bluuebunny/crossref_metadata_2025 huggingface dataset:
Recruiting African American males in Alzheimer's disease education and genetics research
Authors: Starks Takiyah D , Adams Larry D , Byfield Grace , Hamilton‐Nelson Kara L , Howard Jazmine , Edwards Christopher , Scott Aja M , Lacroix Faina C , Laux Renee A , Haines Johnathan L , Cuccaro Michael L , Vance Jeffery M , Mayeux Richard , Kunkle Brian W , Reitz Christiane , Beecham Gary W , Pericak‐Vance Margaret A , Byrd Goldie S
Published: December 2020

Background

Addressing the disparity Late Onset Alzheimer’s disease (LOAD) prevalence among African Americans (AA) requires deliberate inclusion of this population in Alzheimer’s disease (AD) studies. Recruiting AA for research studies remains a significant challenge for AD genetic studies. Recruiting and retaining AA males (AAMs) is an even greater challenge, even when study personnel is AA, many traditional recruitment barriers are removed, and community outreach in AA communities is available and culturally appropriate. In this project, we highlight engagement of African American males in outreach and recruitment in three AD studies, and point to the need for expanded and targeted engagement opportunities for this population. While AA males indicate a willingness to participate equal to women, their actual participation is significantly less and may diminish potential generalization of studies in African Americans.

Method

We used culturally relevant approaches to educate and build trust within AA communities and made significant contributions to AA participation in AD genomic studies. For this study, we tracked AAM participation in community engagement activities and enrollment in AD genomic research studies over time.

Results

Over the past 5 years, 22% of the participants surveyed at an annual AA AD conference were AAM. Participation of AAM’s in large genomic studies such as the Research in African American Alzheimer’s Disease Initiative (24%), African American Alzheimer’s Disease study (24%), the largest Genome Wide Association Study, with 5896 total participants (30%), consistently fell below their non‐Hispanic White counterparts. The average participation of NHW males was 41% over the same period.

Conclusion

We have used culturally relevant strategies to engage AAMs in education and in genomic research studies. Their participation falls far below their representation in the general population and below their NHW counterparts. Implementing evidence‐based strategies that specifically address trust and gender‐specific needs of AAMs will be important in increasing their participation in genomic studies in AD, and thus generalizability of study results.
The regional and local relationships between amyloid and MRI‐visible perivascular spaces in white matter differ according to amyloid load: An ADNI study
Authors: Schwartz Daniel L , Boespflug Erin L , Lahna David , Dodge Hiroko H , Roese Natalie E , Baker Suzanne L , Woltjer Randall , Jagust William J , Kaye Jeffrey , Silbert Lisa C
Published: December 2020

Background

The relationship between amyloid (Aβ) production and clearance is disturbed in Alzheimer’s disease (AD). Evidence suggests that a decrease in clearance efficiency from cortical gray matter (GM) is relevant in late‐onset cases, a framework supported by findings of concomitant decreases in cerebrospinal fluid Aβ. A peri/paravascular bulk flow pathway for CSF and interstitial fluid in parenchyma, which transports solutes like Aβ, was identified in mammals more than 30 years ago; perivascular spaces (PVS) in white matter (WM) are part of this clearance system, and PVS dysfunction may be both a cause and effect of Aβ buildup in GM.

Method

Florbetapir PET, T1, and FLAIR MRI datasets of 95 ADNI subjects were used. Amyloid positive subjects (Aβ+) were defined by ADNI PET thresholds. MRI‐visible PVS were segmented using an automated algorithm and each was manually inspected, resulting in 8,392 PVS; GM was divided into 34 parcels per hemisphere and underlying WM was assigned to a parcel (Figure 1A). After Muller‐Gartner partial volume correction, amyloid SUVR in each GM parcel and PVS density in its associated WM, as well as the amyloid load in juxta‐WM GM (jGM) nearest each confirmed PVS (Figure 1B), were used as variables to describe the regional and local relationships between amyloid and PVS, respectively.

Result

Cohort‐wide amyloid load and PVS density varied widely across brain regions (Figure 2, middle row). Regional measurements of PVS and Aβ significantly correlated in Aβ+ subjects but not Aβ‐ (Figure 2, bottom). A pattern of decreasing amyloid load 1‐4mm away from the nearest jGM voxel was found in both Aβ+ and Aβ‐; amyloid burden in jGM near PVS was higher than non PVS‐associated jGM in Aβ+ but lower in Aβ‐ (Figure 3).

Conclusion

The complicated relationship between WM PVS and amyloid in GM differs according to amyloid load. Regional results suggest that PVS density is higher in regions with higher amyloid load, but only in Aβ+ individuals. Locally, WM PVS can be conceptualized as the clogged drain of a catchment system in Aβ+ subjects but as a functioning clearance system in those with sub‐threshold amyloid burden.
Neuroimaging methods in the randomized pivotal study of Renew NCP‐5 for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease or mild dementia of the Alzheimer's type
Authors: Salat David H , Helfgott Jonathan S , Helmer Karl G , Juttukonda Meher , Loveley Allison , Stufflebeam Steven , Tchoukoua Fridien Nana , Greve Douglas N
Published: December 2020

Background

Vascular disease and even subclinical variation in vascular health are known contributors to cognitive impairment and hasten the progression of symptoms in individuals with Alzheimer’s disease. Recent trials have demonstrated the therapeutic benefit of pharmacological treatments for enhancing vascular health on the incidence of cognitive impairment and on the progression of vascular brain injury measured by magnetic resonance imaging (MRI). Thus, novel vascular therapeutics provide a promising approach to slowing or preventing impairment in older adults. RenewTM NCP‐5 is an FDA‐cleared, external counterpulsation (ECP) device used clinically to improve coronary and peripheral vascular hemodynamics by sequential compression and decompression of vascular beds in synchrony with the cardiac cycle. ECP is currently used to treat patients with chronic angina and congestive heart failure and has been demonstrated to alter cerebral hemodynamics.

Method

Neuroimaging was coordinated across 12 sites (10 in the US and 2 outside of the US) for safety screening as well as for acquisition of exploratory neuroimaging markers of disease stage and treatment modification. Imaging protocols were in created based on a modified cross‐platform protocols developed for the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Additional sequences were added for safety. Coded data are uploaded to the central imaging coordinating site (CICS) at Massachusetts General Hospital. Patient characterization and exploratory outcome measures include T1‐weighted hippocampal volume measures and arterial spin labeling (ASL)‐based measures of cerebral blood flow (CBF). Imaging protocols include phantom scanning and test‐retest at each scan session to evaluate platform specific data quality. Imaging is performed at baseline, 6 months, and 12 months after initial treatment.

Result

Imaging has been performed on 214 individuals to date with 76 6 month and 6 12‐month scans. The imaging protocol is tolerated with minimal motion. ASL imaging is variable quality across scanners due to differences in hardware, software, and imaging support. This study is ongoing and initial study analyses are expected by November 2020.

Conclusion

RenewTM NCP‐5 treatment in Alzheimer's disease may impact cerebral hemodynamics and the ongoing clinical trial will test the effect of this treatment on cognitive symptoms as well the impact on Alzheimer’s or vascular‐associated disease processes in the brain.
Global Alzheimer’s Platform Foundation® (GAP) characterizes successful free memory screening programs
Authors: Zisko Leigh , Trotter Jennifer , Reynolds Allison , Thurman Lisa , Hollingshead Sarah
Published: December 2020

Background

Identification of eligible trial participants is essential to successful Alzheimer’s disease (AD) research. Participants are needed for more than 250 actively recruiting clinical trials in the US. Over 5.8 million Americans are living with AD – many of whom have not been formally diagnosed. It is established that physicians are often unaware of cognitive impairment in a significant percentage of their cognitively impaired patients. Free memory screens (FMS) at research sites provide the ideal environment to identify potential trial participants. This study will characterize successful FMS programs that identify eligible AD trial participants.

Method

The Global Alzheimer’s Platform Foundation® (GAP) developed the GAP Participant Services (GPS) program to provide AD trial‐specific, concierge‐level support for sites in the GAP Network (GAP‐Net). Anecdotal results were collected from over 500 GPS Liaison in‐person visit reports since Jan 2018. These results informed the construct of a survey that will collect more details about FMS programs including the following: Promotion and scheduling, Venue, Education level of staff conducting FMS, Information gathered, tools used, procedures conducted, How research opportunities are presented, and Metrics (including outcomes). GAP will report trends and FMS methods that generate the most successful outcomes.

Result

Quantitative survey results from up to 40 GAP‐Net sites are expected by the end of March 2020. Anecdotal results indicate the following: FMS advertised in the community and conducted both at the site and at community events are accessible and well attended; FMS conducted by master’s level staff or above result in better conversion rates; and Sites with an FMS program rapidly identify more eligible candidates for AD research

Conclusion

Characterizing and replicating successful components of a site‐level FMS program may result in identifying qualified candidates and lead to more rapid trial enrollment.
Genome‐wide association analyses identify genes modifying age‐at‐onset of Alzheimer’s disease
Authors: Martin Eden R. , Sun Shuming , Slifer Susan H. , Naj Adam C. , Gao Xiaoyi R. , Li Yi‐Ju ,   Alzheimer Disease Genetics Consortium (ADGC)
Published: December 2020

Background

Several studies have attempted to identify genes for age‐at‐onset (AAO) of dementia symptoms in Alzheimer’s disease (AD) through genome‐wide linkage (Daw et al. 1999, Li et al. 2002, Choi et al. 2011) and genome‐wide association studies (Kamboh et al. 2012, Naj et al. 2014). Naj et al. conducted a meta‐analysis of 14 datasets from the Alzheimer’s Disease Genetics Consortium (ADGC) with genotype imputation to HapMap2. Using an expanded set of ADGC cohorts, we re‐examined AAO using higher‐quality genome‐wide imputation data and pooled‐data analysis instead of meta‐analysis to identify novel genetic contributors to AAO of AD.

Methods

We combined data from 20 non‐Hispanic white prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data were imputed to the Haplotype Reference Consortium (HRC) r1.1 reference panel using the Michigan Imputation Server and consistent quality control applied to each dataset, after which genotype data were merged across datasets using QCTOOL and GTOOL. We performed case‐only association analyses for log10(AAO) using multivariable linear regression with covariate adjustment for sex, cohort, and principal components capturing population substructure, and then conducted analyses conditioning on dosage of APOE ε4 alleles. Variants with P < 10−5 from conditional analyses were re‐analyzed using linear mixed modeling treating cohort as a random effect.

Results

We used 9,228 AD cases, including 5,307 females (57.4%) with mean (SD) AAO of 74.2(7.7) years. In addition to the APOE region, which reached genome‐wide significance (P < 5 × 10−8), we observed strong novel associations with variants in NTM (encoding neurotrimin) on chr11q25 (rs117589002, P = 1.24 × 10−7) and in an intergenic region on chr3p22.3 (Pmin
 = 1.89 × 10−7). Other AAO loci previously identified in the smaller ADGC dataset (Naj et al 2014) remained nominally significant. After adjusting for APOE ε4, thirty‐two regions showed suggestive association (P < 10−5), with chr3p22.3 and NTM remaining the top loci. Chromosome 11q25 includes a known AD linkage region (Blacker et al. 2003). In addition, NTM variation has been found to be correlated with cognitive function tests (Liu et al. 2007) and intelligence (Pan et al. 2010).

Conclusions

In an expanded ADGC dataset, we confirmed AAO associations in the APOE region and observed evidence for potential novel AD AAO loci including NTM.
Reduced memory and executive functioning significantly relates to participation in early phase clinical research in Alzheimer's disease
Authors: Park Lovingly , Gertsik Lev , Mendoza Zyanya , Morris Lydia , Aguilar Claudia , Sherman Molly , Semenova Svetlana , Jhee Stanford
Published: December 2020

Background

The patient’s decision to enroll in clinical research is hampered by level of impairment, the need for a study partner, inclusion/exclusion criteria as well as factors related to the study design and trial procedures. These are exacerbated in early phase since the objectives center on safety and tolerability, without explicit benefit for the patient to participate. With the scientific advancements in AD, the protocols are increasingly complex with procedures involving CSF, pharmacokinetic sampling, and clinical endpoints. This study delineates the degree to which cognition may influence a patient’s decision to participate in clinical research.

Method

Patients were recruited a memory clinic at Parexel Early Phase Clinical Research Unit. Referrals come from their treating physicians, community outreach, and the research programs if there is a need for a diagnostic evaluation prior to their screening visits. We included a sample of healthy older adults (HNE; n=37, age=65.46, education=15.05), Mild Cognitive Impairment (MCI; n=54; age= 70.78, education= 14.20), AD (n=75, age=77.37, education=13.27), and other neurologic conditions (n=16; age=62.38; education=12.86). A binary logistic regression was used, with interested and not interested in research participation as the DV. The RBANS served as the index for cognition, COWAT and TMT B were the indices for executive functioning. Patients were provided descriptions of the types of procedures involved and a summary of the risks and benefits of participating, before they were asked about their interest in participation.

Result

There were differences in cognition across all diagnostic groups with the healthy elderly performing better across all tests than the others (p<.05) and they were also more likely to participate than others. Results of the logistic regression showed that the relationships among list learning (χ2 =4.97, p<.05), recognition (χ2 =8.03, p<.05), and letter fluency (χ2 =4.11, p<.05) were significantly related to participation.

Conclusion

Findings show that cognition, particularly in initial learning and executive functioning, predicts whether patient’s decision to participate. This is not surprising given the complexity of the information presented to the patient that are associated with most early phase research studies. Careful and tailored conversations about research studies are needed to facilitate recruitment.
Hypertension accentuates reductions in CSF Aβ42 in elderly depressives
Authors: Pomara Nunzio , Bruno Davide , Reichert Chelsea , Lee Sang Han , Sarreal Antero , Hernando Raymundo , Ramos‐Cejudo Jaime , Zetterberg Henrik , Blennow Kaj
Published: December 2020

Background

Hypertension (HTN) is a well‐established risk factor for Alzheimer’s disease (AD). Observations from animal and human PET studies indicate that HTN may be mechanistically linked to AD by increasing brain Aβ deposition which may represent the first pathogenetic event in the onset of AD dementia. For example, a diagnosis of HTN, has been associated with increased brain Aβ on PET imaging in humans. HTN is also common in late‐life depression (LLMD), a disorder which is also associated with increased risk for AD and altered Aβ dynamics consistent with increased brain Aβ burden including reductions in CSF Aβ42. Our group first reported a reduction in CSF Aβ42 which was unrelated to APOE status. However, the neurobiological mechanisms for the association between LLMD and altered Aβ metabolism are not fully understood and might involve co‐morbid vascular factors such as HTN. These considerations prompted us to examine the relationship between LLMD, HTN and CSF AD biomarkers in a cohort of non‐demented elderly.

Methods

CSF was obtained from 47 individuals (28‐LLMD and 19 ‐controls) 60 years or older with MMSE>28 and without significant white matter hyperintensities. A general linear model was used to compare the effect of hypertension status (HTN; Hypertensive or Not Hypertensive) and diagnosis (Dx; LLMD or control) on baseline AD biomarkers (Aβ42, Aβ40).

Results

We found that controls without HTN (mean=361 pg/ml) had sig. higher CSF Aβ42 than LLMD without HTN (mean=220 pg/ml; Tukey adj. p‐value = 0.18) and LLMD with HTN (mean=202 pg/ml; Tukey adj. p‐value = .031) given the significant interaction of HTN and Dx (p=0.05). There was also a main effect of HTN on Aβ40 (p=.025).

Conclusions

These preliminary results suggest that hypertension and LLMD are independently associated with reductions in CSF Aβ42 and that co‐morbid HTN may accentuate its reduction in LLMD. Thus, more effective treatment of depression and HTN may attenuate the increased risk for AD associated with these disorders.
Physical activity patterns in healthy and cognitively impaired older Chileans using wireless‐enabled wearable technology devices
Authors: Rogers Nicole , Lazcano Joaquin , Herrera Sebastian , More Jamileth , SanMartín Carol D , Bennett Magdalena , Romero Cesar , Grinspun Noemí , Valdés Jose L , Behrens María Isabel
Published: December 2020

Background

Increasing physical activity (PA) benefits cognition in older adults, both healthy and cognitively impaired. However, there is a lack of knowledge in the baseline amount and type of PA performed by this age group, especially in underrepresented populations. Furthermore, previous studies with other populations have almost exclusively focused on self‐reported and caregivers' questionnaires, which are considered limited tools for assessing PA and exercise.

Method

We recruited 77 people between the ages of 60 and 91 (average: 72.7 years) from different neighborhoods is Santiago de Chile, both cognitively healthy and with varying degrees of cognitive impairment. They underwent gait and neuropsychological evaluations and a thorough interview and neurological exam. Their PA was registered for a month with the use of a smart wristband activity monitor (Fitbit Alta HR). Daily steps, time spent inactive (sedentary activity, SA), in light physical activity (LPA), and moderate to vigorous physical activity (MVPA) were determined with the help of the algorithms provided by Fitbit.

Result

Healthy participants (HP)(n=53), amnestic mild cognitive impaired (aMCI) patients (n=14), and mild Alzheimer disease (AD) patients (n=10) averaged 6700 steps a day (HP=7015, aMCI=6700, AD=4910). There were no statistically significant differences in mean daily steps between the groups, nor in time they spent in sedentary activity, LPA, and MVPA. There were no significant differences between sexes for these variables. HP, aMCI, and AD patients registered an average of 140%, 220% and 250% more time in SA than what they had previously self‐reported, respectively; interestingly, healthy participants self‐reported higher time spent in SA than the cognitively impaired but average higher means of daily steps, and more time in LPA and MVPA. There was a significant inverse correlation between age and mean daily steps, and with LPA.

Conclusion

The use of wireless wearable‐technology offers a unique opportunity to study to role of PA patterns in other non‐transmissible diseases in healthy and cognitively impaired older individuals. More focus should be put in the prevention of sedentarism and the promotion of PA and exercise since it offers an approachable and measurable way of preventing cognitive decline, as well as shedding light on new biological mechanisms of neuroprotection.
Tau pathology spread in white matter pathways in atypical Alzheimer’s disease
Authors: Eckbo Ryan , Dickerson Brad C. , Makris Nikos , Collins Jessica A.
Published: December 2020

Background

Studies on animal models suggest that pathologic tau propagates along axons in a prion like manner, however there's limited evidence for this transneuronal spread in patients. In the current study we tested this hypothesis in a group of patients with heterogeneous clinical presentations of early Alzheimer's disease (AD) by examining the relationship between focal tau burden and the integrity of connected white matter pathways. We focused our analyses on the middle longitudinal fascicle (MdLF) because it connects several regions that are vulnerable to early tau accumulation across clinical presentations of AD.

Method

25 patients diagnosed with AD (14 PCA, 11 PPA, and 3 with amnestic MCI) underwent a tau (18F‐AV‐1451) PET (HR+ Siemens) scan, a T1‐weighted 3D MEMPRAGE scan, and a diffusion tensor imaging (DTI) (64 directions) scan. PET data were processed with FreeSurfer v6.0's PetSurfer pipeline with partial volume correction (PVC) and the DTI data were processed using UKF tractography. The left and right MdLF were defined in each patient and mean diffusivity (MD) was extracted as a measure of reduced microstructural integrity. Pearson’s r correlations were used to assess the relationship between MdLF MD and tau burden (18F‐AV‐1451 SUVR) in brain regions connected to the MdLF.

Result

Mean MD in the MdLF showed a positive correlation with tau uptake in both hemispheres in precuneus (left: r=0.47, right: r=0.48), superior temporal gyrus (STG) (left: r=0.45, right r=0.54), and supramarginal gyrus (SMG) (left r=0.50, right: r=0.51), all ps < .05, such that patients with higher tau burden in these regions had reduced MdLF microstructural integrity. There was no relationship between tau burden in the temporal poles and MD in the right or left MdLF.

Conclusion

Our results demonstrate that focal tau accumulation is associated with reduced microstructural integrity in connected white matter pathways. These results are consistent with accumulating research suggesting that pathologic tau proteins may propagate along axons from one brain region to another.
Validating the use of spatially resolved spectroscopy to demonstrate improvement of cerebral blood flow following external counterpulsation treatment in patients with mild cognitive impairment or Alzheimer’s disease
Authors: Helfgott Jonathan S.
Published: December 2020

Background

There is a strong correlation between Alzheimer’s Disease (AD) and poor cerebral blood flow (CBF). RenewTM NCP‐5 is an FDA‐cleared, external counterpulsation ECP device, which chronically improves coronary and peripheral vascular hemodynamics, and may provide the same benefit for cerebral perfusion and cognitive function. Accurate measurements of CBF, such as arterial spin labelling MRI, can be extremely costly, and alternative solutions may be less accurate. The moorVMS‐NIRS uses the established spatially resolved spectroscopy technique to measure tissue oxygen saturation (SO2) and relative concentrations of oxygenated haemoglobin (oxyHb) and deoxygenated haemoglobin (deoxyHb) in human tissue

Method

A subset analysis of patients enrolled in the RenewTM NCP‐5‐1001 research protocol (NCT03721705), will be monitored with the VMS‐NIRS device over the course of two 60 minute treatments, first during randomization then during week 24, which mark the start and end of their treatment regimen, respectively. The moorVMS‐NIRS measures oxygenation using a probe which is placed in contact with the skin over patients’ temples. Each probe consists of a detector head which contains two identical photodiodes and emitter head which contains near infrared LEDs emitting light at approximately 750 nm and 850 nm. To ensure replicable measurements from randomization to week 24. A BraiNet cap is used to mark the probe location.

Result

Individual patient data will be analyzed using both the individual patient as their own control (at randomization versus week 24) as well as a therapeutic efficacy comparison between patients randomized to the treatment group versus sham therapy. Acute and chronic changes will be monitored as continuous measurements will be taken during each treatment session. Arterial spin labeling MRI will be measured within 3 weeks of randomization and again within 3 days of the week 24 visit.

Conclusion

MRI results may be able to corroborate and further validate the use of the moorVMS‐NIRS device as an accurate, cost‐effective measurement to detect changes in levels of brain oxygenation for future trials.
Influence of rural vs urban county composition on AD neuroimaging biomarkers
Authors: Risacher Shannon L. , Wang Sophia , West John D. , Deardorff Rachael , Gao Sujuan , McDonald Brenna C. , Apostolova Liana G. , Saykin Andrew J.
Published: December 2020

Background

Individuals from rural and exurban areas are understudied in the context of AD, as academic institutions are generally located in urban areas. We evaluated whether individuals from rural (>50% rural), exurban/suburban (10‐50% rural), and urban (<10% rural) areas, based on population density in each county, differed in A/T/N biomarkers of AD.

Method

An ADRC‐based sample of 142 participants was studied with amyloid PET ([18F]florbetaben or [18F]florbetapir) and 3T MRI; 95 also underwent tau PET ([18F]flortaucipir). Participants were divided into groups by county composition, as described above. Amyloid PET scans were converted to Centiloid values (CL), and cortical CL was extracted. MRIs were processed using FreeSurfer v6 to extract temporal lobe cortical thickness. Tau scans were processed and temporal lobe SUVR was extracted. One‐way ANCOVAs were used to evaluate the relationship of county composition to A/T/N measures, covaried for age, sex, race/ethnicity, education, diagnosis (cognitively normal (CN), subjective cognitive decline (SCD), MCI, or AD), and ICV (MRI only). Chi‐square tests were used to assess the relationship of county composition and diagnosis, as well as amyloid positivity (CL>20).

Result

Of the 142 individuals, 9 were from rural counties, 35 were from exurban/suburban counties, and 98 were from urban counties. No difference in diagnosis by county composition was observed. Participants from rural counties were more likely to be Aβ+ (Figure 1A, p<0.001) than participants from other county compositions. Cortical CL was greater in individuals from rural counties and exurban/suburban counties relative to those from urban counties (Figure 1B, p=0.032). Finally, those from rural and exurban/suburban areas showed greater temporal lobe atrophy relative to urban counties (Figure 1C; p=0.019). No effects of county composition on tau were observed.

Conclusion

Our findings suggest that individuals from rural or exurban areas may have higher AD pathology on imaging. One limitation of this initial ADRC‐based study was the small sample size of rural participants. Future population neuroscience studies designed to recruit rural individuals into neuroimaging studies are needed to fully evaluate the role of rural versus urban residency on AD biomarkers.
Altered expression of mitochondrial genes involved in energy production and mitochondrial biogenesis is related to an increase in inflammatory factors associated with Alzheimer’s disease
Authors: Castora Frank J. , Slocum Jayne A. , Knoble Joseph A. , Kerns Kimberly A. , Hitefield Naomi L. , Gershon Blake , Shugoll Jason , Coleman Randolph A.
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that presents with symptoms such as cognitive impairment and a decline in memory. While often characterized by amyloid plaques and neurofibrillary tangles, there are a number of factors that play a role in this chronic disease. Recent studies have shown that mitochondrial function, and particularly, cytochrome oxidase (COX) activity is decreased in AD, disrupting mitochondrial energy production and potentially contributing to neurodegeneration. More recently, studies have indicated that inflammation plays an important role in the development of neurodegenerative diseases such as AD. Here, we analyzed changes in expression of 162 genes involved in mitochondrial energy production and biogenesis from 16 brain samples (11 AD and 5 age‐matched controls) and examined our findings through the lens of correlating any mitochondrial gene changes with inflammation processes.

Method

Total RNA was isolated from 80‐180 mg of frozen brain tissue from the 16 samples. Total RNA was quantified and assessed for purity using Nanodrop and Bioanalyzer analysis. cDNA was prepared and applied to the Human Mitochondrial Energy Metabolism and the Mitochondria RT² Profiler™ PCR Arrays. The qPCR data was then analyzed using Qiagen RT2 Profiler PCR Array Data Analysis version 3.5. The fold regulation and p‐value data was input into Ingenuity Pathway Analysis software to identify biologically important networks and pathways affected by AD.

Result

Three energy metabolism genes – ATP4A, ATP6VIG3, and NDUFA8 – were found to be strongly up‐regulated in AD vs control brains while 6 mitochondrial biogenesis genes – UCP3, TIMM22, SLC25A21, SLC25A23, SLC25A25 and TIMM9 – were found to be strongly downregulated. Furthermore, two transcriptional regulators, RICTOR and KDM5A were activated while upstream regulators PPARGC1A and RB1 were inhibited in the AD vs control samples. The observed changes in mitochondrial gene expression in our data set were associated with neurodegeneration and inflammatory response networks.

Conclusion

Gene expression data revealed an overall increase in inflammatory activity in AD brains compared to control brains. Further studies are needed to determine the clinical application of these findings, as an anti‐inflammatory approach to AD directed at mitochondrial genes/proteins could potentially slow the development or onset of the disease
AXL activation leads to reduced amyloid plaque deposition in APP/PS‐1 mice
Authors: Owlett Laura , Olschowka John A , Elliott Michael R. , O'Banion M. Kerry
Published: December 2020

Background

Microglia, the immune cells of the brain, play seemingly antagonistic roles in the Alzheimer’s disease (AD) brain. On one hand, microglia contribute to clearance of amyloid beta (Aβ) plaques via phagocytosis. On the other hand, activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis. Axl, a member of the TAM receptor family, is increased on microglia that surround Aβ plaques. Gas6, the primary ligand for Axl, promotes phagocytosis and suppresses inflammation in peripheral immune cells.

Method

To test the hypothesis that manipulation of the Axl‐Gas6 pathway contributes to Aβ clearance, we carried out intrahippocampal injections of an AAV‐Gas6 vector in male and female APP/PS‐1 mice at 4 or 7 months of age.

Result

Hippocampal overexpression of Gas6 for one or six months led to decreased Aβ plaque load when compared to the opposite hippocampus injected with a control AAV‐Gas6(delta) vector that lacks the Gla and EGF domains required for Axl phosphorylation. We are currently quantifying microglial responses in these brains as well as carrying out in vitro studies with microglia from Axl knockout mice to better determine the roles of the Gas6‐Axl signaling pathway in mediating Aβ phagocytosis and microglial inflammatory responses.

Conclusion

Axl activation in vivo leads to reduced Aβ plaque load. Results from this work will provide insight regarding potential mechanisms that may be harnessed to reduce AD‐related pathology.
Neurodegeneration in the Longitudinal Evaluation of Early Onset Alzheimer’s Disease Study (LEADS) sample: Results from the MRI core
Authors: Collins Jessica A. , Ezzo Rania , Vemuri Prashanthi , Borowski Bret J , Iaccarino Leonardo , Joie Renaud , Lesman‐Segev Orit H. , Bourakova Viktoriya , Eloyan Ani , Aisen Paul S , Fagan Anne M. , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , Kramer Joel H. , Koeppe Robert A. , Saykin Andrew J. , Toga Arthur W. , Day Gregory S. , Graff‐Radford Neill R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Salloway Stephen P. , Wolk David A. , Wingo Thomas S. , Carrillo Maria C. , Apostolova Liana G. , Rabinovici Gil D. , Dickerson Brad C.
Published: December 2020

Background

Approximately 5% of the 5.6 million (∼280,000) Americans with Alzheimer’s disease (AD) develop symptoms at age 65 or younger and are classified as having early‐onset AD (EOAD). Although EOAD and late‐onset AD (LOAD) share the same pathologic substrate, there are notable differences in their clinical and biological phenotypes. The Longitudinal Early‐onset AD study (LEADS) is a multi‐site, observational clinical and biomarker study of EOAD. In the present study we utilized the currently available LEADS imaging data to explore the spatial extent and magnitude of neurodegeneration EOAD

Method

95 amyloid positive patients with EOAD, 37 amyloid negative cognitively impaired patients (EOnonAD) , and 55 cognitively unimpaired controls (CNs) were included in the analysis. The magnitude of cortical thinning in the EOAD and EOnonAD groups was estimated using whole‐brain GLMs compared to the CN group. In addition, w‐scores were derived for each EOAD patient for these ROIs: average cortical thickness, hippocampal volume, AD‐signature cortical thickness (typically used in LOAD), and precuneus cortical thickness controlling for age, sex, and acquisition site. The utility of each ROI to differentiate EOAD patients from CNs was assessed by calculating the percentage of patients falling below a W‐threshold of ‐1.5.

Result

In EOAD, a distributed pattern of cortical thinning was observed in lateral temporal, parietal, and frontal cortex (p<.01), and was most prominent in the precuneus (Cohen’s d’ = 1.5). In the EOnonAD group, cortical thinning was observed but was highly variable across individuals. The w‐score analysis in the EOAD group yielded the following results: Mean Cortical thickness: Mean = ‐3.34, SD = 2.97, Classification = 72%.; Hippocampal volume: Mean = ‐2.96, SD = 2.39, Classification = 74%; AD Signature: Mean = ‐4.63, SD = 3.07, Classification = 80%; Precuneus: Mean = ‐5.98, SD = 4.1, Classification = 90%.

Conclusion

Our results are consistent with previous findings demonstrating cortical thinning in lateral parietal, precuneus, and lateral temporal lobes in EOAD with relatively less involvement of the medial temporal lobes. Our results also suggest that the precuneus may be especially vulnerable to neurodegeneration in patients with EOAD and may serve as a useful biomarker for patient classification.
Reduced thalamic volume is associated with early brain pathology in preclinical autosomal dominant Alzheimer’s disease
Authors: Pardilla‐Delgado Enmanuelle , Torrico‐Teave Heirangi , Ramirez‐Gomez Liliana A , Baena Ana , Bocanegra Yamile , Vila‐Castelar Clara , Fox‐Fuller Joshua T. , Guzman‐Velez Edmarie , Martínez Jairo , Sanchez Justin S , Lopera Francisco , Quiroz Yakeel T.
Published: December 2020

Background

Sleep‐wake dysregulation may increase the risk of developing Alzheimer’s Disease (AD). In turn, AD pathology in sleep/wake regulatory brain regions may exacerbate sleep disturbances. It is unclear whether sleep dysregulation occurs before or after the onset of clinical symptoms in AD. In this study, we aimed to investigate whether the volume of brain regions known to regulate sleep/wake cycles (thalamus, brainstem sub‐regions) was different between carriers and non‐carriers of autosomal dominant AD (ADAD); and whether volume of such brain regions is associated with markers of brain pathology (amyloid and tau) and memory performance.

Methods

A total of 36 non‐demented Presenilin‐1 mutation carriers and 32 age‐matched non‐carrier family members (mean age=36.3, SD=6.1) from the Colombia‐Boston (COLBOS) study underwent memory testing, and MRI and PET scanning. The CERAD word list delayed recall was used to assess memory; FreeSurfer was used to analyze bilateral volumes of the thalamus and sub‐regions of the brainstem (medulla, pons, superior cerebellar peduncle, midbrain); Pittsburgh compound‐B and flortaucipir (FTP) were used to assess cortical amyloid and entorhinal tau levels, respectively. Non‐parametric tests were used to assess group differences and correlations between brain volume, brain pathology, and memory.

Results

No MRI volumetric differences were found between groups. In carriers, reduced thalamic volume was associated with greater mean cortical amyloid (r= ‐0.48, p=0.006) and entorhinal tau (r= ‐0.46, p=0.008). Reduced thalamic volume was also associated with worse memory performance (r= 0.38, p=0.03). When controlling for age, which is a proxy for clinical progression in this population, these associations were no longer significant. No associations were observed between memory, pathology, and any of the brainstem sub‐regions .

Conclusion

Findings suggest that brain regions important for sleep‐wake regulation do not show early signs of degeneration in preclinical ADAD. The association between reduced thalamic volume with both cortical amyloid and entorhinal tau supports previous work suggesting that thalamic structures are affected early in the preclinical stage of ADAD. Future research should focus on the functional abnormalities and AD‐related pathology in specific thalamic nuclei during preclinical ADAD, and their potential associations with sleep physiological features, such as thalamic spindles.
DAPT decreases the permeability of the BBB by reducing the ubiquitination and degradation of occludin during permanent brain ischemia
Authors: Ahmed Muhammad Masood , Tian Yun , Andleeb Shumaila , Zhang Gen‐Sheng , Tao Rong Rong , Ji‐Yun Huang , Shah Syed Nisar Hussain , Han Feng
Published: December 2020

Background

Tight junction protein degradation is a principal characteristic of the blood‐brain barrier (BBB) damage that occurs during brain ischemia.The aim of this study is to investigate the mechanisms of occludin degradation that underlie permanent middle cerebral artery occlusion (pMCAO) in rats.

Method

Western blot and Co‐immunoprecipitation data indicates ubiquitination and degradation of occludin in brain after pMCAO, which is consistent with ZO‐1 degradation in penumbra regions as observed at 24 h after pMCAO. It is further investigated that the candidate protease(s) is responsible for the degradation of occludin during pMCAO.

Result

The intraventricular administration of γ‐secretase blocker DAPT significantly inhibited the pMCAO‐induced neurovascular damage, whereas ALLM and Batimastat, which are inhibitors of calpain and metalloproteinase proteases, respectively, were less effective. Notably, it has been found that DAPT significantly inhibited BBB disruption in comparison with vehicle treatment, as assessed by Evans blue excretion. Interestingly, the confocal immunostaining revealed that activation of the E3 ubiquitin ligase Itch is associated with degradation of occludin in brain microvessels following ischemia. Furthermore, these data demonstrate that the inhibition of γ‐secretase signaling and the itch‐mediated ubiquitination of occludin likely underlie the vasoprotective effect of DAPT after pMCAO.

Conclusion

The γ‐secretase blocker DAPT reduces the permeability of the blood‐brain barrier by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia, suggesting that γ‐secretase may represent a novel therapeutic target for preventing neurovascular damage.
Plasma tau is negatively correlated with frontal lobe CBF in hypertensive adults on the AD spectrum
Authors: Swinford Cecily G , Risacher Shannon L. , West John D. , Chumin Evgeny J. , McDonald Brenna C. , Unverzagt Fred W. , Gao Sujuan , Farlow Martin R. , Apostolova Liana G. , Wu Yu‐Chien , Brosch Jared R. , Tallman Eileen F. , Deardorff Rachael , Kamer Aaron P. , Wang Danny J.J. , Zetterberg Henrik , Blennow Kaj , Saykin Andrew J.
Published: December 2020

Background

Hypertension can lead to vascular dementia by causing cerebral hypoperfusion, and it may play a similar role in AD. Hypertensive individuals with AD have poorer cognition than normotensive counterparts (Moonga et al 2017), and CSF tau increases more quickly in at‐risk older adults with hypertension than in those without (Bos et al 2019). We investigated the relationships between cerebral blood flow (CBF), plasma tau and hypertension in two cohorts of older individuals.

Methods

Participants included 30 cognitively normal (CN), 19 subjective cognitive decline (SCD), 17 mild cognitive impairment (MCI), and 8 AD. Groups were defined by CN/SCD and MCI/AD. Participants had 3D pseudo‐continuous arterial spin label (pCASL) 3T Prisma MRI and plasma tau Simoa assay from the same visit. Multiple regression was used to assess the relationship between CBF and plasma tau on a regional and voxel‐wise basis with age, sex, diagnostic group, and total grey matter as covariates. A replication analysis between CBF from 2D pulsed ASL and plasma tau was completed in an independent sample (11 CN, 4 SCD, 15 MCI, 6 AD).

Results

Hypertensive individuals had higher plasma tau than normotensive, regardless of diagnostic group (β=0.254, p=0.031), the replicate sample had the same relationship (β=0.320, p=0.086). Global CBF, however, differed by group (CN/SCD > MCI/AD; p<0.001). Multiple regression analysis revealed negative correlations between CBF and plasma tau in frontal and temporal regions but positive correlations in occipital regions. Within the frontal cortex and anterior cingulate, mean CBF and plasma tau were negatively associated in hypertensive individuals (β=‐0.503, p=0.003) but not in normotensive (β=‐0.143, p=0.283). Similar associations were found in hypertensive (β=‐1.067, p=0.001) and normotensive (β=‐0.257, p=0.183) individuals in the replicate analysis. The interaction term for hypertension by plasma tau was negatively correlated with frontal CBF in both samples (β=‐0.795, p=0.051; β=‐0.912, p=0.052).

Conclusions

Increased plasma tau is associated with decreased CBF in anterior brain regions in individuals with hypertension, suggesting that hypertension exacerbates the effect of AD pathology on cerebrovascular health.
Modeling the effects of respirasome supercomplex formation on AD progression by incorporation of mitochondrial gene expression data
Authors: Shelton Morgan , Castora Frank J. , Kerns Kimberly A. , Coleman Randolph A.
Published: December 2020

Background

Alzheimer’s disease is a specific form of dementia characterized by the aggregation of amyloid‐β plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of respiratory chain activity. Proteomic and genomic data show that these changes are also related to unique gene expression patterns. Supercomplexes (SCs) are assemblages of multiple, functional respiratory complexes. After individual complexes have formed, respiratory complexes (RC) I, III, and IV begin to associate and form SCs. SCs are stable intermediates between respirasomes and individual complexes. We investigated the impact of our observed gene expression changes on new therapeutic options via metabolic flux analysis of SC assembly.

Method

Total RNA was isolated from 80‐180 mg of frozen brain tissue from 11 AD and 5 control samples. Total RNA was quantified and assessed for purity using Nanodrop and Bioanalyzer analysis. cDNA was prepared and applied to the Human Mitochondrial Energy Metabolism and the Mitochondria RT² Profiler™ PCR Arrays. The qPCR data was then analyzed using Qiagen RT2 Profiler PCR Array Data Analysis version 3.5. Gene expression changes were incorporated into the mathematical model created in CellDesigner 4.2 and these were converted into a series of mathematical equations by SBMLsqueezer. This file was imported into COPASI, a biological pathway simulation program. Treatment data were found using COPASI’s time course task. Each treatment represented a mathematical change in gene expression of a selected enzyme.

Result

We investigated 9 mitochondrial genes known to be important for efficient SC assembly. In all cases, the concentration of the gene products was decreased in the AD brain samples. After simulation of respirasome assembly using a reduced model only UQCRC1 treatment increased the percent of CI sequestration into respirasomes.

Conclusion

Our results indicate that protective changes in expression of UQCRCI, a component of electron transport chain respiratory complex III may serve as a potential avenue for AD therapeutics. This work also highlights the importance of metabolic enzyme activity in maintaining proper respiratory activity.We would like to acknowledge support for this work from the Alzheimer’s and Related Diseases Research Award Fund and the Commonwealth Health Research Board.
Progranulin improves memory in normal aging and Alzheimer’s disease
Authors: Farr Susan A. , Niehoff Michael L. , Nguyen Andrew D.
Published: December 2020

Background

Progranulin is a lysosomal and secreted protein that has neurotrophic properties and promotes neurite outgrowth in vitro. Mutations in the progranulin gene have been found to cause frontotemporal dementia. Additionally, reduced progranulin levels may be a risk factor for the development of Alzheimer’s disease (AD). Studies in mouse models of AD support this notion: reducing progranulin exacerbates disease progression whereas increasing progranulin confers protection. However, the physiologic function of progranulin in the CNS is not known.

Method

We tested the effects of CNS‐administered progranulin in the cognition in young male CD‐1 mice, (3‐months of age), old C57/BL male mice (24 months of age) and 3xTG‐AD male and female mice (13 months of age). Immediately following T maze foot shock avoidance training, CD‐1 mice (n = 10 per group) were injected intracerebroventricularly (ICV) with progranulin (0, 0.005, 0.1 or 1.0 ug/2 ul). C57/BL 24 month old (n= 8∼9/group) and the 13 month old 3xTG‐AD mice (n = 8∼9/group) were given either 0 or 1.0 ug/2 ul immediately after training. Retention was assessed one week after training. The number of trails to reach a criterion of 5 avoidances in 6 consecutive trails was determined. Following behavioral testing, cortex, hippocampus, and plasma were harvested.

Result

CD‐1 mice that received and an ICV injection of progranulin 0.1 and 1.0 ug/2 ul had significantly improved retention in T‐maze than the mice which receive vehicle. These mice took significantly fewer trials to make an avoidance than the mice which received 0 ug/2 ul. Progranulin at 1.0 ug/2 ul improved retention in the 24 month old C57/BL mice and the 13 month old 3xTG‐AD mice.

Conclusion

It is becoming increasingly apparent that progranulin is involved in memory dysfunction. We found that progranulin has a direct influence on memory consolidation as its administration following foot shock avoidance training leads to improved memory retention. Our studies suggest that progranulin can directly modulate memory in both cognitively normal and AD mice, indicating that is has an important role not only in the pathogenesis of frontotemporal dementia, but in normal aged‐related cognitive decline and AD progression as well.