Vol 5-3 Mini Review

Microtubule Electrical Oscillations and Hippocampal Function

Maria del Rocio Cantero, Horacio F. Cantiello

Laboratorio de Canales Iónicos, Instituto Multidisciplinario de Salud, Tecnología y Desarrollo (IMSaTeD, CONICET-UNSE) Santiago del Estero, Argentina

Microtubules (MTs) are long cylindrical structures of the cytoskeleton that control cell division, vesicular transport, and the shape of cells. MTs are highly charged and behave as nonlinear electrical transmission lines. However, comparatively little is known about the role(s) these nonlinear electrical properties of MTs play in cell function. MTs form bundles, which are particularly prominent in neurons, where they help developmentally define axons and dendrites. The present review summarizes recent work from our laboratory which demonstrated that 1) bundles of rat brain MTs spontaneously generate electrical oscillations and bursts of electrical activity similar to action potentials; 2) actin filaments control electrostatically the oscillatory response of brain MTs; and 3) neurites of cultured mouse hippocampal neurons generate and propagate electrical oscillations thus, providing a cellular correlate to the isolated MT oscillations. Electrical oscillations are an intrinsic property of brain MT bundles, which may have important implications in the control of various neuronal functions, including a contribution to the intrinsic oscillatory modes of neurons, and thus to higher brain functions, including the formation of memory and the onset of consciousness.

DOI: 10.29245/2572.942X/2020/3.1267 View / Download Pdf
Vol 5-3 Research Article

Gulf War Illness: C-Reactive Protein is Associated with Reduction of the Volume of Hippocampus and Decreased Fractional Anisotropy of the Fornix

Peka Christova1,2, Lisa M. James1,2,3, Adam F. Carpenter1,4, Scott M. Lewis1,4, Rachel A. Johnson1, Brian E. Engdahl1,2,5, Apostolos P. Georgopoulos1,2,3,4*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, US

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

5Department of Psychology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Memory and mood impairments are among the most commonly reported symptoms in veterans with Gulf War Illness (GWI), suggesting hippocampal involvement. Several studies have also documented evidence of inflammation in GWI. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, and hippocampal volume and microstructural alterations of its major output, the fornix. Sixty-three veterans with GWI provided blood samples for evaluation of CRP and underwent a 3T magnetic resonance imaging scan from which hippocampal volume and fornix fractional anisotropy (FA) were obtained. Results demonstrated that CRP was significantly and negatively associated with hippocampal volume and fornix FA in GWI. Given the known closely interwoven associations between inflammation and neurodegeneration, it is possible that the effects we observed could be due to neurodegeneration, secondary to chronic neuroinflammation. Finally, given the known association of hippocampus to memory and mood disorders, our findings provide new insights into memory and mood alterations associated with GWI.

DOI: 10.29245/2572.942X/2020/3.1272 View / Download Pdf
Vol 5-3 Research Article

Human Leukocyte Antigen (HLA) Alleles Prevent Metabolically-Induced Inflammation and Cerebrocortical Thinning in Gulf War Illness

Peka Christova1,2, Lisa M. James1,2,3, Adam F. Carpenter1,4, Scott M. Lewis1,4, Brian E. Engdahl1,5, Apostolos P. Georgopoulos1,2,3,4*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

5Department of Psychology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Independent lines of research have demonstrated that GWI is associated with elevated inflammatory markers, metabolic disruptions, and alterations in brain morphometry. Possessing specific Class II human leukocyte antigen (HLA) alleles, on the other hand, has been shown to protect against GWI and to be inversely associated with symptom severity in a dose-dependent manner. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, body mass index (BMI), and brain morphometry in GWI veterans with and without a protective HLA allele. Sixty-three veterans with GWI provided blood samples for evaluation of CRP and HLA, height and weight for calculating BMI, and underwent a 3T magnetic resonance imaging scan from which the volume, surface area, and cortical thickness of 68 cortical regions of interest (ROI) were determined. Results demonstrated that the CRP was highly significantly associated with BMI and cortical thinning in veterans lacking protective HLA alleles but not in those possessing a protective HLA allele. Given the role of HLA in antibody production against foreign antigens, the findings suggest that persistent foreign antigens stemming from lack of immunogenetic protection against them contribute to inflammation, metabolic disruption, and cortical thinning in GWI. The findings are discussed in terms of GW-related exposures that are known to result in inflammation.

DOI: 10.29245/2572.942X/2020/3.1273 View / Download Pdf
Vol 5-3 Research Article

Assessing Recovery from Mild Traumatic Brain Injury (Mtbi) using Magnetoencephalography (MEG): An Application of the Synchronous Neural Interactions (SNI) Test

Don R. Thorpe1,2, Brian E. Engdahl1-4, Arthur Leuthold2,3, Apostolos P. Georgopoulos1,2,3,5,6*

1Graduate Program in Cognitive Science, University of Minnesota, Minneapolis, Minnesota, USA

2Brain Sciences Center, Minneapolis VA Medical Center, Minneapolis, Minnesota, USA

3Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA

4Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA

5Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA

6Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, USA

Mild traumatic brain injury (mTBI) affects 22% of U.S. service members returning from Afghanistan and Iraq. Its diagnosis is challenging due to the heterogeneous structural and functional alterations inflicted by diverse injury mechanisms. mTBI is diagnosed mainly based on history (trauma) and clinical evaluation, since conventional neuroimaging methods, such as magnetic resonance imaging (MRI) and computerized tomography (CT) of the brain, typically do not reveal clear abnormalities. Similarly, the assessment of recovery following mTBI relies exclusively on clinical evaluation, based on several criteria. With respect to brain function, we hypothesized that mTBI reflects disturbed dynamic interactions among neuronal populations, a disturbance not detectable by the aforementioned techniques. In a quest for an objective tool to detect the presence of mTBI and assess recovery from it, here we used magnetoencephalography (MEG), a modality highly suited to assess the dynamic functional status of the brain. Specifically, we used the Synchronous Neural Interactions (SNI) test to evaluate functional brain status of 257 healthy (“control”) veterans, 19 veterans with a clinical diagnosis of active mTBI (“a-mTBI”), and 18 veterans who suffered from mTBI and, at the time of testing, were deemed to have recovered from it (“r-mTBI”). A stepwise linear discriminant analysis (LDA) yielded 37 SNI predictors that classified 100% correctly of all 257 control and 19 a-mTBI brains. We then used these predictors to classify the 18 r-mTBI brains to control or a-mTBI groups: 9 brains (50%) were classified as control, whereas the other 10 (50%) were classified as a-mTBI. These findings (a) document the power of SNI MEG to correctly detect a-mTBI, and (b) raise concerns regarding the validity of clinical assessment tools to pronounce recovery from mTBI. On the positive side, our results provide an objective brain-based continuum along which the status of a mTBI brain can be assessed. This measure, together with clinical evaluation, should appreciably reduce the uncertainty and considerably improve the quantification of recovery from mTBI, guiding further treatment.

DOI: 10.29245/2572.942X/2020/3.1274 View / Download Pdf
Vol 5-3 Mini Review

Montreal cognitive Assessment Score: A Screening Tool for Cognitive Function in Traumatic Brain Injury (TBI) Population

Keshav Mishra1, Devendra Purohit1*, Somnath Sharma1

1Department of Neurosurgery, SMS Medical College, Jaipur, India

Cognitive impairment is a major cause of morbidity and impaired quality of life in traumatic brain Injury (TBI) patients. Assessment of cognitive function using classically designed scales is time and resource intensive undertaking which also requires expert neuropsychiatrist referral. Montreal cognitive assessment Score (MoCA) is a brief screening tool designed to assess various cognitive domains which has been found to be more sensitive than Mini Mental State Examination (MMSE) score both in Alzheimer disease and subsequently in TBI population. Applied on TBI population, it reliably detects cognitive impairment in mild TBI, compared to normal controls and also differentiates cognitive disturbances between mild and severe TBI but its ability to differentiate cognitive function between mild and moderate TBI is equivocal.

DOI: 10.29245/2572.942X/2020/3.1238 View / Download Pdf
Vol 5-3 Review Article

Anti-Iglon5 Syndrome: What We Know So Far? A Non-Systematic Review

Caroline Figueiredo da Silva1*, Gustavo Figueiredo da Silva1, Washigton Luiz Gomes de Medeiros Junior1, Marcus Vinícius Magno Gonçalves2

1Medical student - Department of Medicine, University of the Region of Joinville (UNIVILLE), Brazil

2Medical Doctor, PhD and Professor of Neurology, University of the Region of Joinville (UNIVILLE), Brazil

The objective of this review is to provide an overview of the current knowledge of Anti-IgLON5 syndrome. The IgLON proteins are a family of cell adhesion molecules and the presence of antibodies against IgLON5 is crucial for the Anti-IgLON5 Syndrome diagnosis. This syndrome has an expanded clinical spectrum that involves prominent sleep disorder, progressive bulbar dysfunction, gait instability with abnormal eye movements reminiscent, and cognitive deterioration sometimes associated with chorea. The main neuropathological finding is the neuronal loss with hyperphosphorylated tau (p-Tau) protein accumulation at the hypothalamus, brainstem tegmentum, hippocampus, periaqueductal gray matter, medulla oblongata, and upper cervical cord. The exact pathogenesis is still unclear and involves a neurodegenerative process and autoimmune response. Early diagnosis is important to avoid unnecessary tests and prevent complications. Important resources for diagnosis are the antibody testing of serum and CSF for IgLON5-IgG. The Anti-IgLON5 syndrome mortality is high and new studies published described a good response to immune therapy. However, the response to immune therapy depends on some clinical and analytical characteristics. In addition, future studies are needed to thoroughly analyze the aspects of pathogenesis and treatment of this important pathological syndrome.

CNS - Central Nervous System

CSF - Cerebrospinal Fluid

IgG - Immunoglobulin G

MRI – Magnetic Resonance Imaging

PSP-like - Progressive Supranuclear Palsy

p-Tau - Hyperphosphorylated Tau Protein

REM - Rapid Eye Movement

DOI: 10.29245/2572.942X/2020/3.1269 View / Download Pdf
Vol 5-3 Research Article

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

Lisa M. James1,2,3, Apostolos P. Georgopoulos1,2,3,4*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Dementia and Parkinson’s disease are the two most common age-related neurodegenerative conditions. Recent studies have identified Human Leukocyte Antigen (HLA) Class II DRB1 alleles that are protective or neutral with respect to dementia. Here we extend those findings to evaluate the association of the population frequency of HLA DRB1 alleles with the prevalence of dementia and Parkinson’s disease in14 Continental Western European countries. Nine HLA DRB1 alleles were identified including four that are protective against dementia (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01), three that are neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01), and two susceptibility alleles (DRB1*11:01, DRB1*04:05). Results demonstrated that the population prevalence’s of dementia and Parkinson’s disease are highly correlated and that the association between the nine DRB1 alleles above and the population prevalence of dementia is highly overlapping with that of Parkinson’s disease. These findings suggest a common HLA Class II DRB1 profile. Given the diverse role of HLA Class II alleles in protection from foreign antigens, autoimmunity, and, possibly, neuroprotection, the shared HLA profile between dementia and Parkinson’s disease indicates that common immunogenetic mechanisms underlie the pathogenesis and manifestation of these diseases.

DOI: 10.29245/2572.942X/2020/3.1275 View / Download Pdf
Vol 5-3 Research Article

C-Reactive Protein is Associated with Brain White Matter Anomalies in Gulf War Illness

Peka Christova1,2, Lisa M. James1,2,3, Adam F. Carpenter1,4, Scott M. Lewis1,4, Rachel A. Johnson1, Brian E. Engdahl1,2,5, Apostolos P. Georgopoulos1,2,3,4*

1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA

2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA

3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA

4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

5Department of Psychology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Independent lines of research have documented elevated peripheral inflammation and brain white matter alterations in Gulf War Illness (GWI). We recently documented an association of C-reactive protein (CRP), a marker of inflammation, and decreased fornix white matter integrity in GWI. The aim of the present study was to extend those findings to evaluate the association between CRP and white matter anisotropy and diffusion throughout the brain in GWI. Sixty-three veterans with GWI provided blood samples for evaluation of CRP and underwent a 3T magnetic resonance imaging scan from which fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were obtained. An additional index characterizing the shape of the diffusion ellipsoid, Ca, which reflects deviation from sphericity (or isotropy) was obtained. Results demonstrated that CRP was significantly associated with decreased FA and Ca and with increased RD and MD, but not AD. These findings documenting a highly significant association between peripheral inflammation and specific white matter alterations in GWI are discussed in terms of GWI-related exposures that may promote systemic inflammation and deleterious neural effects downstream.

DOI: 10.29245/2572.942X/2020/3.1276 View / Download Pdf