bluuebunny/crossref_metadata_2025 huggingface dataset:
Caring of caregivers organically (COCO): Health education for Latinas caring for a family member with Alzheimer's disease or related dementia
Authors: Rocha Judith Susan
Published: December 2020

Background

Latinos have a 1.5 times greater chance of having Alzheimer’s disease or related dementia (ADRD) as compared to their non‐Latino White counterparts. Higher prevalence is attributed to having longer life spans and more health‐related risk factors such as diabetes, high blood pressure and obesity. Those who assume caregiving for persons with ADRD are also affected. Affected by higher levels of caregiver burden and lower general health as compared to non‐Latino Alzheimer’s caregivers, Latinos are at larger disadvantage, considering the already existing health disparities in the community. Latino Alzheimer’s caregivers experience more bodily pain and somatic symptoms than non‐Hispanic White caregivers.

Method

Data were obtained from a mixed methods study that used focus groups of caregivers and other stakeholders to adapt a culturally responsive health education intervention. Participants (n = 20) for the adapted intervention pilot were randomized into the intervention or control group. The Promotoras de Salud peer educator model was used to carry out the intervention. Feasibility and acceptability were measured using qualitative data collected during a final focus group and a satisfaction questionnaire. Using T‐tests, pretest and post‐test data collected were analyzed to compare changes in health‐related self‐efficacy (measured on Chronic Disease Self‐Efficacy Scales), health behaviors (measured on Family Habits Scale), caregiver burden (measured on Zarit Burden Interview), and depressive symptoms (measured on CES‐D).

Result

Phase I and II have rendered an 8‐week adapted intervention for Latinas that care for a family member/loved one with ADRD. Analysis of Phase III (pilot) of the study is currently underway.

Conclusion

There are few established evidence‐based, culturally responsive interventions for Latino families. With the expected exponential growth of the Latino population and prevalence of ADRD, targeting health/healthcare disparities and supporting protective cultural factors is crucial for improving health and mental health outcomes of these caregivers. The pilot‐study will offer preliminary data to help determine if health education with the use of promotoras for Latina ADRD family caregivers is a viable, means of intervening with this highly vulnerable population.
Neurofilament light is a non‐specific marker of aging and white matter integrity
Authors: Meeker Karin L. , Gordon Brian A. , Sutphen Courtney L. , Schindler Suzanne E. , Morris John C. , Fagan Anne M. , Benzinger Tammie L.S. , Ances Beau M.
Published: December 2020

Background

Neurofilament light chain (NfL) is considered a biomarker of neuronal injury and degeneration and is increasingly used to evaluate disease progression across multiple neurological conditions including Alzheimer Disease (AD). Despite growing attention as an injury marker, little is known about how NfL relates to brain structure and what other factors may influence this relationship. The objective of this study was to determine whether NfL level in the cerebrospinal fluid (CSF) is more strongly associated with total gray, white, and/or white matter hyperintensity (WMH) volume and assess how this association changes as a function of age and amyloid status.

Method

CSF NfL was measured in 397 individuals who also underwent structural MRI and amyloid positron emission tomography (PET) using Pittsburgh Compound B (PiB). PiB positivity was defined as having a mean cortical standard uptake value ratio ≥1.42. Images underwent volumetric segmentation using FreeSurfer 5.3. Pearson’s r correlation analysis was used to determine the association between NfL and age. A multivariate regression model was used to determine whether NfL predicts total gray volume, white volume, and/or WMH volumes in PiB positive (PiB+) and negative (PiB‐) individuals. Correlation analyses also assessed the association between NfL and gray, white, and WMH volume. Additional regression models were used to determine region specific associations between NfL and white/gray matter volume. Age was accounted for in all models.

Result

NfL was significantly correlated with age, r=0.63, p<0.001 (Figure 1). Accounting for age, NfL predicted total gray, white, and WMH volume, regardless of PiB status (ps<0.01; Figure 2 and 3). When including gray, white, and WMH volume in the same model, NfL was associated with total WMH volume (r= 0.43, p<0.001), but not gray or white matter volume (ps>0.05) across individuals.

Conclusion

Collectively, these results suggest that NfL is a non‐specific marker of aging and white‐matter integrity with limited sensitivity to amyloid status. Given the association with WMH volume across individuals, it is likely that NfL reflects other processes such as cerebrovascular disease.
Baseline correlations between [18F]GTP1 PET SUVR and MRI white matter hyperintensities in prodromal‐to‐mild Alzheimer's disease suggest independent contributions to cognitive impairment
Authors: Manser Paul T , Teng Edmond , Pickthorn Karen , Blendstrup Mira , Anegondi Neha , Krishnan Anithapriya , Song Zhuang , Carano Richard A.D. , Keeley Michael , Wildsmith Kristin R , Weimer Robby , Bohorquez Sandra Sanabria
Published: December 2020

Background

White matter hyperintensities (WMH) on MRI are commonly seen in Alzheimer’s disease (AD) and thought to represent co‐morbid microvascular ischemic disease. However, the relationship between WMH and tau pathology in AD remains incompletely understood. We explored this question using screening/baseline data from a Phase 2 study of the anti‐tau antibody semorinemab (Tauriel; NCT03289143), which included both MRI and [18F]GTP1 tau PET imaging.

Method

Participants in the Tauriel study are aged 50‐80, meet criteria for AD dementia or mild cognitive impairment (MCI), have MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, evidence of significant amyloid pathology, and significant episodic memory impairment (RBANS delayed memory index < 85), and undergo screening MRIs, with WMH quantified using the Fazekas scale. Analyses were performed on a subset of participants (n=381) who received baseline [18F]GTP1 tau PET scans. Relationships between WMH, [18F]GTP1 SUVR in an AD‐specific temporal lobe ROI, age, and cognitive scales were assessed graphically and quantified using Pearson correlations, Cohen’s D, t‐tests, and multiple linear regression.

Result

Tauriel participants had Fazekas scores of zero (n=161), one (n=208), or two (n=12). Per the Figure, participants with Fazekas scores > 0 tended to be older (Cohen’s D=0.69, p < 0.001) and have lower temporal [18F]GTP1 SUVR (Cohen’s D=0.35, p<0.001). The relationship between temporal [18F]GTP1 SUVR and baseline ADAS‐Cog13 (r=0.39, p<0.001) remained significant after adjusting for Fazekas score and age via multiple regression (p<0.001).

Conclusion

Given the circumscribed range of disease severity seen in prodromal‐to‐mild AD participants at screening/baseline in the Tauriel study, the relationships between MRI WMH and [18F]GTP1 tau PET suggest that these pathologies have additive and independent contributions to cognition that may be age‐related. Clinical trials of anti‐tau therapeutics in similar patient populations may need to account for cerebrovascular co‐morbidities in patient selection and/or efficacy analyses.
Development of a functional 3D brain organoid with microvasculature and a blood‐brain barrier
Authors: Raval Urdhva , Zeng Emma , Pasinetti Giulio Maria Maria
Published: December 2020

Background

Brain organoids are self‐assembled 3D cell aggregates developed from pluripotent stem cells with various cell types and extracellular structures that resemble the embryonic human brain. Induced pluripotent stem cells (iPSC) based organoids show great promise in disease modeling applications. Our previous work has validated the use of novel polyphenolic compounds to combat neurodegenerative diseases in animal and traditional cell culture models. The goal of the present study is to continue to explore the development of a functional brain organoid system with microvasculature and a blood‐brain barrier using iPSCs.

Method

iPSCs were differentiated into neurons, astrocytes, pericytes, oligodendrocytes, brain microvascular endothelial cells, and other relevant cell types. The organoid was developed using previously published protocols. The blood‐brain barrier was constructed by co‐culturing the different cell types.

Result

In this ongoing study, we demonstrate the development of a more accurate and functional brain organoid system with microvasculature and a blood‐brain barrier using iPSCs.

Conclusion

Our organoid will serve as a model for neurodegenerative diseases, drug discovery and the screening of novel polyphenolic compounds from dietary flavanols which have been recently associated with reduced risk of developing Alzheimer’s Dementia.
Cardiovascular risk factors in adolescence and adulthood and late‐life cognition: Study of Healthy Aging in African Americans (STAR)
Authors: George Kristen M , Peterson Rachel , Gilsanz Paola , Barnes Lisa L , Glymour M Maria , Mayeda Elizabeth Rose , Mungas Dan M , DeCarli Charles , Whitmer Rachel A
Published: December 2020

Background

Mid‐life cardiovascular disease (CVD) risk factors are associated with late‐life cognition, but it is unknown whether CVD risk factors before mid‐life affect cognition. African Americans develop CVD risk factors at younger ages compared to other racial/ethnic groups. We examined the relationship between CVD during adolescence and adulthood (early through mid‐life) with late‐life cognition in the Study of Healthy Aging in African Americans (STAR).

Method

STAR evaluated cognitive aging in African Americans (N=676) and enrolled approximately equal proportions of participants ages 50‐64 and 65+. Participants were long‐term Kaiser Permanente Northern California members and completed Multiphasic Health Check‐ups (MHC) from 1964‐1985 at which body mass index (BMI), blood pressure, blood glucose, and serum total cholesterol were measured. At STAR baseline (2019), education, income, and cognition were assessed. Cognitive domains of verbal episodic memory, semantic memory, and executive function were measured using the Spanish and English Neuropsychological Assessment Scales (SENAS). Domain scores were z‐standardized and averaged to create a global z‐score. We used linear regression to analyze the association between adolescent and adulthood CVD risk factors with cognition, adjusted for age, gender, and education.

Result

At MHC, participants were adolescents (N=333; ages 14‐25) and adults (N=343; ages 26‐56). Mean age at cognitive assessments was 68 (SD=9) years. Being overweight/obese did not predict late‐life cognition regardless of age at MHC. Hypertension [pooled β=‐0.18 (‐0.33, ‐0.03)] and diabetes [pooled β=‐0.69 (‐1.15, ‐0.24)] were associated with worse cognition among both MHC age groups. Hypercholesteremia was associated with worse cognition in adults at MHC, but not adolescents [Adults β=‐0.22 (‐0.40, ‐0.05) vs. Adolescents β=0.02 (‐0.16, 0.21); interaction p=0.03]. Having 2+ cardiovascular risk factors predicted worse cognition for both MHC age groups [pooled β=‐0.24 (‐0.40, ‐0.08)]. Looking at cognitive domains separately, associations were consistent for executive function and verbal memory, but non‐significant for semantic memory.

Conclusion

Hypertension, diabetes, or a combination of multiple cardiovascular risk factors at adolescence and adulthood were common and associated with worse late‐life cognition. Hypercholesteremia in adulthood, but not adolescence, was associated with worse cognition. Results suggest that cardiovascular risk as early as adolescence may influence late‐life brain health in African Americans.
A novel MRI contrast weighted ratio method for measuring myelin in older adults at risk for Alzheimer’s disease
Authors: Price Lauren Rose , Deardorff Rachael , Wu Yu‐Chien , West John D. , McDonald Brenna C. , Risacher Shannon L. , Saykin Andrew J.
Published: December 2020

Background

MRI measures sensitive to myelin integrity such as the T1/T2 weighted ratio method (T1w/T2w; Glasser & Van Essen 2011) have been investigated as potential AD biomarkers. Many cohorts have transitioned to T1 and T2‐weighted Fluid Attenuated Inversion Recovery (FLAIR) acquisitions. Our goal was to validate the T1w/T2FLAIRw method in comparison to the T1w/T2w method in the same cohort.

Method

28 cognitively unimpaired (CU, cognitively normal and subjective cognitive decline) and 26 AD‐related cognitively impaired (CI, mild cognitive impairment and AD) individuals were analyzed to determine the correlative validity of association between T1w/T2FLAIRw and T1w/T2w methods. Image processing algorithms were designed in‐house for application to AD, building on previous methods and implemented in SPM12. White matter regions of interest (ROIs) from the Johns Hopkins ICBM‐DTI‐81 white‐matter labels atlas were masked excluding cerebrospinal fluid and white matter hyperintensities. Pearson correlation was used to test associations between the canonical method and our extension. Then, diagnostic group differences were assessed using regional independent sample T‐tests, with Bonferroni correction for independent components (8 independent factors identified by PCA of all white matter tracts).

Result

Myelinated regions associated with cognitive decline, as well as all other atlas ROIs, demonstrated significant (p <.01) positive correlations between T1w/T2w and T1w/T2FLAIR values (r values between .590 and .915) with the exception of the fornix, which was significant at the .05 level in CU. Between‐group analyses using T1w/T2FLAIRw showed lower ratios (reflecting reduced myelin) in CI. Significant differences in group T1w/T2FLAIRw ratios were seen in the left hippocampal cingulum (left, p=.011; right, p=.024), uncinate fasciculus (left, p=.007; right, p=.015), and the right anterior limb of the internal capsule (p=.019) and superior fronto‐occipital fasciculus (p=.011). After Bonferroni correction only the left hippocampal cingulum, left uncinate fasciculus and right superior fronto‐occipital fasciculus approached significance (p = .088; .088; .056 respectively).

Conclusion

Results suggest T1w/T2FLAIRw is a valid alternative to T1w/T2w ratios. Between groups, T1w/T2FLAIRw pointed towards lower myelin in intersecting white matter tracts in cognitively impaired individuals. Although initial results appear promising with reasonably large effect sizes, a larger sample needs to be assessed to provide sufficient statistical power to effectively assess the proposed method.
Relationship between MRI and amyloid PET measures with cognition in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study
Authors: George Kristen M. , Whitmer Rachel A , Glymour M Maria , Mayeda Elizabeth Rose , Mungas Dan M , Gilsanz Paola , DeCarli Charles
Published: December 2020

Background

The U.S. population is aging and becoming more diverse. The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study enrolled 1,712 participants with the aim of evaluating how race/ethnicity and life‐course factors influence late‐life brain health. We examined the association between brain images and cognition in this cohort.

Method

To date, 164 participants have received MRI and PET imaging (25% Asian, 20% Black, 25% Latino, and 30% White). MRI analyses included regional gray matter, cerebrospinal fluid, and white matter hyperintensity (WMH) volumes. Amyloid PET used AV45 and standard SUVR analysis with cerebellar gray matter as the reference region. Participants underwent neuropsychologic testing and received diagnoses of cognitively normal or impaired (syndrome). Cognitive domains of verbal episodic memory, working memory, and executive function were measured using the Spanish and English Neuropsychological Assessment Scales (SENAS). Linear and logistic regressions were used to assess associations between imaging measures with cognition. Race/ethnicity interactions were tested (significant interaction p<0.10).

Result

Participants had a mean age of 75 (SD=6) years. Verbal memory was positively associated with hippocampal volume [β(95% CI):0.16(0.03, 0.28)] and negatively associated with amyloid burden [β:‐0.20(‐0.33, ‐0.06)]. Cerebral and parietal cortex volumes were associated with better working memory [cerebral β:0.21(0.07, 0.35); parietal β:0.15(0.03, 0.28)] and executive function [cerebral β:0.25(0.11, 0.38); parietal β:0.17(0.05, 0.30)]. Lateral and third ventricle volumes were negatively associated with working memory [lateral ventricle β:‐0.17(0.30, ‐0.04); third ventricle β:‐0.22(‐0.34, ‐0.10)] and executive function [lateral ventricle β:‐0.15(0.28, ‐0.02); third ventricle β:‐0.16(‐0.29, ‐0.04)]. Odds of syndrome were lower in those with greater cerebrum gray matter [OR:0.54(0.32, 0.90)], hippocampal [OR:0.27(0.14, 0.52)], and temporal cortex [OR:0.61(0.38, 0.98)] volumes. The positive associations of hippocampal (interaction p=0.08) and occipital cortex (p=0.02) volumes with verbal memory were significant for Asians and Latinos. Cerebrum gray matter (p=0.06) and parietal cortex (p=0.07) volumes were positively associated with working memory in Blacks. Occipital cortex volume (p=0.07) was positively associated with executive function in Asians. Racial/ethnic differences were seen in the relationship of WMH (p=0.07) and amyloid burden (p=0.04) with syndrome, but small numbers prevented race‐stratification.

Conclusion

Regional MRI and amyloid burden were associated with cognition and there were significant racial/ethnic differences.
Associations of orthostatic hypotension with dementia in older adults: A 12‐year follow‐up population‐based study
Authors: Xia Xin , Wang Rui , Vetrano Davide Liborio , Grande Giulia , Laukka Erika J , Fratiglioni Laura , Qiu Chengxuan
Published: December 2020

Background

Orthostatic hypotension (OH) has been linked to dementia in older people in several longitudinal studies. We sought to examine the associations of OH with all‐cause dementia and subtypes of dementia, and further to explore the potential modifying effects of APOE ε4 allele and impaired walking speed on their associations.

Method

This population‐based cohort study included 2,525 dementia‐free participants who had their postural blood pressure measured at baseline (2001‐2004) and were regularly examined until 2013‐2016 in the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K). OH was defined as systolic blood pressure decreases ≥20 mmHg or diastolic blood pressure decreases ≥10 mmHg when assuming the upright position. Dementia was diagnosed according to the DSM‐IV criteria. Alzheimer dementia and vascular dementia were diagnosed following the NINCDS‐ADRDA criteria and the NINDS‐AIREN criteria, respectively. Walking speed was measured through 2.4‐meter or 6‐meter walk test and impaired walking speed was defined as <0.8 m/s. Data were analyzed with Cox proportional‐hazards models after controlling for multiple potential confounders.

Result

At baseline, 613 (24.3%) participants were defined to have OH. During the 12‐year follow‐up periods, 370 people (14.7%) were diagnosed with dementia, including 198 with Alzheimer dementia and 67 with vascular dementia. OH was significantly associated with a multiple‐adjusted hazard ratio (HR) of 1.39 (95% CI: 1.10‐1.76) for all‐cause dementia, 1.58 (1.15‐2.16) for Alzheimer dementia, and 1.20 (0.70‐2.05) for vascular dementia. To further reduce the potential of reverse causality, we repeated the analysis after excluding dementia cases that were diagnosed within the first 3 years of the follow‐up periods, and the results suggested that OH was still significantly associated with all‐cause dementia (HR: 1.33, 95% CI: 1.01‐1.75) and Alzheimer dementia (HR: 1.63, 95% CI: 1.22‐2.19). There was no statistical interaction of OH with either APOE ε4 allele or impaired walking speed on the risk of dementia (p‐value for both interaction tests >0.10).

Conclusion

OH is associated with an elevated risk of dementia, especially Alzheimer dementia, among older adults. Neither APOE ε4 allele nor impaired walking speed could modify the association of OH to dementia.
Role of TREM2 deficiency in Alzheimer’s disease model mice expressing human APOE3 or APOE4
Authors: Fitz Nicholas F. , Nam Kyong Nyon , Letronne Florent , Wolfe Cody M. , Playso Brittany E. , Lefterov Iliya , Koldamova Radosveta
Published: December 2020

Background

Alzheimer’s Disease (AD) is a multifactorial neurodegenerative disease influenced by aging, genetic, and environmental risk factors. Inheritance of APOEε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are two major genetic risk factors for AD, surprisingly little is known about the interplay between these two risks. TREM2 is a receptor of the innate immune system expressed on microglia, indicating a role in AD related neuroinflammation. Recent data showed APOE can bind to TREM2, in an isoform specific manner, thus raising the possibility of an APOE‐TREM2 interaction affecting TREM2 signaling and microglial function. We hypothesize that TREM2 deficiency will modulate the pathological phenotype and microglial transcriptome in AD model mice expressing human APOE3 and APOE4 in a disease progressions‐dependent manner.

Method

In this study, we crossed Trem2 expressing and Trem2ko
mice with APP/PSEN1dE9 mice expressing human APOE3 or APOE4 genes to investigate whether the loss of Trem2 impacts: amyloid pathology, glial response, and whole‐brain transcriptome. To determine the disease progression‐dependent impact of Trem2 deficiency we assessed the AD model mice at an early stage (3.5 mo) and more advanced stage (6.5 mo).

Result

Our study provides evidence that Trem2 deletion worsened cognitive performance, diminished microglia barrier around amyloid plaques, but did not impact overall amyloid load in either APOE genotype at both age groups assessed. Using multi‐color time stamp in vivo plaque labeling for assessing growth kinetics of amyloid plaques, we determined that Trem2 deletion increased plaque diffusivity and growth of newly formed plaque in both APOE isoforms. To get further insight in the specific effects of Trem2 deficiency in relationship to APOE isoform, we performed RNA‐seq using whole brain tissue followed by comparison to known cell‐type specific genetic signatures including known disease associated microglial (DAM) genes. Transcriptionally, we identified: 1) a sub‐set of immune response genes including DAM and homeostatic microglial genes that are downregulated in all experimental groups and comprise the Trem2 signature, and 2) differentially expressed genes that are characteristic for each APOE genotype and age group.

Conclusion

This study significantly increases our understanding of the interaction between APOE isoforms and TREM2 in association with AD pathology.
Infusion of neural precursors improves memory impairment in mouse models of Alzheimer’s disease
Authors: Ruiz Nazaret Gamez , Fuentes Enrique Antonio Armijo , Gomez‐Gutierrez Ruben , Soto Claudio , Moreno‐Gonzalez Ines
Published: December 2020

Background

Currently available treatments for Alzheimer’s disease (AD) are essentially symptomatic and not disease‐modifying, positioning it as a serious global health problem with the increase of the elderly population. This disease is clinically characterized by progressive memory impairment and cognitive dysfunction. The neuropathological hallmarks of AD are the accumulation of extracellular β‐amyloid (Aβ) peptide in senile plaques, intracellular deposition of hyper‐phosphorylated tau as neurofibrillary tangles (TNF), neurodegeneration, synaptic loss throughout the brain, and a neuroinflammatory process governed by the activation of glial cells. Recently, stem cell therapy has provided great potential in treating AD patients. However, there is an urgent need to replace the conventional intracerebral stem cell therapy for a less invasive method to avoid some of the technical challenges. Our recently published results indicated that peripheral treatment with neural precursors (NPs) ameliorates clinical symptoms by reducing the disease‐associated neuroinflammation in a mouse model of Parkinson’s disease. Therefore, we hypothesize that intravenous administration of NPs and their released neurotrophic factors can be used as a non‐invasive therapy to ameliorate memory impairment in mouse models of AD.

Method

In this pre‐clinical study, NPs derived from mesenchymal stem cells (MSC‐NPs) and induced pluripotent stem cells (iPSC‐NPs) were intravenously injected into APP/PS1 and P301S mice at 3 and 6 months old (before and after brain pathology is established). Before treatment and at the age of 7 months old, experimental and control (PBS) animals were subjected to Barnes maze task, novel object recognition and rotarod test.

Result

NPs treated mice displayed an amelioration in memory dysfunction compare to the PBS‐injected animals. In addition, P301S mice injected with NPs showed improved motor function to rotarod coordination test in comparison to the control group.

Conclusion

Peripheral inoculation using NPs could be used as a treatment to reduce AD‐related clinical signs.
Multiple pathologies in an amateur soccer player with severe chronic traumatic encephalopathy
Authors: Rodriguez Roberta Diehl , Suemoto Claudia K. , Brucki Sonia Maria Dozzi , Leite Renata P. , Nowinski Christopher , de Lucena Ferretti‐Rebustini Renata Eloah , Jacob‐Filho Wilson , Pasquallucci Carlos Augusto , Nitrini Ricardo , Grinberg Lea Tenenholz
Published: December 2020

Background

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repeated brain injuries. The presence of co‐pathologies is not uncommon in individuals with CTE. Here, we described clinical and neuropathological findings of amateur soccer with a history of progressive parkinsonism and dementia.

Method

63‐years old male with no family history of neurodegenerative disease or alcohol abuse. He played amateur soccer as a goalkeeper for 42 years. Episode of concussion with loss of conciseness at age of 20, without symptoms afterward. He denied any non‐soccer related episodes of brain trauma. At the age of 65, he started with REM behavior disorder, followed by apathy. At age 67, he developed asymmetric bradykinesia, limb rigidity, and complete anosmia. At the age of 73, a neurological examination demonstrated asymmetric parkinsonism, worse in the left. He denied motor fluctuations or hallucinations. At age 75, cognitive impairment was observed and his MMSE score was 22/30 with temporal disorientation, executive and delayed recall impairments. The working diagnosis was Parkinson's disease dementia. He died at age of 81.

Result

Neuropathological examination showed prominent frontal and temporal atrophy, hippocampal asymmetry and moderate depigmentation of substantia nigra, and locus coeruleus. Hematoxylin and eosin staining showed left hippocampal sclerosis and white matter arteriolosclerosis. Immunohistochemistry evaluation showed aggregates of hyperphosphorylated tau in neurons, astrocytes and cell processes in a patch distribution around vessels, with deep sulcal accentuation in several cortical regions fulfilling criteria for CTE stage III. Additionally, neurofibrillary pathology was found in subcortical and cortical areas (BRAAK stage V) and Aß plaques were distributed in cortical, limbic and diencephalon areas (Thal 4), altogether meeting criteria for an intermediated ADNC. Also, phosphorylated TDP‐43 immunoreactive dot‐like and neuronal cytoplasmatic inclusions were found in entorhinal cortex, amygdala and hippocampus (LATE stage 3). Moreover, diffuse Lewy pathology was observed (Braak 5 of Parkinson´s disease).

Conclusion

Despite showing multiple co‐pathologies, former soccer players may develop CTE changes. This case adds to the increased number of former soccer players showing dementia due to multiple pathologies and CTE. If soccer‐related brain trauma triggers multiple neuropathological processes or if they develop independently remains an open question.
Structural characterization of rare missense variants within known neurodegenerative disease proteins
Authors: Palmer Ellen L. , Moth Christopher , Benchek Penelope , Wheeler Nicholas R. , Kunkle Brian W. , Hamilton‐Nelson Kara L. , Griswold Anthony J. , Naj Adam C. , Farrer Lindsay A. , Martin Eden R. , Pericak‐Vance Margaret A. , Haines Jonathan L. , Sheehan Jonathan H. , Capra John A. , Bush William S.
Published: December 2020

Background

Recent work suggests unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene‐based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impact on protein function before computing gene‐based statistical associations is critical.

Method

We employed the Phenotype Consensus ANalysis (PCAN) approach to identify genes with Mendelian associations to neurodegenerative disorders using semantic similarity, resulting in a candidate gene list of 24 genes not associated with AD and two previously associated genes (PSEN1 and TREM2). We applied the PathProx algorithm to identify Alzheimer’s Disease Sequencing Project (ADSP) Discovery Phase variants significantly clustered with known pathogenic variants compared to benign variants within 3D protein structures. Pathogenic variants for Mendelian neurodegenerative disorders were curated from ClinVar and benign variants from ExAC. Additionally, we predicted the impact of each ADSP variant on protein stability (vs. canonical wildtype amino acid) via change in free energy of folding (∆∆G) estimated by Rosetta software.

Result

Out of 1,365 ADSP missense variants in 26 genes, we identified 230 that were proximal (using PathProx) to known pathogenic variants. A total of 230 variants had ∆∆G values indicating their potential to thermodynamically destabilize a protein’s structure (91 variants were also proximal to known clinical variants). Gene‐based testing using these predicted functional variants identified two novel genes (CSF1R, and SERPINI1) associated with AD risk. Finally, models for PSEN1 and TREM2 using the PathProx or ∆∆G‐identified variants remained statistically significant with similar p‐values to models using all missense variants.

Conclusion

We have identified subsets of missense variants likely to impact the function of proteins associated with neurodegenerative diseases in the ADSP. These annotations can be used in multiple ways, such as highlighting variant sets for use in gene‐based testing and prioritizing variants for in vitro testing. Additionally, functional characterization of rare variants using PathProx and ∆∆G could aide in in heterogeneity testing of multifactorial diseases like AD. Finally, our methodology is phenotype‐centric and applicable to other diseases with overlapping phenotypes to identify candidate genes in a variety of neurological disorders.
Emerging effects of APOE in the Wisconsin Registry for Alzheimer’s Prevention
Authors: Vasiljevic Eva , Koscik Rebecca L. , Jonaitis Erin M. , Betthauser Tobey J. , Christian Bradley T. , Johnson Sterling C. , Engelman Corinne D.
Published: December 2020

Background

APOE ε4 allele status predicts both age of late‐onset Alzheimer’s disease (LOAD) onset and rate of cognitive decline leading up to LOAD. However, most of those studies have been done in older samples and with LOAD diagnosis absent biomarker data. There is less known about when APOE related differences in cognition and LOAD biomarkers emerge. Moreover, modeling APOE using ε4 allele status does not account for non‐linear risk between combinations of ε2, ε3, and ε4 alleles (Belloy et al. 2019, Neuron). Our first objective was to identify if the rate of cognitive decline and the level of amyloid‐beta (Aβ) differ by the APOE score, a composite score of the six APOE allele combinations weighted by the log odds of their association with LOAD (Darst et al., 2017 J. Alzheimers Dis.). Our second objective was to estimate the time that the APOE effect on cognition and Aβ emerges.

Method

We analyzed cognitive trajectories (n=1141) and Aβ (n=219) across APOE scores of participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). WRAP is a longitudinal study of adults age 40‐70 and non‐demented at baseline who were followed for up to 16 years with assessments every 2 years. We compared the rates of decline across the APOE score for four neuropsychological composite scores using a mixed effects regression model for longitudinal change with age. We estimated average Aβ (PiB‐PET DVR) at ages 55, 65 and 75 using a linear regression model with a person’s last scan.

Result

We found a significant age‐by‐APOE interaction in predicting cognitive decline such that the rate of cognitive decline for all four composite scores was greatest for people with the highest APOE score (Figure 1, Table 1). There was also a significant age‐by‐APOE interaction for predicting Aβ burden in the brain such that the average global Aβ was greatest for individuals with the highest APOE score (Figure 2).

Conclusion

We are currently analyzing timing of the emerging APOE effect on cognition. These results indicate that Aβ onset occurs earliest and the rate of cognitive decline is greatest for people with highest APOE risk in the WRAP sample.
Development of an orally bioavailable stress kinase inhibitor with brain exposure that targets the neuroinflammation‐synaptic dysfunction pathophysiology axis
Authors: Watterson Daniel Martin , Arancio Ottavio , Windisch Manfred , Pelletier Jeffrey , Roy Saktimayee M.
Published: December 2020

Background

An ambitious primary goal of NAPA is to identify disease modifying interventions, a goal complicated by the nearly complete failure of all clinical trials. However, a common yet neglected target is the pathophysiology progression theme of synaptic dysfunction associated with aspects of neuroinflammation that contribute to synaptic dysfunction. The neuroinflammation‐synaptic dysfunction hypothesis posits that certain aspects of this axis are amenable to therapeutic intervention. The druggable stress kinase p38αMAPK is a key target in the neuroinflammation‐synaptic dysfunction pathophysiology progression axis. Increased activity in activated glia results in dysregulated innate immunity as evidenced by increased levels of proinflammatory cytokines. Increased activity in neurons results in altered axonal transport and synaptic dysfunction. Neuronal dysfunction, in turn, results in further stimulation of the evolving stress cycle. Concurrent inhibition of the single target p38αMAPK in distinct cells of the pathophysiology axis could provide a novel form of potential pleiotropic intervention with increased potential for efficacy.

Method

A fragment‐based, secondary pharmacology‐filtered experimental approach allowed the custom design and production of a novel p38αMAPKI drug candidate, MW150 (= MW01‐18‐150SRM), with exceptional molecular selectivity and concurrent avoidance of dose limiting barriers identified in prior clinical candidates. IND‐enabling preclinical toxicology integrated with preclinical pharmacokinetics and pharmacodynamics documented a potential for first‐in‐human clinical evaluation (summarized in Roy, S. M., et al., 2019, J.Med.Chem., Drug Annotation: A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction)

Result

MW150 is a unique, orally bioavailable, stress kinase inhibitor that exhibits brain exposure and efficacy in diverse CNS disease models characterized by a neuroinflammation‐synaptic dysfunction axis. Promising results from ongoing studies suggest MW150 may be phase 2‐ready clinical asset available in Q3 2020: 1) phase 1a (SAD) and 1b (MAD) clinical trials; 2) six‐ and nine‐month preclinical toxicology; 3) commercial scale GMP clinical drug suitable for phase 2 and 3 clinical trials.

Conclusion

MW150 has the potential to provide a new therapeutic intervention mechanism for neurologic disease modification. There are no clinical trials of drugs with MW150’s unique profile of molecular recognition, pharmacological selectivity and safety.
Shared imaging biomarkers across Alzheimer’s and Parkinson’s disease
Authors: Zhao Yuji , Kurmukov Anvar , Goldman Jennifer , Gutman Boris A
Published: December 2020

Background

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two of the most common neurodegenerative diseases [1]. In previous studies, AD and PD demonstrate overlap in clinical syndromes, including presence of cognitive impairment, dementia in PD, and post‐mortem studies with regional atrophy and amyloid and tau deposition [2][3]. Here, we propose a novel morphometric‐feature based machine learning model to explore shared degenerative patterns in AD and PD on neuroimaging.

Method

We used T1‐weighted (T1w) MRI data from (PPMI) 166 controls/356 de novo PD patients, and (ADNI‐1) 242 controls/199 AD patients. As a baseline model we trained sparse spatially regularized (TV‐L1) logistic regression [6][7] using subcortical shape and cortical thickness [4][5] from T1w MRI. To train the two models jointly, we constrain the optimization with a cross‐disorder (CD) agreement term: the L2 model difference, weighted by the models’ local normalized mutual information (MI). The CD‐MI term allows the models to guide each other’s optimization, dynamically amplifying information sharing where degenerative patterns are most similar and minimizing sharing where they are dissimilar. We evaluate all models’ ROC area‐under‐the‐curve (ROC AUC) using nested cross‐validation and a shuffle‐split bootstrap test to assess model stability. For subcortical regions, we trained models using all regions, as well as individual models for each region (L/R thalamus, putamen, caudate, pallidum, hippocampus, amygdala, accumbens).

Result

Information sharing significantly improved predictive power for cortical thickness‐based, L amygdala, L caudate, and bilateral putamen models (Table 1, Figure 4). Weight maps of AD and PD models (Figures 1a,b,2) show areas of similar degenerative patterns in frontal and parietal association areas, thalamus caudate and putamen, confirmed by the mutual information maps (Figures 1c,3).

Conclusion

We designed a novel machine learning model to explore joint imaging biomarkers between Alzheimer's and Parkinson’s disease. Our findings on neuroimaging suggest shared topography of frontal, parietal, temporal, and cingulate changes for AD and PD. This may signify overlap of underlying pathologies with co‐existent amyloid and tau burden in both AD and PD.
Association of TREM2 variants and sphingolipid levels with AD in blood and brain
Authors: Proitsi Petroula , Ebshiana Amera A , Hodges Angela , Legido‐Quigley Cristina
Published: December 2020

Background

The TREM2 gene has an effect on AD risk similar to that of ApoE ε4. TREM2 is a microglial receptor, sensitive to lipids associated with neurodegeneration, such as glycerophospholipids and sphingomyelins (SM). Reduced levels of S1P in AD brain and elevated ceramides (CER), likely contribute to disease pathogenesis. The ability to respond to this signal may have important implications for AD. However, the extent to which TREM2 genetic variants affect the relationship between lipid levels and AD has not been examined. Here we investigated the association of lipid levels with AD in post‐mortem brain samples and blood and we interrogated how TREM2 genetic variants modify these associations.

Method

Brain tissue from the hippocampus and BA9 was collected from 48 AD patients and 24 controls, and blood was collected from 58 AD patients, 21 controls and 16 participants with Mild Cognitive Impairment (non‐overlapping). All participants were genotyped for TREM2 AD‐related variants. LCMS analyses were performed on both brain and blood and >250 lipid species were annotated. Linear and mixed effects regression models adjusted for age, sex, APOE ε4 allele, and post‐mortem delay (in brain samples), were used to investigate the association of lipids with AD and to examine whether TREM2 variants modified these associations.

Result

Overall CER and SM levels, especially those of shorter chain lengths, were increased in AD in both hippocampus and BA9 (e.g. AD patients had 1.02 SD higher Cer.d36.1 levels compared to controls (P‐value<1x10‐4 ; pooled estimate across the two brain regions ). TREM2 seemed to modify the associations of specific CER and SM with AD, with lipid levels of AD TREM2 carriers resembling those of controls. Although the associations of lipids with AD in blood were not as strong (with some in opposite direction) the way TREM2 affected association of some lipids with AD was analogous to that in brain.

Conclusion

This is the first study to investigate how TREM2 variants contribute to disease vulnerability through changes in lipid levels in post‐mortem brain tissue and blood. These results could hold special value in AD as they suggest vulnerable processes that could be targeted for therapeutic development.
Biopsychosocial effects of mindfulness intervention on older adults with mild cognitive impairment: A review
Authors: Tan Xiang Ren , Ho Elaine QY , Kua Ee‐Heok , Mahendran Rathi , Ng Ted Kheng Siang
Published: December 2020

Background

Fueled by the repeated failures of pharmaceutical compounds in clinical trials, the dementia field has recently moved towards validating preventive intervention of behavioral nature, such as mindfulness practice, to prevent and delay cognitive impairment. Despite the known cognitive benefits of mindfulness in healthy individuals, the effects on delaying cognitive decline in older adults with MCI (mild cognitive impairment) are largely unknown.

Method

We conducted a literature review on randomized controlled trial (RCT) studies to critically appraise the bio‐psycho‐social effect of mindfulness intervention on older adults aged ≥60 years old with MCI.

Result

A myriad of mindfulness studies have been conducted in Western countries. A total of five RCTs examining subjects with MCI were identified. Four studies showed improved neurocognitive assessments, three studies demonstrated improved neuroimaging measures, one study showed improved bio‐fluid markers and one study showed improved psychosocial well‐being. Most studies had small sample size (N20) and short duration of follow‐up (≤8 weeks), often with inadequate methodological rigor and mostly speculative post‐hoc interpretations.

Conclusion

The MCI population is severely understudied in the field of mindfulness intervention. Given the overall positive preliminary findings, it is time to move towards conducting large scale RCT of high‐quality, comparing the effects of mindfulness between Western and Eastern societies. A number of critical future directions include conducting high‐quality RCTs with more standardized mindfulness interventions, examining dose‐response relationship, longer follow‐up period to examine sustainability, differentiation of the specific effects of mindfulness, and the use of objective measures, particularly bio‐fluid markers.
ApoE ε4 status in pre‐dementia risk states, mild behavioural impairment and subjective cognitive decline, and the risk of incident cognitive decline
Authors: Nathan Santhosh , Gill Sascha , Ismail Zahinoor
Published: December 2020

Background

Dementia has an increasing global burden with over 40 million affected individuals. With sub‐optimal advances in drug development, there is an increasing shift to determine risk of dementia in the non‐demented population. Assessment of neuropsychiatric symptoms (NPS) may offer an opportunity to capture the at‐risk group earlier. Mild Behavioural Impairment (MBI) is a validated neurobehavioural syndrome, characterized by the emergence of sustained NPS in older adults as an at‐risk state for dementia. Cognitively, subjective cognitive decline (SCD) is a dementia at‐risk group in which cognitive symptoms are reported in the absence of objective findings. The apolipoprotein epsilon 4 (ApoE ε4) gene is a well‐known risk marker for dementia. We aim to determine the frequency of ApoE homozygosity in SCD, stratified by MBI status cross‐sectionally, and calculate the hazard of incident cognitive decline in this group longitudinally.

Method

Data from 5005 participants in the National Alzheimer’s Coordinating Center (NACC) were used to capture older adults who were cognitively normal, but had subjective cognitive complaints (SCD). We determined MBI status (+/‐) using a previously published transformation algorithm of NPI‐Q scores. We tabulated ApoE genotype in both groups. We compared proportion of ApoE homozygousity (APOE ε4+/+)in the MBI+ versus the MBI‐ group. Additionally, a Cox proportional hazards regression will be done to capture hazard of incident mild cognitive impairment in MBI+ versus MBI‐.

Result

A two‐sample test of proportions of MBI+/‐ status stratified by ApoE ε4+/+resulted in significant differences between groups with homozygosity more frequent in MBI+ versus MBI‐ (p<0.001). We will also present the results of the Cox proportional hazards regression analysis.

Conclusion

In older adults with subjective cognitive decline, ApoE ε4 allele homozygosity was more frequently seen in the MBI+ group. These findings provide additional evidence for the utility in determining MBI status in SCD.
A retinal hyperspectral imaging biomarker for Alzheimer’s disease: Preliminary study of the influence of eye diseases on imaging scores
Authors: van Wijngaarden Peter , Hui Flora , Dang Darvy , Ha Jason , Fowler Christopher J , Villemagne Victor LL , Rowe Christopher C , Masters Colin L , Williamson Robert , Crowston Jonathan G , Hadoux Xavier
Published: December 2020

Background

We and others have demonstrated that in vivo retinal hyperspectral imaging may serve as a non‐invasive biomarker of brain amyloid beta (Aβ) levels (Hadoux, 2019; More, 2019). We next sought to determine whether individuals with a range of common eye diseases have imaging scores distinct from those of people known to have high Aβ burden on brain PET imaging.

Method

Retinal hyperspectral imaging was performed on people presenting to ophthalmology outpatient clinics with visually significant cataracts (n=10), glaucoma (n=18) or diabetic retinopathy (n=14). Hyperspectral imaging scores were calculated for each participant using image processing methods described previously (Hadoux, 2019). Scores were compared with those of participants with high Aβ burden on brain PET imaging (n=15) and age‐matched PET‐negative controls (n = 20) (Hadoux, 2019).

Result

Participants in each group were similar for gender and age. Significant differences in hyperspectral imaging scores were found between PET+ participants and all other groups (Figure 1). Post‐hoc analysis demonstrated that PET‐ control participants had lower hyperspectral imaging scores than PET+ participants with normal (≥24, n=7; p=0.01) or reduced (<24, n=8; p=0.035) MMSE scores.

Conclusion

We have shown that individuals presenting to outpatient ophthalmology clinics with a range of eye diseases including cataract, diabetic retinopathy and glaucoma have retinal hyperspectral imaging scores that are distinct from those of individuals with high Aβ burden on brain PET imaging. Further studies are warranted to establish the influence these eye diseases on hyperspectral imaging scores in PET+ individuals. We also provide evidence that retinal hyperspectral scores may be elevated in PET+ individuals with normal MMSE scores, indicating that the method may have a role in identifying those with pre‐symptomatic Alzheimer’s disease. Prospective studies are underway to test this hypothesis. References: Hadoux, X, et al. Nature Communications; 2019; More, SS, et al. ACS Chem Neurosci. 2019.