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.

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.

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.

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.

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.

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.

Dendritic and spinal pathology of the Purkinje cells from the human cerebellar vermis in Alzheimer's disease.

BACKGROUND: Alzheimer's disease constitutes one of the main causes of dementia. It is clinically characterized by memory impairment, deterioration of intellectual faculties and loss of professional skills. Furthermore changes in equilibrium and limb coordination are clinically demonstrable in persons with Alzheimer's disease. In the present study we tried to figure out possible changes of the Purkinje cells in Alzheimer's disease brains. SUBJECTS AND METHODS: We studied the Purkinje cells from the vermis of the cerebellum in 5 Alzheimer' disease brains Golgi technique. RESULTS: In the Purkinje cells from the inferior surface of the cerebellar hemispheres severe dendritic and spinal pathology consisting of loss of distal dendritic segments and alterations of dendritic spine morphology can be noticed in Alzheimer's disease brains. CONCLUSIONS: The morphological and morphometric estimation of the dendrites and the dendritic spines of the Purkinje cells from the inferior surface of the cerebellar hemispheres in Alzheimer's disease brains revealed substantial alterations of the dendritic arborization and marked loss of the dendritic spines, which may be related to cognitive impairment and motor deficits in Alzheimer's disease.

Dendritic, axonal, and spinal pathology of the Purkinje cells and the neurons of the dentate nucleus after long-term phenytoin administration: a case report.

Phenytoin is a commonly prescribed anticonvulsant drug; however, there is evidence that long-term administration is related to cerebellar ataxia, cerebellar atrophy, loss of Purkinje cells, and hyperplasia of Bergman glia cells. The aim of the present study was to detect and describe any possible alterations of the Purkinje cells, and neurons of the dentate nucleus, as those can be seen with the use of silver impregnation techniques, such as Golgi and Nauta method. The study was performed on a 7-year-old boy who was under phenytoin treatment for more than 3.5 years and had clinical manifestations of cerebellar ataxia. Golgi silver impregnation technique revealed substantial loss of dendritic spines and tertiary dendritic branches, both on the Purkinje cells and the neurons of the dentate nucleus, whereas the Nauta method demonstrated swollen and degenerated axons of Purkinje cells.

Dendritic and spinal alterations of the spiny stellate cells of the human visual cortex during normal aging.

The visual cortex undergoes age related changes that have been studied mainly in rats Maccaca Mulata, and human beings. Despite the fact that there is no extensive neuronal loss in aged brains, a lot of important pathological changes are found in the morphology of the neurons. The present study describes the morphological alterations of the spiny stel-late cells of the human primary visual cortex during normal aging, using Golgi method, Golgi-Nissl staining and Nissl staining. Two types of spiny stellate cells have been studied. the first one located at layer 4Cß and the second one located at layer 4Cß. Even if some spiny stel-late cells retain high number of primary dendrites in the aged group there seems to be important spine loss, and extensive dendrite pathology. Age-related changes were more significant in spiny stellate cells of layer 4Cß. Dendritic and spinal alterations described in the present study could explain the decline in visual functions during normal aging.

Dendritic pathology and spinal loss in the visual cortex in Alzheimer's disease: a Golgi study in pathology.

Alzheimer's disease is a neurodegenerative disorder characterized by progressive decline in memory, loss of professional skills, impairment of judgement and behavior, and decline in social performances. In terms of neuropathology, the morphological hallmarks of the disease are the accumulation of alpha-beta peptide and the neurofibrillary degeneration, associated with synaptic alterations, involving mostly the dendritic spines. This study is based on the morphological analysis of 10 brains, 5 of which were obtained from patients who suffered from Alzheimer's disease and 5 from nondemented senile individuals used as control group. The segments taken in major from the occipital lobe were studied with the use of Golgi method, as well as Gallyas' and Bielschowski' s staining methods. In most of the pyramidal cells in the affected brains, there seems to be important spine loss and extensive dendrite pathology. Apical dendrites are distorted and tortuous. Horizontal dendritic arborization is severely decreased leading to an amputated, bell-shaped cell soma. Senile plaques have been often revealed, and neurofibrillary changes have also been noticed.

Morphological changes of the human purkinje cells and deposition of neuritic plaques and neurofibrillary tangles on the cerebellar cortex of Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder, characterized by progressive decline in memory and in social performance. The morphological hallmarks of the disease are neuronal loss, loss of dendritic spines, neurofibrillary degeneration and neuritic plaques mainly in the hippocampus and the cortex of the cerebral hemispheres. This study is based on the morphological analysis of the cerebellar cortices of eight brains, 4 patients suffered from Alzheimer's disease and 4 normal controls, by Golgi method, as well as Nissl, Gallyas', Bielschowsky's, Methenamine Silver staining and Congo red methods. Although typical neuritic plaques were not seen in the cerebellar cortex and the diffuse plaques found in the cerebellum in far smaller proportion than plaques in the prefrontal and parietal cortices of the same cases, Golgi impregnation technique revealed a loss of Purkinje cells and a marked decrease in the density of dendritic arborization.

Brain SPECT findings of anosognosia in Alzheimer's disease.

Anosognosia is a common symptom of dementia. The aim of this study was to evaluate the contribution of different regions of the brain to anosognosia in Alzheimer's disease (AD) brains using single photon emission computed tomography (SPECT). Forty-two patients with AD were included in this study. After clinical interviews with the patients and their relatives, the patients were divided into two groups: Anosognosia and No-anosognosia. The patients were studied regarding the severity of dementia. They underwent SPECT with HMPAO and regional cerebral blood flow (rCBF) was measured. Regional CBF significantly differed between Anosognosia and No-anosognosia groups in right prefrontal (P < or = 0.02), right inferior parietal (P < or = 0.00), and right (P < or = 0.01) and left (P < or = 0.01) medial temporal cortex. There was a significant correlation between the severity of dementia and rCBF in medial temporal regions. When comparisons were made between mild and moderate stages separately, the 'right inferior parietal region' was the common region which showed hypoperfusion in both anosognosia subgroups. We conclude that anosognosia may be a reflection of functional impairment in right prefrontal, right frontal and especially right inferior parietal regions in AD.

Plasma levels of amyloid beta1-42 are independent of neuronal function in Alzheimer's disease.

The aggregation of amyloid-beta42 (Abeta42) constitutes one of the major pathogenic events in Alzheimer's disease (AD), and the study of regional cerebral blood flow (rCBF), using single photon emission computed tomography (SPECT), aids the diagnosis of AD. In this study, we evaluated whether there was a correlation between rCBF in brain regions and plasma levels of Abeta1-42 in AD. 29 patients (mean age 71 +/- 9) with a diagnosis of AD who fulfilled NINCDS-ADRDA criteria with a mean Mini-Mental Status Examination score of 15 +/- 9 and 16 normal controls (mean age 64 +/- 8) underwent SPECT brain imaging with hexamethylpropylene amine oxime, and semiquantitative analysis of rCBF was performed. Plasma samples were collected the same day of the SPECT and plasma Abeta1-42 measured by ELISA. A significant reduction of rCBF was observed in most regions in AD compared to controls, whereas mean plasma Abeta42 did not differ between the two groups. There was no correlation between rCBF in any region and plasma Abeta42 nor any correlations between gender, age, and severity with plasma levels of Abeta42. Since rCBF is coupled to neuronal activity, we conclude that plasma Abeta1-42 concentration is independent of neuronal function in every single region of the brain.

A case of intractable epilepsy in a double cortex syndrome.

This article describes a very rare case of a double cortex syndrome in a man aged 32 years old who started from the age of 14 years having seizures and many other epileptic manifestations that continue to the present age, being always intractable to various therapeutic regimes. The neuroimaging revealed cortical ectopias in the cingulum, the visual cortex, in the middle part of the superior temporal gyrus, in the frontal pole as well as in the middle area of precentral gyrus. This article attempts to underline the behavioral disturbances, the learning difficulties, the psychological fluctuations, and the multitude of the seizures that have been released during the clinical course of the patient. The article attempts to correlate the clinical phenomena of the patient and the resistance to therapeutical interventions with the morphological changes as they have been visualized by the neuroimaging techniques, reviewing in addition relevant cases from the literature.

Systemic immune aberrations in Alzheimer's disease patients.

The role of chronic inflammation in the pathogenesis of Alzheimer's disease (AD) has been implied in a plethora of studies. The objective of the present study was to evaluate the immune alterations and the immunological markers in patients suffering from AD. IL-1alpha, IL-2, IL-6, IL-8, IL-10, TNF-alpha cytokine and helper/inducer (CD4), suppressor/cytotoxic (CD8) T lymphocyte levels were investigated in patients with various degrees of cognitive impairment (mild-moderate and severe stage), as well as in age-matched non demented controls. Cytokines were measured using the ELISA immunoassay method and lymphocytes using flow cytometry. Results showed a significant TNF-alpha increase in patients of severe stage serum compared to controls as well as a significant decrease of CD4 lymphocyte subpopulation levels in patients of severe stage compared to those of mild-moderate stage patients and controls. No significant differences were observed on IL-1alpha, IL-2, IL-6, IL-8, IL-10 cytokine levels and on CD8, CD4/CD8 lymphocyte subpopulations levels between patients and controls neither between mild moderate and severe stage patients. CD4 lymphocyte subpopulation and cytokine IL-2 were revealed as having a significant relationship (positive and negative respectively) with the MMSE score of patients. Data suggest the existence of detectable changes of peripheral immune system in AD.

Clinical case: vermis hypoplasia with features of Smith-Lemli-Opitz syndrome.

This article attempts to describe a very unusual case of a boy aged 15, who has had intractable epileptic phenomena, mental retardation, megalocephaly, micrognathy, syndactyly, small tongue, hypoplastic genitalia, gynecomasty, obesity, and slight left body hemiatrophy. Neurologically the patient has had hypotonia of the lower limbs, cerebellar dysfunction including horizontal nystagmus, bilateral intention tremor, dysdiadokokinesia, gait ataxia. The clinical investigation revealed low plasma cholesterol and hypoplasia of the vermis in MRI. The epileptic phenomena were intractable and polymorphous. One should have thought that this is an unusual case of Smith-Lemli-Opitz syndrome associated with features of Joubert syndrome.