bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal change in cortical thickness and hippocampal volume predicts cognitive decline
Authors: Chen Gengsheng , McKay Nicole Sarah , Gordon Brian A. , Liu Jingxia , Dincer Aylin , Keefe Sarah J. , LaMontagne Pamela J. , Koenig Lauren N. , Schultz Stephanie A. , Hassenstab Jason , Morris John C. , Benzinger Tammie L.S.
Published: December 2020

Background

Using biomarkers for early detection of Alzheimer disease (AD) is crucial for developing potential treatments. It has been hypothesized that longitudinal change in cortical thickness and hippocampal volume could be used to predict cognitive decline in individuals with AD. Here, using longitudinal MRI data, we evaluated whether changes in cortical thickness and hippocampal volume predicted changes in cognition, as measured by a battery of standardized tests.

Method

152 Participants (aged: 45‐86) who were enrolled in studies at the Knight ADRC at Washington University were included. Data was obtained through OASIS (www.oasis‐brains.org). Participants were classified as having normal cognition or early symptomatic AD, and were followed for 1‐8 years. Hippocampal volume was extracted, and cortical thickness measures were derived as an average of a set of FreeSurfer cortical regions (Figure 1). A random coefficient model was used to calculate longitudinal change in these biomarkers, and to assess whether these measures predict cognitive decline. Additional correlations between longitudinal changes in cognition and changes in cortical thickness, and hippocampal volume, were calculated using Spearman correlations.

Result

We found that longitudinal change in cortical thickness and hippocampal volume significantly predicted the rate of decline measured from a battery of standardized cognitive tasks (Figure 2). Furthermore, longitudinal changes in these structural biomarkers were strongly correlated with cognitive decline measured by the Logical Memory IIA‐Delayed (Figure 3).

Conclusion

Longitudinal changes in cortical thickness and hippocampal volume significantly predict cognitive decline on neuropsychological tests that address cognitive domains that are typically impacted by AD. To evaluate brain atrophy in a manner that could easily be examined in a clinical context, we did not limit the study to participants with known amyloid biomarker status. It has been postulated that once therapeutic agents for AD become available, we will have difficulty providing large scale screening tests in populations at risk due to limited availability of PET centers. As MRI is widely available, longitudinal volumetric MRI may potentially be used in the future to screen patients as a first step in a workup and evaluation for participation in clinical trials or, once approved, evaluation for therapy.
Early developmental exposure to air pollution increases the risk of Alzheimers disease and amyloid production: Studies in mouse and Caenorhabditis elegans
Authors: Haghani Amin , Johnson Riachard G. , Dalton Hans , Feinberg Jason I. , Lewis Kristy C. , Ladd‐Acosta Christine , Woodward Nicholas C. , Safi Nikoo , Jaffe Andrew E. , Allayee Hooman , Sioutas Constantinos , Campbell Daniel B. , Volk Heather E. , Curran Sean P , Finch Caleb E. , Morgan Todd E.
Published: December 2020

Background

Exposure to air pollution (AirP) as adults increases the risk for dementia in human populations and increases the production of amyloid‐beta peptides in mouse models (Cacciottolo et al 2017 PMID28140404). Gestational exposure to AirP adversely alters early human neurodevelopment and increases risk for cognitive and behavioral disorders. It is unknown if gestational or developmental exposure to AirP can increase the risk for or accelerate cognitive aging or Alzheimer’s disease (AD) in later adulthood.

Methods

To approach this gap, we examined the developmental effects of nano‐sized urban particulate matter (nPM), a subfraction of AirP, on later life stages of mice and nematodes. In C57BL/6J mice, initial transcriptional changes in the cerebral cortex or hippocampus were studied by RNAseq and tested for association with long‐lasting phenotypic effects of gestational nPM exposure. Experiments on Caenorhabditis elegans addressed developmental effects of nPM on AD‐related genes and Aß production in later adulthood.

Results

Gestational exposure to nPM caused sex‐specific gene expression changes in the cerebral cortex of pups at postnatal day 5. The changes included DNA damage, oxidative stress, and immune responses. The top potential upstream regulators of these transcriptome changes included APP, Psen1, and Tau. At age 5 months, neuroinflammatory gene expression in the hippocampus was associated with depressive behavior, weight and fat gain, and increased glucose intolerance. Similarly, the initial responses of the L1 larval stage of C. elegans to nPM included an increase of mRNA levels in genes related to inflammation (e.g. abf‐2) and AD‐gene homologs (e.g. sel‐12/PSEN1). In an AD nematode model, developmental exposure to nPM in the L1 stage resulted in an accelerated paralysis phenotype in adults which is an indicator of increased Aß42 production.

Conclusions

This novel experimental evidence suggests mechanisms by which the developmental exposure to AirP could increase AD risk in later ages. Further studies may reveal the effects of gestational nPM exposure on later‐life cognition, Aß plaque formation, and neuropathology.
Elucidating the role of SORL1 as an APOE receptor using iPSC‐derived astrocytes
Authors: Lee Hyo , Pan Cheryl , Goberdhan Sri , Young Jessica E. , Young‐Pearse Tracy
Published: December 2020

Background

Apolipoprotein E (APOE), the strongest genetic risk factor in late‐onset AD (LOAD), encodes a protein that can interact with Aβ and regulate its clearance. Interestingly, SORL1, another AD risk gene, belongs to the family of APOE receptors involved in Aβ clearance. SORL1 is the only APOE receptor gene that has been identified as a genetic risk factor in LOAD. Recent studies identified SORL1 loss‐of‐function variants in familial AD patients, suggesting that SORL1 may be a causal gene for AD. Here, we investigated the potential convergent mechanisms of APOE and SORL1 function in the brain by examining the novel function of SORL1 in human astrocytes in Aβ clearance.

Method

iPSC‐derived astrocytes were generated from individuals with 1) different APOE isoforms 2) SORL1 knock out (KO), risk SNPs and missense mutations and 3) other AD risk SNPs using two astrocyte differentiation protocols. Aβ clearance assays were performed by treating the astrocytes with synthetic or cell derived Aβ, then monitoring the Aβ level in both media and lysate over time to determine the ability of astrocytes to uptake and clear Aβ.

Result

We have generated iPSC‐derived astrocytes from multiple lines to characterize whether SORL1 functions as an APOE receptor in human astrocytes. We determined that SORL1 is highly expressed in astrocytes, both in cytoplasmic and cell surface compartments, and SORL1 can interact with APOE in iPSCs as shown by co‐immunoprecipitation. Further, our preliminary data show that SORL1 KO astrocytes show elevated endogenous extracellular Aβ levels, and impaired Aβ clearance ability when treated with exogenous or cell derived Aβ. Lastly, when Aβ uptake was examined using APOE isogenic astrocytes, APOE KO show impaired clearance, supporting a role for endogenously secreted APOE in Aβ uptake in human astrocytes. Ongoing studies are interrogating the contribution of SORL1 in APOE‐mediated Aβ clearance.

Conclusion

Here, I have utilized iPSC‐derived astrocytes to examine the novel role of SORL1 as an APOE receptor in astrocytes, and investigate a potential convergent mechanism that APOE and SORL1 play in Aβ clearance.
TREM locus methylation in Alzheimer’s disease
Authors: Weber Grace E. , Khrestian Maria , Shao Yvonne , Tuason Elizabeth D. , Rao Stephen M. , Pillai Jagan A. , Leverenz James B. , Bekris Lynn M.
Published: December 2020

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, and currently lacks a blood‐based biomarker of neuroinflammation. The triggering receptor expressed on myeloid cells 2 (TREM2) R47H genetic variant is associated with increased risk for AD. TREM2 mRNA has been described as elevated in AD leukocytes, and associated with a decrease in TREM2 DNA methylation. In contrast, TREM2 hypermethylation has been described as associated with increased expression in the brain, suggesting differences in DNA methylation of TREM2 according to the tissue microenvironment. DNA methylation can dynamically regulate clusters of genes according to the needs of the cellular microenvironment. The TREM2 gene is part of a complex cluster genes that also includes other TREM and TREM‐like (TREML) genes. Understanding its DNA methylation signature is important to decipher any change in its regulatory state in AD. We hypothesized that TREM locus genes are differentially methylated in whole blood among AD patients compared to cognitively normal controls.

Method

Participants included age‐matched cognitively normal controls (HC), mild cognitive impairment related to AD (MCI‐AD) and AD dementia (confirmed by CSF AD biomarkers). Peripheral blood was collected for DNA extraction. Methylation of peripheral blood DNA was measured using Illumina 450k methylation chip. Percent methylation of CpG sites across the TREM locus were grouped into regions based on genomic context. Hierarchical clustering was used to evaluate relationships between genomic regions.

Result

Genomic regions across the TREM locus exhibited differential methylation where in general promoters are hypomethylated while other non‐promoter regions are hypermethylated. Although levels of methylation were similar between groups, regions within the TREM locus correlated differently between the groups.

Conclusions

Taken together, the results suggest that differential methylation exists at the TREM locus that is genomic region and AD specific. We anticipate that future studies will contribute to a better understanding of TREM2 and its role as a biomarker to aid in earlier diagnosis and interventions of AD.
Use of in‐home remote sensing to measure dietary behavior and weight in aging and cognitive decline: A pilot study
Authors: Wright Kirsten M , Mattek Nora , Gothard Sarah , Beattie Zachary , Sharma Nicole , Dodge Hiroko H , Kaye Jeffrey
Published: December 2020

Background

Weight loss has been associated with earlier onset of dementia and accelerated cognitive decline. Current methods of assessing nutritional health, including body mass and dietary habits, occur in clinic settings semiannually to annually. A home‐based non‐invasive system allows for continuous data collection that could generate clinically meaningful and reliable data providing insight into subtle changes in disease progression, nutritional health and response to treatment. To properly utilize remote sensing approaches in assessing dietary behavior, potentially more sensitive, objective and ecologically valid measures need to be longitudinally acquired and analyzed for feasibility and acceptability in real world, home environments.

Method

A cohort analysis of 66 participants enrolled in prospective longitudinal aging studies with in‐home digital monitoring was performed. Contact sensors attached to refrigerator doors were used to assess the number of door openings per day as a measure of dietary frequency. Daily weight measurements were collected using an in‐home wireless bioimpedence scale. Correlations between dietary frequency and cognitive status (Mini Mental State Examination; MMSE) were performed within 30 days of cognitive assessment.

Result

There is a positive correlation between cognitive status and average number of refrigerator door openings per day (n=66, r=0.31, p=0.01). Remote measures of body weight show increases around known periods of increased food consumption.

Conclusion

Dietary frequency, as measured by refrigerator door openings, and weight are feasible to collect in elders using a non‐invasive home‐based remote system. Continued longitudinal measurements and analysis are needed to determine long‐term feasibility, adherence and acceptability of remote measures of nutritional health.
Sensory‐evoked gamma frequency oscillations in Alzheimer’s disease patients: Biomarker and therapeutic applications
Authors: Hajos Mihaly , Harvey Brian D. , Mortimore Hailey , Strozewski Nathan , Kolin Katharine , Boasso Alyssa , Cimenser Aylin , Marin Anna , Hajos Gabor P , Palumbo Rocco , Spencer Kevin M. , Malchano Zach , Budson Andrew
Published: December 2020

Background

As a potential neurophysiology‐based biomarker of cortical neuronal network integrity, visually evoked steady‐state oscillations (SSVEPs) are investigated in healthy young and elderly subjects, and mild cognitive impaired (MCI) and Alzheimer’s disease (AD) patients. Based on recent findings from the Li‐Huei Tsai Laboratory (Picower Institute, MIT) showing that 40 Hz audio/visual stimulation reverses AD‐related pathologies in transgenic mice, we are evaluating the effects of 40 Hz audio/visual stimulation on brain neurophysiology in healthy subjects, and MCI and AD patients (together with clinical trials assessing impact on severity of clinical symptoms and Aβ PET signals) at Cognito Therapeutics.

Method

We are testing SSVEPs, including 15, 30 and 40 Hz light stimulations, and evoked steady state oscillations in response to combined 40 Hz audio/visual stimulation using 128 or 64 channel EEG recordings, respectively. We analyze phase‐locked evoked potentials, inter‐trial coherence, induced oscillations and network coherence in young subjects, MCI and AD patients and age‐matched healthy elderly individuals.

Result

SSVEPs have been observed in healthy subjects and MCI/AD patients in response to 3 second flashing light using 15, 30 and 40 Hz stimulation frequencies. High test/re‐test reliability has been established in healthy young subjects. Compared to healthy young subjects (< 30 years), diminished inter‐trial coherence in healthy elderly (> 65 years) subjects, and impaired sensory responses in MCI and AD patients were found to light stimulation. Simultaneous audio/visual 40 Hz stimulation, using Cognito Stimulation System elicited 40 Hz entrainment of cortical activity over the entire 1‐hour session in healthy subjects, MCI and AD patients, without adverse events either during or following SSEVP. Cortical 40 Hz entertainment was accompanied with high‐intensity alpha oscillation. Following the audio/visual stimulation, the augmented alpha band power was associated with increased alpha coherence between fronto‐occipital and fronto‐temporal regions.

Conclusion

Reliable 40 Hz steady‐state oscillations can be elicited and maintained in MCI and AD patients, providing an opportunity to evaluate symptomatic and disease‐modifying effects of this therapy. Detecting disease relevant and individual SSVEP abnormalities can support precision medicine by customizing therapy.
Gray and white matter metabolite differences in Alzheimer’s disease and normal human brain tissue
Authors: Hammond Tyler C. , Xing Xin , Nelson Peter T. , Ham Stephanie , Lin Ai‐Ling
Published: December 2020

Background

Gray matter atrophy and white matter alteration are key neurological features of Alzheimer’s disease (AD), but very little has been reported about the biochemical profile of the gray and white matter in AD. Here we measure the metabolites of AD brains and control brains in the gray and white matter to understand what differences are present.

Method

The global biochemical profiles of post‐mortem human brain tissue from Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 53 subjects with AD and 46 cognitively normal subjects were analyzed. Metabolites in gray and white matter were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random Forest.

Result

Gray and white matter metabolites differed in both the AD and the control brains. The gray matter had more metabolites associated with anaerobic metabolism including increased glycine, serine and threonine metabolism, alanine and aspartate metabolism, dipeptides, glycolysis, gluconeogenesis, and pyruvate metabolism, pentose metabolism, BCAA metabolism, phosphatidylcholine, phosphatidylethanolamine, sphingolipid synthesis, ceramides, nicotinate and nicotinamide metabolism, and vitamin B6 metabolism. The white matter had more metabolites associated with aerobic metabolism including oxidative phosphorylation, fatty acid metabolism, long chain monounsaturated fatty acid, Acyl Carnitine Fatty Acid Metabolism, Glycerolipid Metabolism, Monoacylglycerol, Hexosylceramides (HCER), Sterols, and Pantothenate and CoA Metabolism in the white matter vs the gray matter. White and gray matter differences were dependent on disease status for the following metabolites: N‐acetylserine – part of serine metabolism, 1‐arachidonoyl‐GPA (20:4) – a lysophospholipid, Valylleucine – a dipeptide, and octadecenedioate (C18:1‐DC) and oleoylcarnitine (C18:1) – both fatty acids.

Conclusion

In our cohort, gray matter showed more metabolite differences dependent on anaerobic metabolism and white matter showed more metabolite differences dependent on aerobic metabolism. Some metabolite differences were dependent on disease status. Researchers using brain metabolomics data should be aware of these gray and white matter differences so that their results aren’t due simply to differences in concentration of gray and white matter between samples. An understanding of how the brain metabolites differ depending on AD disease status can give important insights into disease pathology.
Evidence that semaphorin 4D is upregulated in neurons in Huntington’s and Alzheimer’s diseases: Effects of a SEMA4D blocking antibody on FDG‐PET in a clinical trial, and treatment rationale for its use in AD
Authors: Evans Elizabeth E. , Fisher Terrence L. , Leonard John E. , Reader Alisha M. , Mishra Vikas , Mallow Crystal L. , Balch Leslie , Howell Alan , Smith Ernest S. , Feigin Andrew , Siemers Eric R. , Zauderer Maurice
Published: December 2020

Background

Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin B1 and plexin B2 receptors. SEMA4D is upregulated in neurons and oligodendrocytes in response to stress and triggers inflammatory activation of plexin B1/B2 positive astrocytes with concomitant loss of some normal astrocyte functions. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington’s disease (HD) and Alzheimer’s disease (AD). SIGNAL‐HD is a double‐blind, placebo‐controlled study of pepinemab in HD. Given previous studies of fluorodeoxyglucose (FDG) positron emission tomography (PET) loss in HD and the mechanism of action of pepinemab, FDG‐PET imaging was included in the SIGNAL‐HD study.

Method

Transgenic mouse models for HD (Q175) and AD (CVN) as well as human pathological tissue was used for immunohistochemistry. The SIGNAL‐HD study includes participants with late prodromal and early manifest HD. Results from 36 subjects in Cohort A informed group size and treatment duration in Cohort B. A subset of participants in Cohort A underwent PET scanning using FDG at baseline, at the end of the 6‐month placebo‐controlled period and at 12 months at the end of the open‐label treatment period.

Result

SEMA4D was upregulated and astrocyte activation was present for HD and AD based on samples from transgenic models and staged patient autopsy samples. SIGNAL‐HD Cohort A (n=36) has been completed and Cohort B (n=265) is fully enrolled. For participants in Cohort A undergoing FDG‐PET imaging (n=19), those in the pepinemab group showed increases in FDG uptake compared to baseline (median 8.6%, range: 0.5‐20.4%) while participants taking placebo showed the expected decrease after 6 months. Nominal statistical significance (p<0.05) pepinemab compared to placebo was achieved for 11/14 frontal and parietal brain regions.

Conclusion

Transgenic mouse models and human neuropathological analyses are consistent with an upregulation of SEMA4D in HD and AD. The increase in FDG‐PET signal in SIGNAL‐HD Cohort A suggests central target engagement and improvement in brain metabolic activity. SIGNAL‐AD, a randomized, placebo‐controlled, phase 1b/2 study of pepinemab in early AD, will also incorporate FDG‐PET and is planned to begin mid‐2020.
Lipid profiles of extracellular vesicles are distinct for Alzheimer’s disease cases
Authors: Martins Tânia Soares , Magalhães Sandra , Rosa Ilka Martins , da Cruz e Silva Odete , Nunes Alexandra , Henriques Ana Gabriela
Published: December 2020

Background

Extracellular vesicles (EVs) are secreted by most of the cells and their content can reflect physiological and pathological stages, making them attractive biomarker sources for a wide range of diseases, including Alzheimer’s disease (AD). AD molecular‐based diagnosis in cerebrospinal fluid is a powerful approach nonetheless the identification of biomarkers in peripheral biofluids represents an attractive clinical tool. The procedure to isolate blood‐derived EVs is less invasive, cost‐effective and can be widely available. In addition, Fourier Transformed Infrared (FTIR) Spectroscopy is a highly reproducible, rapid and inexpensive technique. This study addressed the value of FTIR and serum‐derived EVs in AD.

Method

Serum was obtained from the pcb‐Cohort (primary care‐based cohort), established by the group (Rosa I.M.et al.2017, Dement Geriatr Cogn Disord;43:15–28). Serum‐derived EVs enriched in exosome‐like vesicles were isolated using Exosome Precipitation Solution (ExoQuick); characterized by Nanoparticle Tracking Analysis and Transmission Electron Microscopy, as described (Soares Martins T.et al.2018, PLoS One;13:e0198820). The FTIR spectra of serum‐derived EVs from AD cases and Controls were acquired (ATR‐FTIR spectrometer); data analysed using multivariate (PCA‐LDA, PCA‐QDA) and univariate (second derivative peak area calculation) approaches.

Result

Focus was given to FTIR spectra of lipid regions (3000‐2888 cm‐1 and 1767‐1721 cm‐1). Differences were observed between the average spectra of EV’s from AD and Controls, for both normalized spectra and second derivative spectra. PCA‐LDA and PCA‐QDA revealed that FTIR spectra, in the lipid absorption regions, of serum‐derived EVs has potential disease discriminatory value. In accordance, the second derivative peak area calculation of EVs spectra also revealed significant differences among Controls and ADs. This is in line with previous work where distinct nucleic acid profiles were reported for EVs from AD vs Controls (Soares Martins T.et al.2020, J Alzheimers Dis; in press).

Conclusion

Taken together data suggests to that metabolic profile of EVs has AD diagnostic potential. To this end research was funded by PTDC/DTPPIC/5587/2014, supported by iBiMED‐UIDB/04501/2020, FCT, COMPETEprogram, QREN, European Union; “pAGE” (CENTRO2020‐CENTRO‐01‐0145‐FEDER‐000003), Centro2020program, Portugal2020, European Union. Conference participation is supported by MEDISIS (CENTRO‐01‐0246‐FEDER‐000018), Centro2020program, European Union, FEDER. We thank volunteers, their families and health professionals. Health Ethics Committee (CES) ARS Centro (No.012804‐04.04.2012) and CNPD (No.369/2012).
Graphical user interfaces for regulatory‐endorsed quantitative drug development tools in Alzheimer’s disease
Authors: Romero Klaus , Hanan Nathan J. , Sivakumaran Sudhir , Sinha Vikram , Haeberlein Samantha Budd , Gold Michael
Published: December 2020

Background

Model‐informed drug development (MIDD) can improve cost effectiveness of research and development (R&D) decision‐making. The Critical Path for Alzheimer’s Disease (CPAD) Consortium has developed a mild‐to‐moderate Alzheimer’s disease clinical trial simulator, which is intended to optimize clinical trial design in this target population, when using ADAS‐Cog as the primary endpoint. This tool represented the first‐ever FDA and EMA‐endorsed quantitative drug development tool. The CPAD team has also developed a pre‐dementia disease progression model, which received an EMA letter of support, as a trial enrichment tool for pre‐dementia trials that use CDR‐SB as the primary endpoint. In order to democratize the use of these tools, graphical user interfaces (GUIs) were developed for these two models.

Method

The GUIs were developed using R‐Shiny, focusing on the drug‐disease‐trial model aspects of the clinical trial simulator for mild‐to‐moderate AD, with emphasis on the sources of variability (APOE4, sex, baseline MMSE and age); and focusing on the disease progression predictors of the trial enrichment model for pre‐dementia (baseline MMSE, age and hippocampal volume, APOE4 and sex).

Result

The GUIs were beta‐tested by pharmacometricians, statisticians, clinical trialists and clinicians. Their feedback was used to further improve the functionality of the GUIs. Focus was put on the ability of the users to intuitively set up the simulation framework for specific studies, the underlying assumptions, and the graphical and tabular output of simulated results.

Conclusion

The publicly accessible GUIs will increase the usability of these quantitative drug development tools. Examples of their application include informing stage‐gate decisions; optimization of study design; patient selection; and sample size estimations.
Effect of polyphenol treatment for mild cognitive impairment (MCI) and diabetes
Authors: Pasinetti Giulio Maria , Iqbal Umar Haris , Rosenberg Paul B.
Published: December 2020

Background

As the prevalence of Alzheimer’s disease (AD) continues to rise, alternative approaches are sought to have a greater understanding of this neurological disease. One approach of interest would be to identify individuals who are at risk of Alzheimer’s disease (AD) and determine the efficacy of a selected therapeutic. Persons with Mild Cognitive Impairment (MCI) are at risk of incident dementia, and being coupled with deficits in short‐term recall, significantly increases their risk of incident AD. In addition, having risk factors of the metabolic syndrome, such as prediabetes, has also been found to augment the risk of incident cognitive impairment. This is further strengthened by evidence showing neurons in AD brains being insulin resistant. Previous animal studies have found that a nutraceutical containing grape seed polyphenol extract (GSPE) and resveratrol to be associated with improved cognition and lowering brain amyloid and tau burden. The current clinical study is being taken as a first step to investigate the safety and tolerability of GSPE and resveratrol in patients who have Mild Cognitive Impairment (MCI) and diabetes. In addition, this study will also quantify the bioavailability of selected polyphenols and their metabolites, and determine if any changes are seen between the treatment and placebo group at the end of the study in regards to cognitive test scores, and CSF content of tau/β‐amyloid 42.

Method

Participants were entered into a 4 month double‐blinded study and given either a placebo, or a mixture containing 450 mg of GSPE and 125 mg of resveratrol. Serum samples were taken at baseline, 2 months, and 4 months, whereas CSF samples were taken at the start and end of the study.

Result

The study is still ongoing and additional individuals are enrolling in the study. No adverse events related to GSPE and resveratrol have been observed from the participants to date, and compliance has been good.

Conclusion

At the conclusion of this clinical trial, in addition to determining the safety and tolerability of GSPE and resveratrol, a greater understanding will be attained as to the potential association of selected polyphenol metabolites and biomarkers of AD neuropathology in CSF.
Diabetes and stroke potentiate hippocampal inhibitory tone: A link to Alzheimer's disease/vascular dementia
Authors: Buitrago Luna , Li Jei , Neymottin Samuel , Barone Frank , Brickman Adam M. , Luchsinger Jose , Moreno Herman
Published: December 2020

Background

Mice expressing mutated hAPP in the entorhinal cortex (EC) display, hypersynchrony of the EC‐hippocampus circuit, caused by decreased inhibitory tone (Angulo et al., NBD 2017). A similar EC inhibitory failure was also observed in mice expressing hAPOE4, (Nuriel et al., Nat Neursc 2017). Here we evaluated changes in EC‐hippocampus synaptic plasticity and neuronal properties produced by two additional AD risk factors, diabetes and ischemic stroke

Method

Hippocampal synaptic plasticity and single cell recordings were made from leptin mutant (db/db, diabetes) and normoglicemic (db/+) heterozygous mice 4‐6 m.o. one month following stroke (transient middle cerebral artery occlusion (tMCAo) or sham surgery. tMCAo was produced by a monofilament occluding the origin of MCA for 30 minutes. Recordings were made from horizontal hippocampal slices in aCSF. Schaffer collaterals to CA1 evoked field excitatory postsynaptic potential (fEPSPs) were measured before and after induction of long term potentiation (LTP). Finally, miniature inhibitory post‐synaptic currents (mIPSCs) in CA1 pyramidal neurons were recorded, using the whole cell configuration of patch‐clamp technique.

Result

Both control and diabetic mice developed a paradoxical larger LTP at the CA3‐CA1 synapse after stroke (i.e. db/db‐sham vs. db/db‐stroke,% of slope EPSP change = 180+/−21% vs. 250+/−16% respectively, p < 0.05. Modeling with the program NEURON simulator suggested that this was due to loss of synaptic inhibition. We found that the peak amplitude of mIPSCs was smaller in CA1 neurons in the stroked hemisphere compared to the sham CA1 hemisphere in db/+ mice (db/+ sham vs. db/+ tMCAo = ANOVA; F = 14,99, p = 0.01). By contrast, CA1 mIPSCs frequency, but not amplitude, decreased in db/db tMCAo compared with db/db sham (F = 6.4, p = 0.022). The mean peak amplitude in db/db sham mice were significantly smaller than in db/+ sham mice (F = 6,2, p = 0.021)

Conclusion

The data suggest that the observed difference in sham vs. tMCAo mIPSCs amplitude observed in db/+ mice is due to a post‐synaptic change in either GABA‐A receptor number or function. While, in db/db sham mice we observed a post‐synaptic inhibitory alteration, as seen in db/+ mice with stroke. After acute ischemia, an additional presynaptic inhibitory dysfunction in db/db occurs. Modeling suggests that the mechanism occurs via inhibitory synaptic pruning.
Educational intervention for primary care to improve the prevention and detection of dementia in two Latin American countries: The PREDES dementia trial
Authors: Roa‐Rojas Paloma , Martinez‐Ruiz Adrian , Parada Gabriel
Published: December 2020

Background

The worldwide prevalence of dementia is increasing, especially in Latin American countries like Mexico and Chile. Prevention and early diagnosis of dementia within primary care is important because it allows those with the disease and their care givers to engage with support services and plan for the future. However, evidence suggests that dementia remains under‐detected and sub‐optimally managed in general practice. Considering this, there are several studies about the effectiveness of educational interventions for improvement of detection rates and management of dementia in primary care, but they have showed mixed results. For example, practice‐based educational workshops are effective for improving rates of detecting dementia but not for changing clinical management. Hence, the challenge still is to find effective educational methods for prevention, detection and management of dementia. In this study, our main goal is to test the effectiveness of an educational intervention developed for general practice, designed to promote prevention detection and management of dementias in both countries, Mexico and Chile. The educational intervention combines practice‐based workshops and on‐line support materials. Its effectiveness will be tested in a two phases unblinded cluster randomised controlled trial with a pre‐post intervention design, with two arms; normal care versus the educational intervention. Primary care practices in both countries will be recruited with the aim of reviewing 400 clinical files. We will examine whether the educational intervention is effective within the primary care setting. Our primary outcome measure will be an increase in the proportion of patients who receive timely detection and propper channeling. We will also examine important secondary outcomes such as improvements in knowledge and attitudes towards dementia in both countries. Also as a secondary outcome, the benefits to patients in terms of quality of life will be evaluated. The PREDES trial builds on previous evidence about the effectiveness of educational interventions in improving timely detection and management of dementia in primary care. However, this intervention is different because it also considers prevention. If this trial is successful it could have implications for the implementation of the National Dementia Strategies in both countries.
Brain atrophy coupled to cognitive decline 3 years after stroke
Authors: Brodtmann Amy , Werden Emilio , Khlif Mohamed Salah , Bird Laura J , Bradshaw Jennifer , Egorova Natalia , Restrepo Carolina , Churilov Leonid , Cumming Toby
Published: December 2020

Background

Cardiovascular risk factors and stroke are associated with increased risk of all‐cause dementia. More than one third of stroke patients will develop dementia, but mechanisms are unclear. Vascular brain burden from accumulated risk factors may contribute to cognitive impairment at the time of stroke, with the stroke being yet another manifestation of vascular disease. We examined total brain volume (TBV) and hippocampal volume (HV) in a group of stroke patients 3 years after their clinical event. We compared those who were cognitively impaired (CI) at 3 months after stroke to those who were cognitively normal (CN). We hypothesized that CI patients would exhibit greater total brain volume loss over the ensuing 3 years than those with normal cognition.

Method

The Cognition And Neocortical Volume After Stroke (CANVAS) study is an observational cohort study of 135 patients with ischemic stroke examining brain volume and cognition over 3 years. All ischemic stroke types and etiologies were included. A history of cognitive impairment was an exclusion criterion. Participants were tested at baseline (within 6 weeks of stroke), 3 months, 1 year and 3 years after stroke. Total brain and hippocampal volume and neuropsychological testing were performed at each time‐point with the primary comparison being brain volume change between 3 months and 3 years. Only participants with usable MRI scans were included in this analysis (n=92). Clinical dementia panels were convened to produce consensus reports for CN, CI, or dementia.

Result

At 3‐months post‐stroke, 67 patients (67.4 years, 15 women) were cognitively normal and 25 were cognitively impaired (74.7 years, 11 women); none had dementia. Total brain volume decline was greater in the CI group (M = 30.67 cm3 n = 25) relative to the CN group (M = 19.63 cm3; SD = 13.84 cm3; n = 67). Hippocampal volume change between 3‐months and 3‐years was comparable in both groups.

Conclusion

Total brain volume decline is greater over 3 years in stroke patients who have cognitive impairment at 3‐months post‐stroke. Hippocampal volume loss was not significantly associated with cognitive decline. Cognitive impairment at 3 months is associated with accelerated neurodegeneration in people with stroke.
Vascular risk and physical activity as modulators of cognitive and neurodegenerative trajectories: Independent and interactive effects with beta‐amyloid
Authors: Chhatwal Jasmeer P , Rabin Jennifer S , Yang Hyun‐Sik , Klein Hannah , Scott Matthew R , Kirn Dylan , Pruzin Jeremy J , Yau Wai‐Ying , Schultz Aaron P , Johnson Keith A , Sperling Reisa A
Published: December 2020

Background

Understanding the extent to which vascular and lifestyle factors operate independently and synergistically with Alzheimer’s disease pathology is critical to designing optimized clinical trials and to assessing the efficacy of interventions to delay cognitive impairment. We examined this question by leveraging data from a longitudinal cohort study with detailed cognitive and multi‐modal imaging data (the Harvard Aging Brain Study; HABS).

Method

We used cross‐sectional and longitudinal data from HABS (n = 223; mean age at entry: 72y; mean follow‐up of 5.9y), including 11C‐Pittsburgh‐Compound‐B (PiB) amyloid PET, 18F‐Flortaucipir (FTP) tau PET, MRI, pedometer‐measured physical activity data, cognitive testing (Preclinical Alzheimer Cognitive Composite; PACC), and the Framingham Heart Study Cardiovascular Disease Risk Score (FHS‐CVD). Using linear mixed effects models, we examined the interplay of vascular risk factors, imaging measures of cerebrovascular injury, and physical activity with PET measures of b‐amyloid burden as they relate to longitudinal cognitive performance, neurodegeneration, and tau pathology.

Result

We observed that higher FHS‐CVD at study entry was predictive of poorer longitudinal cognitive performance on the PACC, alone and interactively with PiB‐PET (both p<0.001). Greater baseline physical activity (mean steps) was predictive of better longitudinal cognitive performance when interacted with PiB‐PET (p <0.001). Lower FHS‐CVD and greater physical activity were both predictive of less neurodegeneration (longitudinal MRI measures of hippocampal and gray matter volumes) when interacted with PiB‐PET (all p < 0.01). In the subset of participants with available tau PET, FHS‐CVD but not physical activity interacted with PiB‐PET to significantly predict cross‐sectional and longitudinal tau accumulation (p < 0.05). Diffusion but not FLAIR measures of white matter disruption added to FHS‐CVD in predicting cognitive decline.

Conclusion

Together with many prior studies, these data indicate strong additive and/or synergistic effects of vascular risk and physical activity with b‐amyloid in prediction of longitudinal cognition, neurodegeneration, and tau accumulation. These results suggest interventions targeting physical activity and vascular risk in order to delay cognitive decline may be particularly effective in people with elevated β‐amyloid burden. Similarly, consideration of vascular and lifestyle factors may improve our understanding of the potential clinical effectiveness of anti‐amyloid and tau therapies currently in testing.
Cardiovascular and stroke risk, cognitive change, and mild cognitive impairment: Results from the HCHS/SOL and SOL‐INCA
Authors: Tarraf Wassim , Wu Benson , Ramos Alberto R , Gallo Linda , Stickel Ariana , Gonzalez Hector M , Vasquez Priscilla M , Daviglus Martha , Zeng Donglin , Schneiderman Neil , Lipton Richard B , Isasi Carmen R , Lamar Melissa , Smoller Sylvia , Cai Jianwen
Published: December 2020

Background

Cardiovascular and cerebrovascular health problems significantly increase risk for Alzheimer’s Disease and Related Dementias (ADRDs), and Hispanics/Latinos are arguably at higher risk for ADRDs compared to Whites. Middle‐age may be a crucial time in which cardiovascular health starts to notably impact cognition. Most research supporting connections between cardiovascular and cognitive health and ADRDs has been conducted with non‐Hispanic/Latino White samples. Diverse Hispanics/Latinos may differentially benefit from improvements in cardiovascular health to an equal or greater extent than Whites. The purpose of the study was to characterize the associations between mid‐life cardiovascular health and 7‐year change in cognition in diverse Hispanics/Latinos.

Methods

We used prospective data from middle‐age and older Latinos (45‐74 years and older at Visit1; 2008‐2011) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Visit 1) who were cardiovascular disease‐free and stroke/TIA‐free at Visit1 (unweighted n=3,345) to examine relationships between baseline cardiovascular health, assessed using the multiethnic Global Vascular Risk Score (GVRS), and change in cognition from Visit1 to Visit2 (SOL‐INCA; 2016‐2018), an average of 7‐years later, and Mild Cognitive Impairment (MCI) prevalence at Visit2. In addition to MCI, cognitive outcomes included global and domain specific (verbal learning and memory, verbal fluency, executive functioning, attention, and psychomotor speed tasks) cognitive change. We fit survey generalized linear regressions to model the associations between the cardiovascular risk exposure and our cognitive outcomes and examined modifications by sex and age.

Results

Adjusting for covariates, higher GVRS scores (10% increments) were associated with more pronounced decline (SD units) in global (β=‐0.35; SE=0.06; p<0.001) and domain specific cognitive performance. Higher GVRS scores were also associated with higher odds ratio of MCI (OR=1.59; 95% CI=[1.10;2.38]; p=0.023) at Visit 2. We found no statistical evidence to support sex or age modifications in the associations between GVRS, cognitive change, and MCI.

Conclusion

Cardiovascular and stroke risk is associated with accelerated cognitive decline and an increased risk of MCI. Effects did not differ by age. These results raise the possibility that vascular risk factor modification in Hispanics/Latinos may promote successful cognitive aging and reduce the risk for MCI.
The novel omega‐6 fatty acid docosapentaenoic acid positively modulates brain innate immune response for resolving neuroinflammation at early and late stages of humanized APOE‐based Alzheimer’s disease models
Authors: Ma Qiulan‐Ma , Zhu Chansheng , Caoili Kaitlin , Frautschy Sally A. , Cole Gregory M
Published: December 2020

Background

Neuroinflammation has been well established to play a crucial role in the pathogenesis and progression of Alzheimer’s disease (AD), and strong epidemiological studies have shown clear evidence of nonsteroidal anti‐inflammatory drugs (NSAIDs) for preventing the onset of AD in middle‐aged people, but NSAIDs and all other anti‐inflammatory drugs such as selective cyclooxygenase 2 (COX2) inhibitors have failed to treat moderate to severe or early stage AD in clinical trials. In this study, we report the mechanism and efficacy of omega‐6 fatty acid linoleic acid (LA) on the reduction and resolution of neuroinflammation at early and late stages of humanized APOE‐based AD models. We found that the novel LA metabolite docosapentaenoic acid (DPAn‐6) has robust anti‐inflammatory and neuronal protective effects in old ApoE4x5FAD mice with pre‐existing severe amyloid burden, gliosis, behavior deficits and neurodegeneration.

Method

Two different ages of ApoE4x5FAD animals were used for the study. First, 3 to 4‐month‐old adult ApoE3x5FAD and ApoE4x5FAD were treated by dietary linoleic acid for four months. Secondly, 11 to 14‐month‐old ApoE4x5FAD mice were treated by oral DPAn‐6 for three weeks. Treatment efficacy was analyzed by novel object recognition, ELISA, RNAseq and immunohistochemistry.

Result

We found that dietary LA reduced proinflammatory cytokines and COX2 gene expression and resolved neuroinflammation evidenced by reduced IL1&beta and IL6 but increased anti‐inflammatory IL‐10 in adult ApoE3x5FAD and ApoE4x5FAD mice. In this study, the high LA diet increased its CNS metabolite DPAn‐6 greater with ApoE4. Thus, we further tested DPAn‐6 in old ApoE4x5FAD administering by gavage for three weeks. DPAn‐6 significantly reduced microgliosis, astrogliosis, innate immune inflammatory and caspase gene expression. In parallel, DPAn‐6 coordinately increased BDNF, VGF, ADCYAP1 and neuronal pentraxin 2 expression, indicating increased neurotrophin and plasticity‐related gene expression relevant to novel object memory improvement. In addition, COX expression was also reduced by LA or DPAn‐6 in vivo and in vitro amyloid‐&beta42 oligomer‐challenged microglial BV2 cells.

Conclusion

Taken together, we demonstrated that a novel n‐6 fatty acid docosapentaenoic acid modulated innate immune responses to resolve neuroinflammation at early and late stages of AD models with or without ApoE4. This was accompanied by synaptic, neuronal and cognitive benefits.
Pre‐clinical development of a blood‐brain barrier (BBB)‐penetrating anti‐amyloid‒β fusion protein
Authors: Chakravarthy Balu , Comas Rosa , Atkinson Trevor , Menard Michel , Brunette Eric , Jiang Susan , Haukenfrers Julie , Charlebois Claudie , Delaney Christie , Dudani Renu , Aylsworth Amy , Tauskela Joseph , Haqqani Arsalan , Rennie Kerry , Pon Robert , Agbayani Gerard , Bihun Craig , Akache Bassel , McCluskie Michael , Guhados Ganesh , Callaway Jim , Gillard John , Yoganathan Nathan , Stanimirovic Danica
Published: December 2020

Background

We have developed a blood‐brain barrier (BBB) crossing anti‐amyloid fusion protein KG207 as a potential AD therapeutic. This humanized bi‐functional molecule was generated by fusing an Aß oligomer (AßO)‐ binding peptide (ABP) with a BBB carrier FC5 via IgG‐1 Fc fragment. Present study shows that KG207 crosses the BBB in vitro and in vivo (mouse, rat and dog), penetrates target regions of the brain (cortex and hippocampus) and engages parenchymal Aß. KG207 neutralizes AßO‐induced toxicity in vitro and does not stimulate pro‐inflammatory cytokine production in mouse microglia. Studies demonstrated that KG207 was safe up to 300 mg/kg.

Method

Recombinant KG207 was produced in CHO cells. BBB‐permeability was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat, mouse and dog) models. AßO binding was determined by ELISA. Following iv injection, serum, CSF and brain levels of KG207 and Aß were assessed by nanoLC‐ MRM, ELISA and Western blot methods. Aß toxicity studies were done in human neuroblastoma (SH‐SY5Y) cells and rat primary cortical neuronal cells. Following exposure to KG207, cytokine levels in BV2 microglia were measured using Millipore Luminex assay kit. Safety studies were done in Sprague Dawley rats at 30, 100 and 300 mg/kg.

Result

KG207 retained both Aß‐oligomer binding activity and BBB‐permeability in vitro. When injected iv into rats and mouse, KG207 rapidly appeared in the CSF and brain parenchyma (cortex and hippocampus) indicating active transport of ABP across BBB by FC5 in vivo. In AD transgenic mice, KG207 treatment showed a significant reduction of brain Aß levels. KG207 significantly reduced AßO‐induced toxicity in both human neuroblastoma cells and primary cortical neurons in vitro. KG207 blocked AßO binding to cellular proteins in vitro. KG207 did not activate BV2 mouse microglia and induce pro‐inflammatory cytokines. No adverse effects were seen in rats injected with up to 300 mg/kg, including neurotoxicity.

Conclusion

Collectively, these results indicate that KG207 can effectivey cross the blood‐brain barrier, penetrate the brain and facilitate Aß clearance in vivo. In vitro data suggest that KG207 can safely clear Aß without eliciting pro‐inflammatory cytokine secretion by microglia.