Dimitrios Kapogiannis

Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease

Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimers disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimers disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.

GLP-1 Receptor Stimulation Reduces Amyloid-β Peptide Accumulation and Cytotoxicity in Cellular and Animal Models of Alzheimer’s Disease

Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimers disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-beta protein (Abeta) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Abeta and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Abeta protein precursor and Abeta, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance.

Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study

Proteins pathogenic in Alzheimers disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD.

Cognitive and neural foundations of religious belief

We propose an integrative cognitive neuroscience framework for understanding the cognitive and neural foundations of religious belief. Our analysis reveals 3 psychological dimensions of religious belief (Gods perceived level of involvement, Gods perceived emotion, and doctrinal/experiential religious knowledge), which functional MRI localizes within networks processing Theory of Mind regarding intent and emotion, abstract semantics, and imagery. Our results are unique in demonstrating that specific components of religious belief are mediated by well-known brain networks, and support contemporary psychological theories that ground religious belief within evolutionary adaptive cognitive functions.

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Methods: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003). Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimers disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)‐serine‐type 1 insulin receptor substrate (IRS‐1) and less P‐tyrosine‐IRS‐1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P‐serine 312‐IRS‐1 and P‐pan‐tyrosine‐IRS‐1 by ELISA and the ratio of P‐serine 312‐IRS‐1 to P‐pan‐tyrosine‐IRS‐1 (insulin resistance factor, R) for AD and DM2 and P‐serine 312‐IRS‐1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significandy higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P‐serine 312‐IRS‐1, P‐pan‐tyrosine‐IRS‐1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimers disease. FASEB J. 29, 589‐596 (2015). www.fasebj.org

Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network.

The balance between excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons determines the function of cortical microcircuits. How these neurotransmitters relate to the functional status of an entire macro-scale network remains unknown. The posteromedial cortex (PMC) is the default mode network (DMN) node with the greatest functional connectivity; therefore, we hypothesized that PMC glutamate and GABA predict intrinsic functional connectivity (iFC) across the entire DMN. In 20 healthy men, we combined J-resolved magnetic resonance spectroscopy to measure glutamate and GABA in the PMC and resting fMRI followed by group Independent Components Analysis to extract the entire DMN. We showed that, controlling for age and partial GM volume in the MRS voxel, PMC glutamate and GABA explained about half of the variance of DMN iFC (represented by the networks beta coefficient for rest). Glutamate correlated positively and GABA correlated negatively with DMN iFC; in an alternative statistical model which included the glutamate/GABA ratio, the ratio correlated positively with DMN iFC. Age had no independent association with DMN iFC. No other network was associated with PMC glutamate or GABA. We conclude that regional neurotransmitter concentrations in a network node strongly predict network but not global brain iFC.

FTD and ALS: a tale of two diseases

The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders.FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.

The Five Factors of personality and regional cortical variability in the Baltimore Longitudinal Study of Aging

Although personality changes have been associated with brain lesions and atrophy caused by neurodegenerative diseases and aging, neuroanatomical correlates of personality in healthy individuals and their stability over time have received relatively little investigation. In this study, we explored regional gray matter (GM) volumetric associations of the five‐factor model of personality. Eighty‐seven healthy older adults took the NEO Personality Inventory and had brain MRI at two time points 2 years apart. We performed GM segmentation followed by regional analysis of volumes examined in normalized space map creation and voxel based morphometry‐type statistical inference in SPM8. We created a regression model including all five factors and important covariates. Next, a conjunction analysis identified associations between personality scores and GM volumes that were replicable across time, also using cluster‐level Family‐Wise‐Error correction. Larger right orbitofrontal and dorsolateral prefrontal cortices and rolandic operculum were associated with lower Neuroticism; larger left temporal, dorsolateral prefrontal, and anterior cingulate cortices with higher Extraversion; larger right frontopolar and smaller orbitofrontal and insular cortices with higher Openness; larger right orbitofrontal cortex with higher Agreeableness; larger dorsolateral prefrontal and smaller frontopolar cortices with higher Conscientiousness. In summary, distinct personality traits were associated with stable individual differences in GM volumes. As expected for higher‐order traits, regions performing a large number of cognitive and affective functions were implicated. Our findings highlight personality‐related variation that may be related to individual differences in brain structure that merit additional attention in neuroimaging research. Hum Brain Mapp 34:2829–2840, 2013.

Low neural exosomal levels of cellular survival factors in Alzheimer's disease.

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural‐derived exosomes of Alzheimers disease or frontotemporal dementia patients and matched controls. Exosomal levels of low‐density lipoprotein receptor‐related protein 6, heat‐shock factor‐1, and repressor element 1‐silencing transcription factor all were significantly lower in Alzheimers disease patients than controls (P < 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1‐silencing transcription factor than in controls. Exosomal transcription factors were diminished 2–10 years before clinical diagnosis of Alzheimers disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimers disease neurotoxic proteins.