Publications by authors named "Dimitrios Kapogiannis"

104 Publications

Neuronal and Astrocytic Extracellular Vesicle Biomarkers in Blood Reflect Brain Pathology in Mouse Models of Alzheimer's Disease.

Cells 2021 Apr 23;10(5). Epub 2021 Apr 23.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 212241, USA.

Circulating neuronal extracellular vesicles (NEVs) of Alzheimer's disease (AD) patients show high Tau and β-amyloid (Aβ) levels, whereas their astrocytic EVs (AEVs) contain high complement levels. To validate EV proteins as AD biomarkers, we immunocaptured NEVs and AEVs from plasma collected from fifteen wild type (WT), four 2xTg-AD, nine 5xFAD, and fifteen 3xTg-AD mice and assessed biomarker relationships with brain tissue levels. NEVs from 3xTg-AD mice had higher total Tau ( = 0.03) and p181-Tau ( = 0.0004) compared to WT mice. There were moderately strong correlations between biomarkers in NEVs and cerebral cortex and hippocampus (total Tau: cortex, r = 0.4, = 0.009; p181-Tau: cortex, r = 0.7, < 0.0001; hippocampus, r = 0.6, < 0.0001). NEVs from 5xFAD compared to other mice had higher Aβ42 ( < 0.005). NEV Aβ42 had moderately strong correlations with Aβ42 in cortex (r = 0.6, = 0.001) and hippocampus (r = 0.7, < 0.0001). AEV C1q was elevated in 3xTg-AD compared to WT mice ( = 0.005); AEV C1q had moderate-strong correlations with C1q in cortex (r = 0.9, < 0.0001) and hippocampus (r = 0.7, < 0.0001). Biomarkers in circulating NEVs and AEVs reflect their brain levels across multiple AD mouse models supporting their potential use as a "liquid biopsy" for neurological disorders.
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http://dx.doi.org/10.3390/cells10050993DOI Listing
April 2021

Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease.

Ageing Res Rev 2021 Apr 5;68:101339. Epub 2021 Apr 5.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address:

Objective: To investigate the effects of monoclonal antibodies against Aβ on cognition, function, amyloid PET and other biomarkers, as well as risk for amyloid-related imaging abnormalities (ARIA) and other adverse events, in Alzheimer's disease (AD).

Methods: Pubmed, Web of Science, ClinicalTrials.gov and gray literature were searched for phase III RCTs and random-effects meta-analyses were performed.

Results: Seventeen studies (12,585 patients) were included. Antibodies statistically improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95 % CI (-0.10; -0.02), I = 0%]} and MMSE {SMD = 0.05 [95 % CI (0.01; 0.09), I = 0%]} by small effect sizes, but did not improve the cognitive/functional measure CDR-SOB {SMD = -0.03 [95 % CI (-0.07; 0.01), I = 18 %]}. Moreover, antibodies decreased amyloid PET SUVR {SMD = -1.02 [95 % CI (-1.70; -0.34), I = 95 %]} and CSF p181-tau {SMD = -0.87 [95 % CI (-1.32; -0.43), I = 89 %]} by large effect sizes. They also increased risk for ARIA {RR = 4.30 [95 % CI (2.39; 7.77), I = 86 %]} by a large effect size. Antibody effects on reducing amyloid PET SUVR were correlated with their effects on improving ADAS-Cog (r = +0.68, p = 0.02). In subgroup analyses by individual drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL by small effect sizes and decreased amyloid PET SUVR and CSF p181-tau by large effect sizes. Solanezumab improved ADAS-Cog and MMSE by small effect sizes, and increased (improved) CSF Aβ levels by a moderate effect size. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes. Bapineuzumab and Gantenerumab decreased CSF p181-tau by a small and large effect size, respectively. All drugs except Solanezumab increased ARIA risk.

Conclusions: In this meta-analysis of phase III trials in AD, we found that monoclonal antibodies against Aβ induced clinical improvements of small effect sizes, biomarker improvements of large effect sizes, and increases in risk for the hallmark adverse event, ARIA, by a large effect size, when all drugs were pooled together. Among individual drugs, Aducanumab produced the most favorable effects followed by Solanezumab. These findings provide moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.
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http://dx.doi.org/10.1016/j.arr.2021.101339DOI Listing
April 2021

Peripheral inflammatory biomarkers define biotypes of bipolar depression.

Mol Psychiatry 2021 Mar 3. Epub 2021 Mar 3.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.
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http://dx.doi.org/10.1038/s41380-021-01051-yDOI Listing
March 2021

Astrocytes deliver CK1 to neurons via extracellular vesicles in response to inflammation promoting the translation and amyloidogenic processing of APP.

J Extracell Vesicles 2020 Dec 31;10(2):e12035. Epub 2020 Dec 31.

Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections Johns Hopkins University School of Medicine Baltimore Maryland USA.

Chronic inflammation is thought to contribute to the early pathogenesis of Alzheimer's disease (AD). However, the precise mechanism by which inflammatory cytokines promote the formation and deposition of Aβ remains unclear. Available data suggest that applications of inflammatory cytokines onto isolated neurons do not promote the formation of Aβ, suggesting an indirect mechanism of action. Based on evidence astrocyte derived extracellular vesicles (astrocyte derived EVs) regulate neuronal functions, and data that inflammatory cytokines can modify the molecular cargo of astrocyte derived EVs, we sought to determine if IL-1β promotes the formation of Aβ indirectly through actions of astrocyte derived EVs on neurons. The production of Aβ was increased when neurons were exposed to astrocyte derived EVs shed in response to IL-1β (astrocyte derived EV-IL-1β). The mechanism for this effect involved an enrichment of Casein kinase 1 (CK1) in astrocyte derived EV-IL-1β. This astrocyte derived CK1 was delivered to neurons where it formed a complex with neuronal APC and GSK3 to inhibit the β-catenin degradation. Stabilized β-catenin translocated to the nucleus and bound to gene at promoter regions. An increased cellular concentration of hnRNP C promoted the translation of APP by outcompeting the translational repressor fragile X mental retardation protein (FMRP) bound to APP mRNA. An increased amount of APP protein became co-localized with BACE1 in enlarged membrane microdomains concurrent with increased production of Aβ. These findings identify a mechanism whereby inflammation promotes the formation of Aβ through the actions of astrocyte derived EV-IL-1β on neurons.
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http://dx.doi.org/10.1002/jev2.12035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775567PMC
December 2020

The "authentic subjective experience" of memory in Alzheimer's disease.

Transl Neurosci 2020 3;11(1):201-207. Epub 2020 Jun 3.

Univ. Lille, CNRS, CHU Lille, UMR 9193 - SCALab - Sciences Cognitives et Sciences Affectives, F-59000 Lille, France.

Most research has mainly focused on the decline of the subjective experience in Alzheimer's disease (AD). However, few attempts have been made to evaluate whether subjective experience may be maintained in AD. In this narrative review, we attempt to provide a positive view, according to which patients with AD can enjoy, to some extent, subjective experience during memory retrieval. Memory and expression difficulties (e.g., aphasia) limit the ability of patients with AD to describe their memories, resulting in a little specificity of reported memories. However, according to the "authentic subjective experience" view, we propose in this study that the ability to mentally relive these memories could be preserved in the patients. By proposing the authentic subjective experience view, we attempt to provide an alternative view to the general consideration that the patients suffer a diminished subjective experience. This view can contribute to a larger clinical framework that gives a positive meaning to the subjective experience of patients with AD. Furthermore, several clinical and empirical implications can be drawn from the authentic subjective experience view, including the possibility to evaluate behavioral correlates of the subjective experience in AD.
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http://dx.doi.org/10.1515/tnsci-2020-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712381PMC
June 2020

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

J Psychiatr Res 2021 01 4;133:82-92. Epub 2020 Dec 4.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855678PMC
January 2021

Mitochondrial RNA in Alzheimer's Disease Circulating Extracellular Vesicles.

Front Cell Dev Biol 2020 16;8:581882. Epub 2020 Nov 16.

Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, United States.

Alzheimer's disease (AD) is the most common type of dementia. Amyloid β (Aβ) plaques, tau-containing neurofibrillary tangles, and neuronal loss leading to brain atrophy are pathologic hallmarks of AD. Given the importance of early diagnosis, extensive efforts have been undertaken to identify diagnostic and prognostic biomarkers for AD. Circulating extracellular vesicles (EVs) provide a platform for "liquid biopsy" biomarkers for AD. Here, we characterized the RNA contents of plasma EVs of age-matched individuals who were cognitively normal (healthy controls (HC)) or had mild cognitive impairment (MCI) due to AD or had mild AD dementia (AD). Using RNA sequencing analysis, we found that mitochondrial (mt)-RNAs, including mRNAs and other protein-coding and non-coding mt-RNAs, were strikingly elevated in plasma EVs of MCI and AD individuals compared with HC. EVs secreted from cultured astrocytes, microglia, and neurons after exposure to toxic conditions relevant to AD pathogenesis (Aβ aggregates and HO), contained mitochondrial structures (detected by electron microscopy) and mitochondrial RNA and protein. We propose that in the AD brain, toxicity-causing mitochondrial damage results in the packaging of mitochondrial components for export in EVs and further propose that mt-RNAs in plasma EVs can be diagnostic and prognostic biomarkers for MCI and AD.
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http://dx.doi.org/10.3389/fcell.2020.581882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701247PMC
November 2020

Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in Communities Study.

Neurobiol Aging 2021 01 1;97:65-72. Epub 2020 Oct 1.

Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities-Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736127PMC
January 2021

Burnout of Healthcare Workers in Acute Care Geriatric Facilities During the COVID-19 Crisis: An Online-Based Study.

J Alzheimers Dis 2020 ;78(2):847-852

Nantes Université, Univ Angers, Laboratoire de Psychologie des Pays de la Loire (LPPL - EA 4638), Nantes, France.

Background/objective: The COVID-19 crisis has been increasing the burden of healthcare workers in acute care geriatric facilities. These workers have been dealing with drastic changes in the care they provide to their residents including cancelation of group activities and communal dining and even restrictions of activities outside rooms. Healthcare workers have also been devoting more time and energy to perform COVID-related medical duties. Geriatric facilities have been facing shortages in equipment and supplies, as well as staffing shortages. Finally, healthcare workers have been facing challenges regarding their personal safety and that of their families. Consequently, we hypothesized the presence of high levels of burnout among healthcare workers during the COVID-19 crisis.

Methods: To evaluate burnout in healthcare workers in French acute care geriatric facilities, we used an online survey based on the Oldenburg Burnout Inventory. Eighty-four healthcare workers answered the survey, during April of 2020.

Results: Analysis demonstrated that they were experiencing medium levels of burnout, exhaustion, and disengagement.

Conclusion: This level of burnout reflected their fatigue, loss of energy, and/or feelings of being overextended and exhausted. Considering the expected cumulative impact of various stressors, the medium level of burnout observed has come as a surprise to us and might actually be considered as relatively good news. Nevertheless, no level of burnout is negligible and has wide ranging negative consequences.
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http://dx.doi.org/10.3233/JAD-201029DOI Listing
November 2020

The picture of the past: Pictures to cue autobiographical memory in Alzheimer's disease.

J Clin Exp Neuropsychol 2020 11 1;42(9):914-923. Epub 2020 Oct 1.

CNRS, CHU Lille, UMR 9193 - SCALab - Sciences Cognitives et Sciences Affectives, Univ. Lille , Lille, France.

Introduction: This study investigated the effect of pictorial cues on autobiographical memory in Alzheimer's disease (AD). We assessed autobiographical memory of patients with AD and cognitively normal older adults in two conditions.

Methods: In one condition, the participants were provided with verbal instructions to retrieve three autobiographical memories. In the second condition, the same verbal instructions were provided; however, the participants were simultaneously presented with three pictures. We analyzed autobiographical memory regarding specificity, that is, the ability to remember unique events situated in time and space.

Results: Analysis demonstrated higher autobiographical memory after verbal-and-visual cuing than after the no cue condition in both patients with AD and cognitively normal older adults.

Discussion: Pictorial cues seem to be an effective method to alleviate autobiographical compromise in AD.
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http://dx.doi.org/10.1080/13803395.2020.1825636DOI Listing
November 2020

Mitochondrial Protrusions in Neuronal Cells.

iScience 2020 Aug 29;23(9):101514. Epub 2020 Aug 29.

Laboratory of Clinical Investigation, NIA/NIH Biomedical Research Center, Baltimore, MD 21224, USA. Electronic address:

Mitochondrial function relies on multiple quality control mechanisms, including the release of mitochondrial vesicles. To investigate the ultrastructure and prevalence of mitochondrial membranous protrusions (and, by extension, vesicles) in neurons, we surveyed mitochondria in rat and planarian brains using transmission electron microscopy (EM). We observed that mitochondrial protrusions mostly extend from the outer membrane. Leveraging available 3D EM datasets of the brain, we further analyzed mitochondrial protrusions in neurons of mouse and Drosophila brains, identifying high-resolution spatial views of these protrusions. To assess whether the abundance of mitochondrial protrusions and mitochondria-derived vesicles respond to cellular stress, we examined neurons expressing fluorescently tagged mitochondrial markers using confocal microscopy with Airyscan and found increased numbers of mitochondrial protrusions and vesicles with mild stress. Future studies using improved spatial resolution with added temporal information may further define the functional implications of mitochondrial protrusions and vesicles in neurons.
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http://dx.doi.org/10.1016/j.isci.2020.101514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501463PMC
August 2020

Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury.

Elife 2020 08 17;9. Epub 2020 Aug 17.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, United States.

Traumatic brain injury (TBI) is a serious global health problem, many individuals live with TBI-related neurological dysfunction. A lack of biomarkers of TBI has impeded medication development. To identify new potential biomarkers, we time-dependently evaluated mouse brain tissue and neuronally derived plasma extracellular vesicle proteins in a mild model of TBI with parallels to concussive head injury. Mice (CD-1, 30-40 g) received a sham procedure or 30 g weight-drop and were euthanized 8, 24, 48, 72, 96 hr, 7, 14 and 30 days later. We quantified ipsilateral cortical proteins, many of which differed from sham by 8 hours post-mTBI, particularly GAS-1 and VEGF-B were increased while CXCL16 reduced, 23 proteins changed in 4 or more of the time points. Gene ontology pathways mapped from altered proteins over time related to pathological and physiological processes. Validation of proteins identified in this study may provide utility as treatment response biomarkers.
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http://dx.doi.org/10.7554/eLife.55827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473773PMC
August 2020

High depression and anxiety in people with Alzheimer's disease living in retirement homes during the covid-19 crisis.

Psychiatry Res 2020 09 13;291:113294. Epub 2020 Jul 13.

Unité de Gériatrie, Centre Hospitalier de Tourcoing, Tourcoing, France.

To cope with Covid-19 and limits its spread among residents, retirement homes have prohibited physical contact between residents and families and friend and, in some cases, even between residents or between residents and caregivers. We investigated the effects of measures against Covid-19 on the mental health of participants with Alzheimer's disease (AD) who live in retirement homes in France. We instructed on-site caregivers to assess depression and anxiety in participants with mild AD who live in retirement homes. Fifty-eight participants consented to participate in the study. The participants rated their depression and anxiety during and before the Covid-19 crisis. Participants reported higher depression (p = .005) and anxiety (p = .004) during than before the Covid-19 crisis. These increases can be attributed to the isolation of the residents and/or to the drastic changes in their daily life and care they receive. While, in their effort to prevent infections, retirement homes are forced to physically separate residents from the outside world and to drastically reduce residents' activities, these decisions are likely to come at a cost to residents with AD and their mental health.
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http://dx.doi.org/10.1016/j.psychres.2020.113294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357507PMC
September 2020

Brain glucose and ketone utilization in brain aging and neurodegenerative diseases.

Int Rev Neurobiol 2020 10;154:79-110. Epub 2020 Jul 10.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.

To meet its high energy demands, the brain mostly utilizes glucose. However, the brain has evolved to exploit additional fuels, such as ketones, especially during prolonged fasting. With aging and neurodegenerative diseases (NDDs), the brain becomes inefficient at utilizing glucose due to changes in glia and neurons that involve glucose transport, glycolytic and Krebs cycle enzyme activities, and insulin signaling. Positron emission tomography and magnetic resonance spectroscopy studies have identified glucose metabolism abnormalities in aging, Alzheimer's disease (AD) and other NDDs in vivo. Despite glucose hypometabolism, brain cells can utilize ketones efficiently, thereby providing a rationale for the development of therapeutic ketogenic interventions in AD and other NDDs. This review compares available ketogenic interventions and discusses the potential of the potent oral Ketone Ester for future therapeutic use in AD and other NDDs characterized by inefficient glucose utilization.
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http://dx.doi.org/10.1016/bs.irn.2020.03.015DOI Listing
July 2020

Synaptic and complement markers in extracellular vesicles in multiple sclerosis.

Mult Scler 2021 Apr 17;27(4):509-518. Epub 2020 Jun 17.

Laboratory of Clinical Investigation, National Institutes of Aging, Baltimore, MD, USA/Biomedical Research Center, National Institute on Aging, National Institute of Health, Baltimore, MD, USA/ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Synaptic loss is a feature of multiple sclerosis pathology that can be seen even in normal-appearing gray matter. Opsonization of synapses with complement components may underlie pathologic synapse loss.

Objective: We sought to determine whether circulating neuronal-enriched and astrocytic-enriched extracellular vesicles (NEVs and AEVs) provide biomarkers reflecting complement-mediated synaptic loss in multiple sclerosis.

Methods: From plasma of 61 people with multiple sclerosis (46 relapsing-remitting multiple sclerosis (RRMS) and 15 progressive MS) and 31 healthy controls, we immunocaptured L1CAM + NEVs and GLAST + AEVs. We measured pre- and post-synaptic proteins synaptopodin and synaptophysin in NEVs and complement components (C1q, C3, C3b/iC3b, C4, C5, C5a, C9, Factor B, and Factor H) in AEVs, total circulating EVs, and neat plasma.

Results: We found lower levels of NEV synaptopodin and synaptophysin in MS compared to controls ( < 0.0001 for both). In AEVs, we found higher levels of multiple complement cascade components in people with MS compared to controls; these differences were not noted in total EVs or neat plasma. Strikingly, there were strong inverse correlations between NEV synaptic proteins and multiple AEV complement components in MS, but not in controls.

Conclusion: Circulating EVs could identify synaptic loss in MS and suggest a link between astrocytic complement production and synaptic loss.
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http://dx.doi.org/10.1177/1352458520924590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744427PMC
April 2021

Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer's Disease Patients Effect Complement-Mediated Neurotoxicity.

Cells 2020 07 4;9(7). Epub 2020 Jul 4.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA.

We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer's disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.
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http://dx.doi.org/10.3390/cells9071618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407141PMC
July 2020

Extracellular vesicle biomarkers of Alzheimer's disease associated with sub-clinical cognitive decline in late middle age.

Alzheimers Dement 2020 09 26;16(9):1293-1304. Epub 2020 Jun 26.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland, USA.

Introduction: Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age-associated cognitive decline.

Methods: This case-control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change.

Results: Declining compared to stable individuals showed higher baseline total, p231-, and p181-tau with older age and higher annualized change for p-IR and p-IGF-1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively.

Discussion: Combining nEV biomarkers can identify individuals with age-associated cognitive decline.
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http://dx.doi.org/10.1002/alz.12130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984100PMC
September 2020

The Effects of Confinement on Neuropsychiatric Symptoms in Alzheimer's Disease During the COVID-19 Crisis.

J Alzheimers Dis 2020 ;76(1):41-47

Nantes Université, Univ Angers, Laboratoire de Psychologie des Pays de la Loire (LPPL - EA 4638), Nantes, France.

Background: Neuropsychiatric symptoms, such as depression, anxiety, apathy, agitation, and hallucinations, are frequent in Alzheimer's disease (AD) and their prevalence tends to increase with external stressors.

Objective: We offer the first investigation of the effects of confinement during the COVID-19 crisis on neuropsychiatric symptoms in patients with AD.

Methods: We contacted caregivers of 38 patients with AD who were confined to their homes for nearly two months and asked them to report whether patients experienced any change in neuropsychiatric symptoms during, compared to before, the confinement and rate its severity and impact on themselves using the Neuropsychiatric Inventory-Questionnaire.

Results: Among the 38 patients, only 10 demonstrated neuropsychiatric changes during the confinement. Cognitive function of these 10 patients, assessed with the Mini-Mental State Examination, was worse than that of patients who did not demonstrate neuropsychiatric changes. Interestingly, among the 10 patients with neuropsychiatric changes, the duration of confinement significantly correlated with the severity of symptoms as well as with their caregivers' distress.

Discussion: The confinement seems to impact neuropsychiatric symptomatology in AD patients with low baseline cognitive function.
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http://dx.doi.org/10.3233/JAD-200604DOI Listing
July 2020

Exosome Biomarkers Revolutionize Preclinical Diagnosis of Neurodegenerative Diseases and Assessment of Treatment Responses in Clinical Trials.

Adv Exp Med Biol 2020 ;1195:149

National Institute on Aging, NIH, Bethesda, MD, USA.

Alzheimer's disease and other neurodegenerative diseases have long preclinical phases with active and progressively irreversible pathology. Therefore, biomarkers are essential for identifying patients early in the course of these diseases, when they may benefit the most from disease-modifying interventions. A limitation of biomarkers measured in the soluble phase of blood is their tenuous link to brain pathology. A new approach to biomarker discovery that addresses this limitation is deriving extracellular vesicles (EVs) enriched for neuronal and astrocytic origin from peripheral blood. EVs are membranous particles (subdivided into smaller exosomes and larger microvesicles) that are shed by all cells and found in all biofluids. Neuronal and astrocytic EVs have been implicated in the pathogenesis of several neurodegenerative diseases. Given their origin, neuronal and astrocytic enriched EVs harvested from blood can be used to interrogate brain pathologic processes previously inaccessible in vivo. In a long series of case control studies based on these EV subpopulations, we have identified candidate protein biomarkers for Alzheimer's disease and other neurodegenerative diseases. In GeNeDis 2018, an update of these studies and results from a validation study of these biomarkers in preclinical Alzheimer's disease will be presented. In addition, we will present results from studies demonstrating EV biomarker responses to experimental interventions. EV-based biomarkers are a valuable new tool that will enable researchers to test hypotheses in proof of concept studies with carefully selected participants at the preclinical phase, spearheading therapeutic discovery in neurodegenerative disease.
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http://dx.doi.org/10.1007/978-3-030-32633-3_19DOI Listing
September 2020

Effects of saffron (Crocus sativus L.) on cognitive function. A systematic review of RCTs.

Neurol Sci 2020 Oct 23;41(10):2747-2754. Epub 2020 May 23.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aginga, National Institutes of Health, Baltimore, 3001 S Hanover St, Baltimore, MD, 21225, USA.

Introduction: Improvement of cognitive function may be desirable for healthy individuals and clinically beneficial for those with cognitive impairment such as from Alzheimer's disease (AD) or mild cognitive impairment (MCI). The aim of this systematic review is to investigate the cognitive effects of oral saffron intake, in patients with MCI/AD and/or in non-demented individuals, by following the PRISMA guidelines.

Methods: We performed a literature search on MedLine, Cochrane library, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) investigating the effects of oral saffron administration in patients with MCI/AD and/or in non-demented individuals.

Results: Five studies (enrolling 325 individuals) met our inclusion criteria. Four studies included patients with MCI/AD, and one study included cognitively normal individuals. Saffron was well-tolerated in all groups. Regarding cognitively impaired patients, scores on Alzheimer's Disease Assessment Scale-cognitive subscale or Mini mental state examination were significantly better when saffron was compared with placebo and did not differ significantly when saffron was compared with donepezil or memantine. Saffron effects on functional status were similar with its effects on cognition.

Conclusions: Saffron was shown to be equally effective to common symptomatic drugs for MCI/AD and resulted in no difference in the incidence of side effects, when compared with placebo or drugs. The promising results should be seen cautiously, since the evidence was derived from studies with potentially high risk of bias (ROB). RCTs with larger sample sizes and low ROB are required to definitively assess the potential role of saffron as an MCI/AD treatment.
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http://dx.doi.org/10.1007/s10072-020-04427-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484083PMC
October 2020

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression.

Cells 2020 04 6;9(4). Epub 2020 Apr 6.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 20892, USA.

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants ( = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ = 9.275, = 0.026), NF-κB (χ = 13.825, = 0.003), and inhibitor of NF-κB (IκBα) (χ = 7.990, = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ = 7.997, = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, = 0.029), but not placebo-treated, patients (r = 0.196, = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.
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http://dx.doi.org/10.3390/cells9040895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226726PMC
April 2020

Endothelial-derived plasma exosome proteins in Alzheimer's disease angiopathy.

FASEB J 2020 04 10;34(4):5967-5974. Epub 2020 Mar 10.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Small cerebral vascular disease (SCeVD) demonstrated by white matter hyperintensity (WMH) on MRI contributes to the development of dementia in Alzheimer's disease (AD), but it has not been possible to correlate onset, severity, or protein components of SCeVD with characteristics of WMH in living patients. Plasma endothelial-derived exosomes (EDEs) were enriched by two-step immunoabsorption from four groups of participants with no clinical evidence of cerebrovascular disease: cognitively normal (CN) without WMH (CN without SCeVD, n = 20), CN with SCeVD (n = 22), preclinical AD (pAD) + mild cognitive impairment (MCI) without SCeVD (pAD/MCI without SCeVD, n = 22), and pAD/MCI with SCeVD (n = 16) for ELISA quantification of cargo proteins. Exosome marker CD81-normalized EDE levels of the cerebrovascular-selective biomarkers large neutral amino acid transporter 1 (LAT-1), glucose transporter type 1 (Glut-1), and permeability-glycoprotein (p-GP, ABCB1) were similarly significantly higher in the CN with SCeVD and pAD/MCI with SCeVD groups than their corresponding control groups without SCeVD. CD81-normalized EDE levels of Aβ40 and Aβ42 were significantly higher in the pAD/MCI with SCeVD group but not in the CN with SCeVD group relative to controls without SCeVD. Levels of normal cellular prion protein (PrPc), a receptor for amyloid peptides, and phospho-181T-tau were higher in both CN and pAD/MCI with SCeVD groups than in the corresponding controls. High EDE levels of Aβ40, Aβ42, and phospho-181T-tau in patients with WMH suggesting SCeVD appear at the pre-clinical or MCI stage of AD and therapeutic lowering of neurotoxic peptide levels may delay progression of AD angiopathy.
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http://dx.doi.org/10.1096/fj.202000034RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233139PMC
April 2020

False Memory in Alzheimer's Disease.

Behav Neurol 2020 19;2020:5284504. Epub 2020 Feb 19.

Unité de Gériatrie, Centre Hospitalier de Tourcoing, Tourcoing, France.

Patients with Alzheimer's Disease (AD) not only are suffering from amnesia but also are prone to memory distortions, such as experiencing detailed and vivid recollections of episodic events that have never been encountered (i.e., false memories). To describe and explain these distortions, we offer a review to synthesize current knowledge on false memory in AD into a framework allowing for better understanding of the taxonomy and phenomenology of false memories and of the cognitive mechanisms that may underlie false memory formation in AD. According to this review, certain phenomenological characteristics of memories (e.g., high emotional load, high vividness, or high familiarity) result in misattributions in AD. More specifically, this review proposes that generalized decline in cognitive control and inhibition in AD may result in difficulties in suppressing irrelevant information during memory monitoring, especially when irrelevant (i.e., false) information is characterized by high emotion, vividness, or familiarity. This review also proposes that binding deficits in AD decrease the ability to retrieve relevant contextual details, leading to source monitoring errors and false memories. In short, this review depicts how phenomenological characteristics of memories and failures of monitoring during retrieval contribute to the occurrence of false memory in AD.
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http://dx.doi.org/10.1155/2020/5284504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049840PMC
November 2020

Traumatic brain injury increases plasma astrocyte-derived exosome levels of neurotoxic complement proteins.

FASEB J 2020 02 8;34(2):3359-3366. Epub 2020 Jan 8.

Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.

Possible involvement of complement (C) systems in the pathogenesis of traumatic brain injury (TBI) was investigated by quantifying Cproteins in plasma astrocyte-derived exosomes (ADEs) of subjects with sports-related TBI (sTBI) and TBI in military veterans (mtTBI) without cognitive impairment. All sTBI subjects (n = 24) had mild injuries, whereas eight of the mtTBI subjects had moderate, and 17 had mild injuries. Plasma levels of ADEs were decreased after acute sTBI and returned to normal within months. Cprotein levels in ADEs were from 12- to 35-fold higher than the corresponding levels in neuron-derived exosomes. CD81 exosome marker-normalized ADE levels of classical pathway C4b, alternative pathway factor D and Bb, lectin pathway mannose-binding lectin (MBL), and shared neurotoxic effectors C3b and C5b-9 terminal C complex were significantly higher and those of C regulatory proteins CR1 and CD59 were lower in the first week of acute sTBI (n = 12) than in controls (n = 12). Most C abnormalities were no longer detected in chronic sTBI at 3-12 months after acute sTBI, except for elevated levels of factor D, Bb, and MBL. In contrast, significant elevations of ADE levels of C4b, factor D, Bb, MBL, C3b and C5b-9 terminal C complex, and depressions of CR1 and CD59 relative to those of controls were observed after 1-4 years in early chronic mtTBI (n = 10) and persisted for decades except for normalization of Bb, MBL, and CD59 in late chronic mtTBI (n = 15). Complement inhibitors may be useful therapeutically in acute TBI and post-concussion syndrome.
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http://dx.doi.org/10.1096/fj.201902842RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459190PMC
February 2020

The subjective experience of recollection and familiarity in Alzheimer's disease.

Behav Brain Sci 2020 01 3;42:e290. Epub 2020 Jan 3.

Nantes Université, Univ Angers, Laboratoire de Psychologie des Pays de la Loire (LPPL - EA 4638), F-44000Nantes,

Although the integrative memory model proposed by Bastin et al. is interesting, particularly for Alzheimer's disease, it may benefit from incorporating the subjective experience of recollection. We therefore offer complementary lines of interpretation to explain how recollection and familiarity in Alzheimer's disease can be dissociated based not only on accounts of their neural correlates but, critically, on the subjective experience of memory in patients.
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http://dx.doi.org/10.1017/S0140525X19001766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470455PMC
January 2020

Medium Chain Triglycerides induce mild ketosis and may improve cognition in Alzheimer's disease. A systematic review and meta-analysis of human studies.

Ageing Res Rev 2020 03 20;58:101001. Epub 2019 Dec 20.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA. Electronic address:

Introduction/aim: The brain in Alzheimer's disease shows glucose hypometabolism but may utilize ketones for energy production. Ketone levels can potentially be boosted through oral intake of Medium Chain Triglycerides (MCTs). The aim of this meta-analysis is to investigate the effect of MCTs on peripheral ketone levels and cognitive performance in patients with mild cognitive impairment and Alzheimer's disease.

Methods: Medline, Scopus and Web of Science were searched for literature up to March 1, 2019. Meta-analyses were performed by implementing continuous random-effects models and outcomes were reported as weighted Mean Differences (MDs) or Standardized Mean Differences (SMDs).

Results: Twelve records (422 participants) were included. Meta-analysis of RCTs showed that, compared with placebo, MCTs elevated beta-hydroxybutyrate [MD = 0.355; 95 % CI (0.286, 0.424), I = 0 %], showed a trend towards cognitive improvement on ADAS-Cog [MD = -0.539; 95% CI (-1.239, -0.161), I = 0 %], and significantly improved cognition on a combined measure (ADAS-Cog with MMSE) [SMD = -0.289; 95 % CI (-0.551, -0.027), I = 0 %].

Conclusions: In this meta-analysis, we demonstrated that MCTs can induce mild ketosis and may improve cognition in patients with mild cognitive impairment and Alzheimer's disease. However, risk of bias of existing studies necessitates future trials.
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http://dx.doi.org/10.1016/j.arr.2019.101001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050425PMC
March 2020

miR-212 and miR-132 Are Downregulated in Neurally Derived Plasma Exosomes of Alzheimer's Patients.

Front Neurosci 2019 26;13:1208. Epub 2019 Nov 26.

Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood. These findings raise the possibility that brain-derived EV's present in blood can be used to monitor disease processes occurring in the cerebrum. Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer's disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD ( = 5), high pathological control (HPC) ( = 5), or cognitively intact pathology-free controls ( = 5). Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.
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http://dx.doi.org/10.3389/fnins.2019.01208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902042PMC
November 2019

(-)-Phenserine tartrate (PhenT) as a treatment for traumatic brain injury.

CNS Neurosci Ther 2020 06 11;26(6):636-649. Epub 2019 Dec 11.

Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Aim: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely.

Discussion: We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman.

Conclusion: In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.
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http://dx.doi.org/10.1111/cns.13274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248544PMC
June 2020

The (fatalistic) present as experienced by individuals with Alzheimer's disease: a preliminary study.

Neurol Sci 2020 Feb 11;41(2):427-433. Epub 2019 Nov 11.

CNRS, CHU Lille, UMR 9193 - SCALab - Sciences Cognitives et Sciences Affectives, Univ. Lille, F-59000, Lille, France.

Background: The "time perspectives theory" describes how individuals emphasize some time frames over others (e.g., present vs. future) and thus create their unique approach to time perception. Building on this theory, we investigated three time orientations in Alzheimer's disease (AD): (1) present-hedonistic orientation, which focuses on current sensations and pleasures without considering the future, (2) present-fatalistic orientation, characterized by a bias of hopelessness and helplessness toward the future, and (3) future orientation, which focuses on achieving personal goals and future consequences of present actions.

Methods: Participants with mild AD (n = 30) and controls (n = 33) were assessed with a questionnaire regarding time perspectives and a questionnaire of depression.

Results: Results demonstrated low future orientation and high present-fatalistic orientation in AD participants, whereas older adults demonstrated the reverse pattern. Depression positively correlated with fatalistic-present orientation, but negatively correlated with hedonistic-present and future orientations.

Discussion: Although our findings are preliminary and the sample size is small, depression in mild AD seems to be related with a fatalistic orientation toward the present, as well as a hopeless and helpless perspective on the future, an orientation that results in little desire to enjoy the present.
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http://dx.doi.org/10.1007/s10072-019-04121-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473485PMC
February 2020

Insulin-signaling abnormalities in drug-naïve first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin.

Eur Psychiatry 2019 10 4;62:124-129. Epub 2019 Oct 4.

Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany. Electronic address:

Background: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES.

Methods: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting.

Results: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3β (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends.

Conclusion: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.
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http://dx.doi.org/10.1016/j.eurpsy.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941668PMC
October 2019