment of Alzheimer’s disease by modulation of microglial neuroinflammation by nasal anti‐CD3 mAb
Authors: Weiner Howard L , Lopes Juliana , Zhang Xiaoming , Baufeld Caroline , Rezende Rafael , Selkoe Dennis J , Butovsky Oleg
Published: December 2022

Background

Neuroinflammation and microglial activation play a role in AD as shown pathologically and by microglial PET imaging (Zhou et al, Front Immunol 2021). We found that nasal anti‐CD3 mAb induced IL‐10‐secreting T cells in the cervical lymph node that migrate to the brain, suppress microglial inflammation and ameliorate disease in a model of progressive MS (Mayo et a,l Brain 2016). In humans we found that nasal anti‐CD3 (Foralumab) decreased inflammation and accelerated resolution of lung inflammation in patients with mild COVID‐19 (Moreira et al, Front Immunol 2021) and modulated microglial activation in progressive MS as measured by microglial PET imaging (Chitnis et al, unpublished). We thus tested nasal anti‐CD3 in animal models of AD.

Method

We treated AD mice (3xTg and APP/PS1) with nasal anti‐CD3, isotype control antibody or PBS 3x/week for 6 months (3xTg) or 3x/week for 2 months (APP/PS1) and investigated cognitive behavior (Morris water maze and Y‐maze), microglia gene profile using a Nanostring myeloid codeset and T cell infiltration in the brain by immunofluorescence.

Result

We found that microglia lose their homeostatic (M0) signature and acquire a neurodegenerative (MGnD) signature in animal models of AD. In 3xTg mice, we found that nasal anti‐CD3 restored the M0 signature by increasing the expression of Cx3cr1, Mafb, and Jun, and lessened the MGnD signature by decreasing the expression of Trem2, Nos2 and Ccl5. Nasal anti‐CD3 improved cognition in 3xTg mice as measured by the Y‐maze and Morris water maze tests and in APP/PS1 mice as measured by the Y‐maze test. Nasal anti‐CD3 induced migration of T cells to the brain which interacted with microglia.

Conclusion

Nasal anti‐CD3 restores the microglial M0 signature and improves behavior in animal models of AD. Based on these results and the successful administration of nasal anti‐CD3 to subjects with progressive MS and COVID‐19, phase 1 trials of nasal Foralumab are planned in subjects with mild AD to assess safety, clinical effects and microglial activation as measured by microglial PET imaging. Nasal anti‐CD3 is a novel approach to treat AD by targeting microglial inflammation.