Post-Concussion Syndrome and Chronic Traumatic Encephalopathy: Narrative Review on the Neuropathology, Neuroimaging and Fluid Biomarkers.

Traumatic brain injury is a significant public health issue and represents the main contributor to death and disability globally among all trauma-related injuries. Martial arts practitioners, military veterans, athletes, victims of physical abuse, and epileptic patients could be affected by the consequences of repetitive mild head injuries (RMHI) that do not resume only to short-termed traumatic brain injuries (TBI) effects but also to more complex and time-extended outcomes, such as post-concussive syndrome (PCS) and chronic traumatic encephalopathy (CTE). These effects in later life are not yet well understood; however, recent studies suggested that even mild head injuries can lead to an elevated risk of later-life cognitive impairment and neurodegenerative disease. While most of the PCS hallmarks consist in immediate consequences and only in some conditions in long-termed processes undergoing neurodegeneration and impaired brain functions, the neuropathological hallmark of CTE is the deposition of p-tau immunoreactive pre-tangles and thread-like neurites at the depths of cerebral sulci and neurofibrillary tangles in the superficial layers I and II which are also one of the main hallmarks of neurodegeneration. Despite different CTE diagnostic criteria in clinical and research approaches, their specificity and sensitivity remain unclear and CTE could only be diagnosed post-mortem. In CTE, case risk factors include RMHI exposure due to profession (athletes, military personnel), history of trauma (abuse), or pathologies (epilepsy). Numerous studies aimed to identify imaging and fluid biomarkers that could assist diagnosis and probably lead to early intervention, despite their heterogeneous outcomes. Still, the true challenge remains the prediction of neurodegeneration risk following TBI, thus in PCS and CTE. Further studies in high-risk populations are required to establish specific, preferably non-invasive diagnostic biomarkers for CTE, considering the aim of preventive medicine.

Coronaviruses and their relationship with multiple sclerosis: is the prevalence of multiple sclerosis going to increase after the Covid-19 pandemia?

The purpose of this review is to examine whether there is a possible (etiological/triggering) relationship between infection with various Coronaviruses, including Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2), the virus responsible for the Coronavirus disease-19 (Covid-19) pandemia, and Multiple Sclerosis (MS), and whether an increase of the prevalence of MS after the current Covid-19 pandemia should be expected, examining new and preexisting data. Although the exact pathogenesis of MS remains unknown, environmental agents seem to greatly influence the onset of the disease, with viruses being the most popular candidate. Existing data support this possible etiological relationship between viruses and MS, and experimental studies show that Coronaviruses can actually induce an MS-like demyelinating disease in animal models. Findings in MS patients could also be compatible with this coronaviral MS hypothesis. More importantly, current data from the Covid-19 pandemia show that SARS-CoV-2 can trigger autoimmunity and possibly induce autoimmune diseases, in the Central Nervous System as well, strengthening the viral hypothesis of MS. If we accept that Coronaviruses can induce MS, it is reasonable to expect an increase in the prevalence of MS after the Covid-19 pandemia. This knowledge is of great importance in order to protect the aging groups that are more vulnerable against autoimmune diseases and MS specifically, and to establish proper vaccination and health policies.

Morphological and morphometric changes in the Purkinje cells of patients with essential tremor.

Essential tremor (ET) is a progressive neurological syndrome characterised by involuntary tremors of the hands or arms, head, jaw and voice. The pathophysiology of ET is not clearly understood yet. However, previous studies have reported several changes in the brain of patients with ET. One of the brain areas extensively investigated is the cerebellum. In the present study, a morphometric analysis of Purkinje cells in patients with ET and ET-plus was performed, and subsequently compared with normal controls using the Golgi silver staining method and 3D neuronal reconstruction. Substantial morphological changes were uncovered in the Purkinje cells of patients with ET compared with normal controls, including a decreased dendritic length and field density, an overall loss of terminal branches and a decreased density of dendritic spines.

Morphological alterations of the pyramidal and stellate cells of the visual cortex in schizophrenia.

Schizophrenia is a severe brain disorder characterized by certain types of delusion, hallucination and thought disorder. Studies have revealed impaired synaptic plasticity and reduced gamma-aminobutyric acid levels of the visual cortex in patients with schizophrenia. While previous work established a critical role for interneurons and cortical connectivity in the generation of hallucinations, the present study set out to examine the morphology of pyramidal cells and interneurons from layers 3 and 4 in the primary visual cortex from schizophrenic brains and to identify any dendritic and spinal alterations in comparison to normal control brains. The morphological and morphometric changes of the pyramidal cells and the interneurons of the visual cortices of 10 brains obtained from patients with schizophrenia, in comparison to 10 age-matched controls, were studied using the Golgi method and 3D neuronal reconstruction techniques. Analysis using the Golgi impregnation technique revealed a significant loss of distal dendritic segments, tortuous branches and varicosities and an overall restriction of the dendritic field in the brains of schizophrenic patients in both pyramidal cells and in aspiny interneurons. The present results may explain certain clinical phenomena associated with the visual cortex usually encountered in schizophrenia.

Unraveling the Possible Routes of SARS-COV-2 Invasion into the Central Nervous System.

PURPOSE OF REVIEW: To describe the possible neuroinvasion pathways of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2), the virus responsible for the Coronavirus disease-19 (Covid-19) pandemic. RECENT FINDINGS: We present data regarding the family of Coronaviruses (CoVs) and the central nervous system (CNS), and describe parallels between SARS-CoV-2 and other members of the family, which have been investigated in more depth and combine these findings with the recent advancements regarding SARS-CoV-2. SUMMARY: SARS-CoV-2 like other CoVs is neuroinvasive, neurotropic and neurovirulent. Two main pathways of CNS penetration seem to be the strongest candidates, the hematogenous and the neuronal. Τhe olfactory route in particular appears to play a significant role in neuroinvasion of coronaviruses and SARS-CoV-2, as well. However, existing data suggest that other routes, involving the nasal epithelium in general, lymphatic tissue and the CSF may also play roles in SARS-CoV-2 invasion into the CNS.

Purkinje Cells Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the main causes of dementia in senium and presenium. It is clinically characterized by memory impairment, deterioration of intellectual faculties, and loss of professional skills. The cerebellum is a critical part in the distributed neural circuits participating not only in motor function but also in autonomic, limbic, and cognitive behaviors. In present study, we aim to investigate the morphological changes in the Purkinje cells in different cerebellar regions in AD and to correlate them with the underlying AD pathology. Purkinje cells exhibit significant morphometric alterations in AD and prominently in the anterior lobe which is related to higher cognitive functions. The present study gives new insights into the cerebellar pathology in AD and confirms that Purkinje cells pathology is a key finding in AD brains and that AD is characterized by regional-specific atrophy picked in the anterior cerebellar lobe.

Relating the blood-thinning effect of pentoxifylline to the reduction in the elastic modulus of human red blood cells: an in vivo study.

The blood thinning properties of pentoxifylline have been attributed to its ability to increase the deformability of red blood cells and improve their rheological properties. To interpret and substantiate these observations a novel approach is taken by measuring the stiffness of individual red blood cells from healthy humans before and after subscription to pentoxifylline for nine days. Atomic force microscopy nanoindentation experiments reveal that the elastic modulus of the red blood cells decreased by 30%-40%, after pentoxifylline subscription. This decrease in elastic modulus is related to the ability of pentoxifylline to increase the production of ATP and lower Ca2+ concentrations in red blood cells. The present in vivo experiments provide a deeper understanding of the mode of action of pentoxifylline, and pave the way to using indentation in medicine. A further unique advantage of this study is that it was performed on healthy volunteers, rather than requiring in vitro incubation.

Does cognitive dysfunction correlate with neurofilament light polypeptide levels in the CSF of patients with multiple sclerosis?

OBJECTIVE: To investigate whether neurofilament light polypeptide (NfL) level in cerebrospinal fluid (CSF), currently a prognostic biomarker of neurodegeneration in patients with multiple sclerosis (MS), may be a potential biomarker of cognitive dysfunction in MS. METHODS: This observational case-control study included patients with MS. CSF levels of NfL were determined using enzyme-linked immunosorbent assay. Cognitive function was measured with the Brief International Cognitive Assessment for MS (BICAMS) battery and Paced Auditory Serial Addition Test (PASAT3), standardized to the Greek population. RESULTS: Of 39 patients enrolled (aged 42.7 ± 13.6 years), 36% were classified as cognitively impaired according to BICAMS z-scores (-0.34 ± 1.13). Relapsing MS was significantly better than progressive forms regarding BICAMS z-score (mean difference [MD] 1.39; 95% confidence interval [CI] 0.54, 2.24), Symbol Digit Modality Test score (MD 1.73; 95% CI 0.46, 3.0) and Greek Verbal Learning Test (MD 1.77; 95% CI 0.82, 2.72). An inversely proportional association between CSF NfL levels and BICAMS z-scores was found in progressive forms of MS (rp = -0.944). CONCLUSIONS: This study provides preliminary evidence for an association between CSF NfL levels and cognition in progressive forms of MS, which requires validation in larger samples.

Purkinje cells pathology in schizophrenia. A morphometric approach.

OBJECTIVES: Schizophrenia is a brain disorder that affects more than 21 million people worldwide. Ventricle enlargement and reduction in the volume of the temporal lobe overall and in medial temporal structures constitutes the main macroscopic findings, whilst synaptic and spinal changes as well as gliosis in the hippocampal formation, the prefrontal and the entorhinal cortex stand among cardinal microscopic findings in the schizophrenic brains. In recent years, accumulated evidence comes to light about the role of cerebellum in the pathophysiology of schizophrenia. MATERIALS AND METHODS: The present study is based on the morphological analysis and 3D neuronal reconstruction of the Purkinje cells from 10 schizophrenic brains and 10 normal controls. RESULTS: Significant morphological alterations such as loss of distal and terminal dendritic branches and decrease of the density of the dendritic spines constitute the main morphological findings found in the present study. CONCLUSIONS: The present findings may be added to accumulated evidence on macroscopic and microscopic pathology of the cerebellum in schizophrenia. Morphological alterations of Purkinje cells seem to be a central feature of neuropathology of schizophrenia, reflecting to impairment of neuronal connectivity and functionality, and related to motor and cognitive symptoms.

Spinal Alterations of Reil Insula in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that involves numerous cellular and biochemical mechanisms resulting in synaptic alterations and extensive neuronal loss. It is primarily characterized by impairment of memory, associated frequently with mood disorders. Continuous studies have shown that insula may be an important target of AD, but neuropathological alterations have not been described extensively. In the present study, we attempted to describe the morphometric and morphological changes of the spines of Reil insula in AD in comparison with normal aging using a silver impregnation technique. We classified spines into 3 types: (1) long neck, (2) short stubby, and (3) other types; and we measured and correlated the length of them in normal controls and in individuals with AD using ImageJ application. Statistical analysis was based on the Student t test on the basis of 360 cells in SPSS v.17.0, and significance was taken as P < .05.

Mammillary Bodies in Alzheimer's Disease: A Golgi and Electron Microscope Study.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by irreversible memory decline, concerning no rarely spatial memory and orientation, alterations of the mood and personality, gradual loss of motor skills, and substantial loss of capacities obtained by previous long education. We attempted to describe the morphological findings of the mammillary bodies in early cases of AD. Samples were processed for electron microscopy and silver impregnation techniques. The nuclei of the mammillary bodies demonstrated a substantial decrease in the neuronal population and marked abbreviation of dendritic arbors. Decrease in spine density and morphological abnormalities of dendritic spines was also seen. Synaptic alterations were prominent. Alzheimer's pathology, such as deposits of amyloid-ß peptide and neurofibrillary degeneration, was minimal. Electron microscopy revealed mitochondrial alterations and fragmentation of Golgi apparatus, associated frequently with synaptic pathology.

Brain capillaries in Alzheimer's disease.

Alzheimer's disease is the most common cause of irreversible dementia, affecting mostly the presenile and senile age, shaping a tragic profile in the epilogue of the life of the suffering people. Due to the severity and the social impact of the disease an ongoing research activity is in climax nowadays, associated with many legal, social, ethical, humanitarian, philosophical and economic considerations. From the neuropathological point of view the disease is characterized by dendritic pathology, loss of synapses and dendritic spines, affecting mostly selective neuronal networks of critical importance for memory and cognition, such as the basal forebrain cholinergic system, the medial temporal regions, the hippocampus and many neocortical association areas. Tau pathology consisted of intracellular accumulation of neurofibrillary tangles of hyperphosphorilated tau protein and accumulation of Aß-peptide's deposits, defined as neuritic plaques, are the principal neuropathological diagnostic criteria of the disease. The neurotoxic properties of the oligomerics of the Aß-peptide and tau mediated neurodegeneration are among the main causative factors of impaired synaptic plasticity, neuronal loss, dendritic alterations and tremendous synaptic loss. The gradual degeneration of the organelles, particularly mitochondria, smooth endoplasmic reticulum and Golgi apparatus, visualized clearly by electron microscopy (EM), emphasize the importance of the oxidative stress and amyloid toxicity in the pathogenetic cascade of the disease. The vascular factor may be an important component of the whole spectrum of the pathogenesis of AD. It is of substantial importance the concept that the structural alterations of the brain capillaries, may contribute in the pathology of AD, given that the disruption of the BBB may induce exacerbation of AD pathology, by promoting inflammation around the blood capillaries and in the neuropile space diffusely. From the morphological point of view, silver impregnation techniques revealed a marked tortuosity of the capillaries in early cases of AD. In addition, the distance between two branch points is longer in capillaries of AD brains, whereas the branch point density as well as the ratio of the branch point density to astrocytic density is substantially decreased in AD in comparison with age matched normal controls. EM revealed, that the most frequent morphological alterations of the brain capillaries in AD consist of thickness, splitting and duplication of the basement membrane, reduction of the length of tight junctions, decrease of the number of tight junctions per vessel length, associated as a rule, with morphological alterations of the mitochondria of the endothelial cells, the pericytes and the perivascular astrocytic processes. The number of the pinocytotic vesicles is substantially increase in the endothelium of the brain capillaries in AD in comparison with age matched normal controls. Endothelial cells play a very important role in the transport systems in the brain. Subsequently, the dysfunction of the endothelial cells and the disruption of the BBB may induce serious impairment in the transport system. The dysfunction of the brain capillaries may result in releasing neurotoxic factors, such as thrombin, pro-inflammatory cytokines, nitric oxide and leukocyte adhesion molecules, and in abnormal regulation of Aß-peptide homeostasis in the brain. The impairment of the brain capillaries in structures of the brain, which are crucial for the homeostatic equilibrium, such as the hypothalamic nuclei, may induce autonomic dysfunction, which usually occur in the advanced stages of AD, affecting dramatically the viability of the patients. Degeneration of the pericytes is also observed emphasizing even more the importance of the vascular factor in AD. Pericytes may serve as integrators, coordinators and effectors of blood-brain barrier structure and maintenance, and play a key role in microvascular stability, capillary density and angiogenesis. The correlation between AD pathology and vascular pathology, at the level of brain capillaries and BBB, raises the rational question, whether the efficient treatment of the vascular factor might be beneficial for the patients who suffer from AD. It is reasonable that any protection of the brain capillaries at the initial stages of the disease might contribute in the abbreviation of the long chain of pathological alteration, which occur following the disruption of the BBB, which serves as the essential interface between the vascular system and the brain.

Age-related dendritic and spinal alterations of pyramidal cells of the human visual cortex.

INTRODUCTION: Normal aging is characterized by deterioration of visual abilities, affecting mainly visual acuity, contrast and wavelength sensitivity. In the present study we attempted to describe the morphological and morphometric alterations of the dendrites and the dendritic spines of the pyramidal cells of the visual cortex during normal aging, in order to approach the visual impairment of aged individuals from a neuropathological point of view. MATERIAL AND METHODS: We studied the visual cortex in 20 brains using the Golgi technique. RESULTS: In pyramidal cells, which represent the majority of cortical neurons, age-related pathology can be observed in cell somata as well as, most importantly, in dendrite number and morphology. The apical dendrites of some pyramidal cells are distorted and tortuous. Horizontal dendritic arborization is also severely decreased. These alterations were more prominent in the corticocortical pyramidal neurons of the 5th layer. CONCLUSIONS: The morphological and morphometric assessment of the dendrites and the dendritic spines in the visual cortex in normal aging revealed substantial alterations of the dendritic arborization and marked loss of the dendritic spines, which may be related to visual impairment even in normal aging.

Staining of dead neurons by the Golgi method in autopsy material.

Golgi silver impregnation techniques remain ideal methods for the visualization of the neurons as a whole in formalin fixed brains and paraffin sections, enabling to obtain insight into the morphological and morphometric characters of the dendritic arbor, and the estimation of the morphology of the spines and the spinal density, since they delineate the profile of nerve cells with unique clarity and precision. In addition, the Golgi technique enables the study of the topographic relationships between neurons and neuronal circuits in normal conditions, and the following of the spatiotemporal morphological alterations occurring during degenerative processes. The Golgi technique has undergone many modifications in order to be enhanced and to obtain the optimal and maximal visualization of neurons and neuronal processes, the minimal precipitations, the abbreviation of the time required for the procedure, enabling the accurate study and description of specific structures of the brain. In the visualization of the sequential stages of the neuronal degeneration and death, the Golgi method plays a prominent role in the visualization of degenerating axons and dendrites, synaptic "boutons," and axonal terminals and organelles of the cell body. In addition, new versions of the techniques increases the capacity of precise observation of the neurofibrillary degeneration, the proliferation of astrocytes, the activation of the microglia, and the morphology of capillaries in autopsy material of debilitating diseases of the central nervous system.

The hypothalamus in Alzheimer's disease: a Golgi and electron microscope study.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by irreversible decline of mental faculties, emotional and behavioral changes, loss of motor skills, and dysfunction of autonomic nervous system and disruption of circadian rhythms (CRs). We attempted to describe the morphological findings of the hypothalamus in early cases of AD, focusing our study mostly on the suprachiasmatic nucleus (SCN), the supraoptic nucleus (SON), and the paraventricular nucleus (PVN). Samples were processed for electron microscopy and silver impregnation techniques. The hypothalamic nuclei demonstrated a substantial decrease in the neuronal population, which was particularly prominent in the SCN. Marked abbreviation of dendritic arborization, in association with spinal pathology, was also seen. The SON and PVN demonstrated a substantial number of dystrophic axons and abnormal spines. Alzheimer's pathology, such as deposits of amyloid-ß peptide and neurofibrillary degeneration, was minimal. Electron microscopy revealed mitochondrial alterations in the cell body and the dendritic branches. The morphological alterations of the hypothalamic nuclei in early cases of AD may be related to the gradual alteration of CRs and the instability of autonomic regulation.

Dendritic and spinal alterations of neurons from Edinger-Westphal nucleus in Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, causing a progressive decline of intellectual faculties, impairment of behavior and social performance, and impairment of speech eloquence, associated with various neurological manifestations based on a variable neuropathological background. Edinger-Westphal nucleus is a selective target of Alzheimer pathology early in the course of the disease. We attempted to determine the morphological alterations of the dendrites and the dendritic spines in Edinger-Westphal nucleus of 7 cases that fulfilled the diagnostic criteria for Alzheimer's disease. For the histological study, we applied (a) routine neuropathological techniques and (b) rapid Golgi method. We proceeded to 3D neuronal reconstruction for the estimation of dendritic and spinal changes in Alzheimer's disease. The morphological and morphometric analysis revealed a substantial neuronal loss and synaptic alterations in Edinger-Westphal nucleus in all the cases of Alzheimer's disease. Distal dendritic branches are prominently affected. The neuronal loss and alteration of the spines in Edinger-Westphal nucleus in Alzheimer's disease may be related to the exaggerated pupillary reaction to cholinergic antagonists. Furthermore, the vulnerability of distal branches to Alzheimer's disease might be related to neuroplasticity impairment.

The fine structure of ependymomas.

Electron microscopy is a useful diagnostic technique in order to confirm or establish a definitive diagnosis in brain tumors that may have an atypical histological pattern, which requires a concrete diagnosis. In ependymomas, electron microscopy reveals morphological characters that have a pathognomonic diagnostic value, therefore allowing a definitive diagnosis. The main fine structural criteria of ependymomas consist of the numerous microvilli and cilia, which are incorporated in the cell body or extended freely in the intracellular space; the centriole or blepharoplast, which is located in the basis of the cilia; the large number of the fragmented microtubules in the perikaryon and the cellular processes (any small cellular projection into the neutrophil or intracellular space); the junctional apparatus between the cells, such as zonula adherens, zonula occludens and puncta adherentia; the basement membrane-like structure, seen in papillary ependymomas and ependymomas of the filum terminale; and the elongated cells in the loose intracellular space, commonly seen in myxopapillary ependymomas.

Golgi apparatus and protein trafficking in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degeneration of the brain, inducing memory decline, inability in learning, and behavioral alterations, resulting progressively in a marked deterioration of all mental activities and eventually a vegetative state. The main causative factor, however, is still unclear. The implication of amyloid-ß, AßPP, tau protein, the selective loss of neurons, the alteration of the synapses, the cytoskeletal changes, and the morphological alterations of the brain capillaries contribute substantially to the pathogenetic profile of the disease, without sufficiently enlightening the initial steps of the pathological procedures. The ultrastructure of the neuronal organelles as well as histochemical studies revealed substantial alterations, primarily concerning mitochondria. In this study, the morphological and morphometric alterations of the Golgi apparatus (GA) are described in the Purkinje cells of the cerebellum in twenty AD brains, studied with electron microscopy. As it is well established, GA has a very important role to play in many procedures such as glycosylation, sulfation, and proteolysis of protein systems, which are synthesized in the endoplasmic reticulum of nerve cells and glia. GA may also play a crucial role in protein trafficking and in misfolding of protein aggregates. In addition, the hyperphosphorylation of tau protein is closely related with the pathology of GA. In AD cases, described in this study, an obvious fragmentation of the cisternae of GA was observed in the Purkinje cells of the vermis and the cerebellar hemispheres. This alteration of GA may be associated with alterations of microtubules, impaired protein trafficking, and dendritic, spinal, and synaptic pathology, since protein trafficking plays an essential role in the three dimensional organization of the dendritic arbor and in the integrity of the synaptic components.

The probable auto-antigenic role of lipids (anti-ganglioside antibodies) in the pathogenesis of Alzheimer's disease.

We examined the sera of 103 demented patients of a mean age of 75 years and 60 age-matched healthy individuals, using ELISA, to investigate the levels of IgM antibodies against GM1, GD1b, and GQ1b gangliosides and their possible correlation with clinical parameters (age, severity, and type of dementia). All the individuals that demonstrated positive titers of anti-ganglioside antibodies were demented patients whereas normal controls showed borderline or negative values. Significant correlation was revealed between IgM anti-GM1 and both the age of the patients and the severity of dementia. Most of the patients with increased IgM anti-GD1b titers suffered from AD.