Stavros J. Baloyannis

Mitochondrial alterations in Alzheimer's disease.

Morphological alterations of mitochondria may be related to metabolic and energy deficiency in neurons in Alzheimers disease and other neurodegenerative disorders. Mitochondrial dysfunction is also a hallmark of beta peptide induced neuronal toxicity in Alzheimers disease. A general change in glucose utilization, increased oxidative stress, and Ca;{2+} deregulation are additional metabolic defects in the AD brain that may also be associated with defective mitochondrial function the result is a cycle of increased mitochondrial dysfunction causing increased oxidative damage until the cellular energy supply falls below the threshold for cellular survival. In a series of studies on the morphological and morphometric estimation of mitochondria in Alzheimers disease, by electron microscopy we noticed substantial morphological and morphometric changes in the neurons of the hippocampus, the acoustic cortex, the frontal cortex, the cerebellar cortex, the climbing fibers, the thalamus, the globus pallidus, the red nucleus and the locus coeruleus. The morphological alterations consisted of considerable changes of the mitochondrial cristae, accumulation of osmiophilic material, and decrease of their size, in comparison with the normal controls. Mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization. The ultrastructural study of large number of neurons in the thalamus and the red nucleus revealed that the mitochondrial alterations did not coexist with cytoskeletal pathology and accumulation of amyloid deposits, though they were prominent in neurons, which demonstrated fragmentation of the cisternae of the Golgi apparatus. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimers disease. The relationship between the site and extent of mitochondrial abnormalities and the synaptic alterations suggests an intimate and early association between these features in Alzheimers disease.

Systemic immune aberrations in Alzheimer's disease patients

The role of chronic inflammation in the pathogenesis of Alzheimers 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.

Mitochondrial alterations Alzheimer's disease

Morphological alterations of mitochondria may be related to metabolic and energy deficiency in neurons in Alzheimers disease (AD) and other neurodegenerative disorders. In previous studies on the morphological and morphometric estimation of mitochondria in AD, electron microscopy revealed substantial morphological and morphometric changes in the hippocampus, the acoustic cortex, the frontal cortex, and the cerebellum. This study extends this observation to subcortical centers, namely the thalamus, the globus pallidus, the red nucleus, and the locus caeruleus in 10 brains of patients who suffered from AD. The morphological alterations consisted of very obvious changes of the mitochondrial cristae, accumulation of osmiophilic material and decrease of their size, in comparison with the normal controls. Mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization. The ultrastructural study of a large number of neurons in the thalamus and the red nucleus revealed that the mitochondrial alterations did not coexist with cytoskeletal pathology and accumulation of amyloid deposits. However, they were prominent in neurons, which demonstrated fragmentation of the cisternae of the Golgi apparatus. The morphological alterations of the mitochondria presumably suggest oxidative damage in neurons in AD brains.

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.

The vascular factor in Alzheimer's disease: a study in Golgi technique and electron microscopy.

Although the etiopathological background of Alzheimers disease (AD) is mostly associated with the deposition of Αβ-peptide, the hyperphosphorylation of τ protein, the synaptic pathology and the mitochondrial alterations, the vascular factor may play substantial role in plotting the multifactorial pattern of the disease. We attempted to study the blood capillaries in the hippocampus, the acoustic, the visual and the parietal cortex in twelve early cases of Alzheimers disease. Samples were processed for Golgi silver impregnation technique and electron microscopy. The morphological findings were compared with normal controls. The study of the brain capillaries in cases of AD, revealed numerous fusiform dilatations, tortuosities, abnormal branching and fusion, though the morphometric estimation revealed a decrease of the number of capillaries per mm(3) in comparison with normal control brains. The ultrastructural study revealed mitochondrial abnormalities in the endothelial cells of a substantial number of capillaries and marked degeneration of the pericytes. Perivascular microglial proliferation was also prominent in the hippocampus and the parietal lobe. Our findings both in Golgi staining and electron microscopy plead in favor of the essential role that the microvascular alterations may play in the broad pathogenetic spectrum of AD.

Efficacy and safety of donepezil in patients with Alzheimer's disease: results of a global, multinational, clinical experience study.

BackgroundDonepezil has consistently been shown to be effective and well tolerated in the symptomatic treatment of Alzheimer’s disease in placebo-controlled clinical trials. It has been shown to provide significant benefits in cognition, global function and activities of daily living in patients with mild-to-moderate Alzheimer’s disease. However, in order to control for confounding factors, some clinical trials of donepezil have excluded patients with comorbid illness and concomitant medication use.ObjectiveThe objective of this study was to evaluate the efficacy, tolerability and safety of donepezil in a wider and more diverse sample of patients and centres than previous trials, reflecting routine clinical practice.MethodsIn this 12-week, open-label, multicentre trial, patients with probable mild-to-moderate Alzheimer’s disease received donepezil 5 mg/day for 28 days, after which the dosage was increased to 10 mg/day according to the investigating clinician’s judgement. Patients were enrolled at 246 study centres in 18 countries worldwide. Cognition was assessed by a trained clinician using the Mini-Mental State Examination (MMSE) at baseline, week 4 and week 12 (or last visit). Changes in patient activity and social interaction were evaluated using a caregiver diary. Each week, caregivers recorded their impression of change compared with baseline on three aspects of patient behaviour using a 5-point scale. Efficacy analyses were performed on the intent-to-treat population. Significance was determined using the paired t-test (0.05 significance level). Tolerability and safety were assessed by monitoring adverse events, physical examinations, vital signs, clinical laboratory test abnormalities and ECG findings throughout the study.ResultsA total of 1113 patients received donepezil (mean baseline MMSE score [±SD] 18.74 ± 5.21). 989 (88.9%) patients completed the study; 59 (5%) patients discontinued because of adverse events. Most patients were taking at least one concomitant medication (n = 802; 72%) and had at least one comorbid medical condition (n = 745; 67%) on study entry. Donepezil significantly improved cognition compared with baseline at weeks 4 and 12, and at week 12 using a last observation carried forward (LOCF) analysis (all p < 0.0001). Mean change from baseline MMSE score (±SE) at week 12-LOCF was +1.73 ± 0.10. Donepezil was also associated with significant improvements in patient social interaction, engagement and interest, and initiation of pleasurable activities at all weekly assessments and week 12-LOCF (all p < 0.0001). Donepezil was generally well tolerated; adverse events were consistent with the known safety profile of donepezil.ConclusionDonepezil treatment resulted in statistically significant improvements in cognition and patient activity and social behaviour, and was generally well tolerated despite high levels of comorbid illness and concomitant medication use. The results of this open-label study in a large patient population are consistent with those from controlled trials and support that donepezil is effective in the treatment of mild-to-moderate Alzheimer’s disease in everyday practice.

A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 ± 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.

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.

Morphological alterations of the synapses in the locus coeruleus in Parkinson's disease

Parkinsons disease is the most common movement disorder in the broad spectrum of neurodegenerative diseases, associated frequently with gradual decline of the higher mental faculties. From the morphological point of view it is characterized by the degeneration of a substantial number of dopaminergic neurons of the substantia nigra and a considerable degeneration of neuronal networks in locus coeruleus, putamen, globus pallidus, thalamus and some areas of the cortex of the brain hemispheres. Filamentous inclusions, in the form of Lewy bodies and Lewy neuritis, composed mainly of alpha synuclein, been the hallmark of diffuse Lewy body dementia, have been described in the neurons of the substantia nigra in many cases of Parkinsons disease associated with dementia. In previous studies we have described the morphological alterations in the synapses in the caudate nucleus and the globus pallidus in cases of Parkinsons disease. In the present study we attempted to describe the morphological and morphometric alterations of the locus coeruleus in patients who suffered from Parkinsons disease with normal cognitive function and in patients who suffered from Parkinsons disease associated with dementia, comparing them with normal controls. The morphological alterations of the neurons, the dendrites, the retrograde axonic collaterals and the synapses were more impressive in cases of Parkinsons disease associated with dementia than in Parkinsons disease with normal cognitive function. The majority of the synapses demonstrated changes in size and shape of the pre- and postsynaptic components, polymorphism of the synaptic vesicles and marked morphological alterations of the mitochondria. The morphological alterations of the synapses in cases of Parkinsons disease associated with dementia, plead in favor of the importance of the neuronal circuits of locus coeruleus in cognitive functions.

Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological and morphometric estimation by Golgi technique and electron microscopy

Conclusions. The morphological and morphometric estimation of the dendrites and the dendritic spines in the acoustic cortex in Alzheimers disease revealed substantial alterations of the dendritic arborization and marked loss of the dendritic spines. This may be related to communication impairment even in early cases of Alzheimers disease. Objectives. Alzheimers disease is characterized by progressive loss of memory, impairment of judgment, and decline in communication and speech eloquence. In the present study we attempted to describe the morphological and morphometric alterations of the dendrites and the dendritic spines in the acoustic cortex in early cases of Alzheimers disease, in order to approach the communication impairment of patients suffering from Alzheimers disease, from the neuropathological point of view. Materials and methods. We studied the acoustic cortex in 22 cases of Alzheimers disease by Golgi technique and electron microscopy. Results. The morphological and morphometric estimation of the acoustic cortex revealed loss of Cajal-Retzius cells in layer I, as well as an impressive abbreviation of the dendritic fields associated with loss of dendritic spines in all layers of the cortex. Numerous distorted, dystrophic and degenerated dendritic spines were also seen, which were intermixed with a considerable number of giant spines. The dendritic and spinal alterations were closely associated with mitochondrial alterations.