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.

Epilepsy, behavior, and art (Epilepsy, Brain, and Mind, part 1).

Epilepsy is both a disease of the brain and the mind. Brain diseases, structural and/or functional, underlie the appearance of epilepsy, but the notion of epilepsy is larger and cannot be reduced exclusively to the brain. We can therefore look at epilepsy from two angles. The first perspective is intrinsic: the etiology and pathophysiology, problems of therapy, impact on the brain networks, and the "mind" aspects of brain functions - cognitive, emotional, and affective. The second perspective is extrinsic: the social interactions of the person with epilepsy, the influence of the surrounding environment, and the influences of epilepsy on society. All these aspects reaching far beyond the pure biological nature of epilepsy have been the topics of two International Congresses of Epilepsy, Brain, and Mind that were held in Prague, Czech Republic, in 2010 and 2012 (the third Congress will be held in Brno, Czech Republic on April 3-5, 2014; www.epilepsy-brain-mind2014.eu). Here, we present the first of two papers with extended summaries of selected presentations of the 2012 Congress that focused on epilepsy, behavior, and art.

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.

Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer's disease patients.

BACKGROUND: It is believed that in Alzheimer's disease (AD) some areas of the brain are particularly vulnerable to specific degenerative processes and that they could exhibit neuronal dysfunction in the earliest stage of the disease. The implications of the hippocampus in memory processes are very well known and it is likely that the hippocampus would be among the first areas of the brain affected by the pathogenic mechanisms occurring in AD. However, the distinction between the neurodegenerative changes that accompany normal ageing and those that characterize AD is not clear. Also, the distribution of the hippocampal cell loss in both normal aging and AD is not very well understood. SUBJECTS AND METHODS: In this context, we focused on the quantification of the neuronal density in the four specific areas of the hippocampus (CA1-CA4) of AD brains, as compared to an age-matched control group, by using the Nissl staining technique. RESULTS: We found a significant reduction of neuronal density especially in the CA1 and CA3 hippocampal areas. The most prominent decrease was found at the CA1 area level, as compared to all other 3 areas which were analyzed. CONCLUSIONS: In the present study we managed to demonstrate and confirm a significant neuronal loss of hippocampus in AD, as compared to an age-matched control group. Moreover, it seems that this decrease of hippocampal neuronal density is more prominent especially at the CA1 and also in the CA3 hippocampal areas. This could have important implications in the design of therapeutic and investigative strategies of AD. However, larger samples are necessary in order to provide the basis for firmer conclusions in this area of research.

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.

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.

Increase in interleukin-6 levels is related to depressive phenomena in the acute (relapsing) phase of multiple sclerosis.

The aim of the present study was to investigate the possible connection between interleukin-6, the acute phase (relapse) of multiple sclerosis (MS), and depression. The authors determined and statistically evaluated the levels of interleukin-6 and its soluble receptor in the serum of 28 MS patients in relapsing, 14 MS patients in remission, and 20 control subjects, as well as the presence of depression among these individuals. The results of our study indicate that depression is not only very common during relapses of MS, but also that the levels of IL-6 increase during the acute phase of the disease, especially when depression is detected.

Synaptic plasticity: a unifying model to address some persisting questions.

Since it was first observed, synaptic plasticity has been considered as the experimental paradigm most likely to provide us with an understanding of how information is stored in the vertebrate brain. Various types have been demonstrated over these past 45 years, most notably long-term potentiation and long-term depression, and their established characteristics as well as their induction and consolidation requirements are highly indicative of this plasticity being the substrate for skills acquisition and mnemonic engraving. The molecular, biochemical, and structural models that have been proposed in the past, although most accommodate some aspect of synaptic plasticity observations, admittedly cannot offer a universally functional connection between all the phenomena that surround and result in the different modifications of synaptic efficacy. As a result, there are a number of persisting questions. In an attempt toward synthesis, we reviewed the most important studies in the field and believe that we can now propose a unifying Model for synaptic plasticity that can accommodate the experimental evidence and reconcile most of the contradictions. Moreover, from this model emerge potential answers to several unyielding questions, namely, accounting for the induction and expression of long-term depression, identifying the plasticity switch, offering a possible explanation for the sliding modification threshold, and proposing a new mechanism for synaptic tagging.

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 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.

Epidemiology of multiple sclerosis in Europe: a review.

Multiple sclerosis (MS) is a progressive demyelinating and degenerative disease of the CNS with symptoms dependent on the type of the disease and the site of lesions. During the progression of the disease, symptoms become more permanent and progressive disability ensues. MS is a disease characterized by wide variations between patients, thus making categorization difficult. The aim of the current study was to review the existing epidemiological data of MS in Europe published during the last decade (2000-2009), using PubMed. Findings revealed an increasing incidence of MS during the last decade. Recent data indicate that latitude does not play a key role in determining the onset of the disease. MS has a significant impact on the quality of life for most patients over many years. The disease is twice as common in women than in men, and is at its peak in the most economically productive years of life. Pregnancy, postpartum status and vaccines may influence the onset and the course of the disease. Only one of the reviewed papers provides a view of progression from onset to death.

Kimmerle's anomaly as a possible causative factor of chronic tension-type headaches and neurosensory hearing loss: case report and literature review.

Kimmerle's anomaly also known as ponticulus posticus is a common anatomical variation of the atlas, the first cervical vertebra. It is the product of the complete or incomplete ossification of the posterior atlanto-occipital membrane over the vertebral artery groove resulting in the formation of a foramen (arcuate foramen) containing the vertebral artery and the posterior branch of the C-1 spinal nerve. This variation has been associated with vertebro-basilar insufficiency symptoms, various types of headaches, and acute hearing loss. The aim of the present study is to substantiate whether Kimmerle's anomaly is the possible cause of chronic tension-type headaches and neurosensory-type hearing loss in a patient with a known history of headaches and accompanied unilateral hearing loss. The headaches demonstrated the characteristics of the chronic tension-type; the audiometric investigation concluded the hearing loss to be of the neurosensory type; whereas, the imaging examinations revealed the existence of a partial osseous bridge, that is an incomplete arcuate foramen (ponticulus posticus or Kimmerle's anomaly) on the upper surface of atlas. Both the clinical and the radiological findings of this case are indicative of a possible connection between Kimmerle's anomaly and the manifestation of chronic tension-type headaches and neurosensory-type hearing loss.

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.

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 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.

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.

Antibodies against GM1 in demented patients.

The aim of this study was to evaluate the levels of anti-GM1 in demented patients, correlating them with the type and severity of dementia as well as with the eventually coexistent polyneuropathy. Anti-GM1 concentrations were measured in the sera of 33 demented patients with a male-to-female ratio of 1:2.7 (the mean age was 69.7 years for males and 70.1 years for females). Eighty-two percent of the patients revealed increased values of anti-GM1, but only 18.2% demonstrated polyneuropathies. Fifty-nine percent of the patients suffered from vascular dementia. The most severely demented patients demonstrated a Mini-Mental State Examination score of 5 to 23 out of 30 and revealed the most increased levels of anti-GM1 (>40 EU/mL). The findings of this study are indicative of a possible correlation between the levels of anti-GM1 and the severity of dementia, mainly of the vascular type.

Pathological alterations of the climbing fibres of the cerebellum in vascular dementia: a Golgi and electron microscope study.

The climbing fibres originating from the inferior olivary nucleus act as a powerful excitation on the Purkinje cells of the cerebellar cortex that may play a substantial role in the motor performances and the learning of new motor skills. In vascular dementia the existent vascular alterations may induce many hypoxic or ischemic phenomena, among the others, in the olivocerebellar system affecting the climbing fibres in their way to the molecular layer of the cerebellar cortex. In autopsy cases of vascular dementia, the application of silver impregnation technique and electron microscopy revealed a substantial decrease of the number of the climbing fibres in the cortex of the vermis, the flocculus and the cerebellar hemispheres. The presynaptic varicosities and the synaptic terminals of the climbing fibres on the Purkinje cell dendrites were decreased in number and moreover were characterized by a marked poverty of synaptic vesicles. The synaptic cleft was mostly abnormal and wider than 20 nm. Mitochondrial abnormalities, such as elongated mitochondria with disruption of the cristae were seen in the terminal branches of the climbing fibre arborization as well as in the presynaptic components. The blood capillaries demonstrated a considerable thickness of the basal membrane and perivascular astrocytic proliferation, whereas the tight junctions between the endothelial cells were ultrastructurally intact. We would hypothesize that the morphological and morphometric alterations of the climbing fibres of the cerebellar cortex in cases of vascular dementia might be associated with the frequently noticed difficulty in the performance of fine and skilful movements by the patients.