Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events whi... more Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events which coincide with broadly defined phases of behavioral and cognitive development. During the early fetal period, early produced neurons make initial synapses which form the basis for the earliest electrical activity of the human brain. The overall immaturity of neuronal connections, in particularly in cortical areas, correlates with the absence of any behavioral pattern or goal-directed movements. In the late fetus and preterm infant, transient accumulation of major afferent pathways, the presence of transient layers (subplate zone) and transient pattern of transmitter-related organization form the neurological basis of cortical electric responses as well as transient behavioral states and sleep patterns. Parallel to the profound structural and chemical reorganization of the human cerebrum during the first 6 postnatal months there is a disappearance of transient behavioral and motor patterns. The previously close spatio-temporal correlation between these events becomes progressively looser. The overproduction of circuitry elements during the subsequent period peaks in associative cortex between 1 and 2 years of age, corresponding to the emergence of skilled actions and cognitive functions. After the elimination of some circuitry elements after the second year of life, the prolonged maturation of goal-directed behavior and the protracted emergence of different cognitive functions correlates with the developmental plateau of synapse production which can be seen up to 16 years of age. Parallel to the prolonged maturation of postsynaptic elements, there are well defined maturational changes in the chemical properties of associative pyramidal neurons of cortical layer III. These findings correspond to the prolonged maturation of movement-related brain macropotentials as well as other cognition-related potentials, where the last prominent changes were seen after 10 years of age. Although the coincidence of the developmental events does not necessarily mean a causal relationship, the combination of structural and physiological data opens new vistas for the further investigation of the neurobiological basis of goal-directed movement and cognitive behavior. l Corresponding author. Tel.: (041) 271-254. ment of voluntary,
Proceedings of the National Academy of Sciences, 2011
The major mechanism for generating diversity of neuronal connections beyond their genetic determi... more The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by twoto threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders. association cortex | critical period | schizophrenia | synaptogenesis
The International journal of developmental biology, 1991
The aim of this paper was to offer for the first time a selective and systematic description of t... more The aim of this paper was to offer for the first time a selective and systematic description of the "Zabreb Neuroembryological Collection" of human brains and to illustrate the major results of our research team. Throughout these 16 years of continuous and systematic research, we have applied different techniques for demonstrating the cytoarchitectonics (Nissl staining), neuronal morphology (Golgi impregnation), synaptogenesis (EM analysis), growing pathways (acetylcholinesterase histochemistry) and transmitter-related properties of developing neuronal populations (immunocytochemistry and acetylcholinesterase histochemistry) on several hundred human brains ranging in age from the 5th week post-conception to 90 years. The combination of classical and modern research techniques applied to the constantly growing developmental collection, as well as the continuous evaluation of our data in the light of experimental work in non-human primates, has led to the discovery of an ear...
Sporadic Alzheimer&am... more Sporadic Alzheimer's disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ1-42) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ1-42 accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ1-42-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.
Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) represent an important diff... more Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) represent an important differential diagnostic problem in clinical practice. The identification for new biomarkers that would help establishing the diagnosis and primary cause of the dementia is therefore highly relevant. The aim of this study was to investigate the diagnostic accuracy of three potential CSF biomarkers, total tau protein (t-tau), tau protein phosphorylated at threonine 181 (p-tau181), and tau protein phosphorylated at serine 199 (p-tau199) in the differential diagnosis of AD and FTLD patients in relatively young age groups. The concentrations of the three CSF biomarkers were measured in 25 FTLD patients, 27 AD patients, and 25 non-demented (ND) subjects. The CSF concentrations of all three markers were significantly higher in AD than in FTLD cases (p < 0.001) or ND controls (p < 0.001). No difference was observed in FTLD compared to the ND group, except for p-tau181 (p = 0.028). When sensitivity was set at 85% or higher, specificity in differentiation between FTLD and AD patients reached 40% for t-tau, 37.5% for p-tau181 and 56% for p-tau199. Improvement of the diagnostic accuracy upon logistic regression analysis with t-tau and p-tau199 as independent variables showed that 22 out of 25 FTLD patients could be correctly classified. In conclusion, none of the markers per se fulfilled the criteria for the "ideal" marker (sensitivity and specificity higher than 85%). However, combination of t-tau and p-tau199 classified correctly 88% of FTLD patients, thus largely satisfying practical requirements.
The verrucae areae entorhinalis (VAE) are a characteristic feature of the human brain that occupy... more The verrucae areae entorhinalis (VAE) are a characteristic feature of the human brain that occupy the anterior and posterolateral parts of the parahippocampal gyri and correspond to the islands of layer II neurons. We analyzed VAE in 60 neurologically normal subjects ranging from 23 to 85 years of age using a casting method. In 10 of these subjects the total number of neurons in the entorhinal islands was estimated stereologically using the optical fractionator. The number and surface area of VAE were higher in the left hemisphere compared with the right, and this leftward asymmetry was highly significant. Regression analysis showed a negative correlation between average VAE area and age in both hemispheres, representing a rate loss of about 800 m 2 per year. The estimated number of neurons obtained with the optical fractionator showed no significant difference between the left and the right hemisphere (468,000؎144,000 vs. 405,000؎117,000). There was a highly significant negative correlation between neuron numbers and age in both sides. In addition, clusters of small, undifferentiated layer II neurons ('heterotopias') were frequently observed in the rostral part of the entorhinal cortex in young and elderly adults.
Amyloid β 1-42 (Aβ 1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) are the main cerebro... more Amyloid β 1-42 (Aβ 1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) are the main cerebrospinal fluid (CSF) biomarkers for early diagnosis of Alzheimer's disease (AD). Detection of AD is critically important in view of the growing number of potential new drugs that may influence the course of the disease in its early phases. However, cut-off levels for these CSF biomarkers have not yet been established. Variability in absolute concentrations of AD biomarkers is high among studies and significant differences were noticed even within the same datasets. Variability in biomarkers levels in these assays may be due to many aspects of operating procedures. Standardization of pre-analytical and analytical procedures in collection, treatment, and storage of CSF samples is crucial because differences in sample handling can drastically influence results. Multicenter studies showed that usage of ELISA kits from different manufacturers also affects outcome. So far only very few studies tested the efficiency of ELISA kits produced by different vendors. In this study, the performance of Innogenetics (Gent, Belgium) and Invitrogen (Camarillo, CA, USA) ELISA kits for t-tau and Aβ 1-42 was tested. Passing-Bablok analysis showed significant differences between Invitrogen and Innogenetics ELISA methods, making it impossible to use them interchangeably.
On the occasion of the launch of Translational Neuroscience, we extend a warm welcome to all the ... more On the occasion of the launch of Translational Neuroscience, we extend a warm welcome to all the readers and authors. We would also like to express our gratitude to the Editorial Board Members for their sustained support to make the launch of this new journal possible. We certainly could not publish an outstanding journal without the extraordinary efforts of our reviewers. The willingness and expertise of the professionals who serve as reviewers are essential to maintaining technical and editorial standards. So it is with great appreciation and gratitude that we express our thanks to each of the peer reviewers whose efforts help to ensure that this journal becomes one of the leading journals in the field of neuroscience.
The dopaminergic system subserves many aspects of normal human behavior and is involved in the pa... more The dopaminergic system subserves many aspects of normal human behavior and is involved in the pathogenesis of a number of psychiatric and neurological conditions, such as schizophrenia, drug abuse, and depression [1]. There is evidence that projections from midbrain dopaminergic neurons to limbic regions of the ventral striatum, amygdala, hippocampus and the prefrontal cortex (PFC) comprise the core of the universal brain reward system [2]. The firing frequency of these dopaminergic ventral tegmental area (VTA) neurons (mainly from the A10 group) increases during any naturally occurring pleasant experience of eating food, during sexual activity or while bonding with a child ("behavioral activation"), whereas long-term changes and alterations in synaptic plasticity of these projections that may result from lack of care during early postnatal period can lead to profound and lasting changes in emotional development, attachment behavior, and their increased responsiveness to stress and stimulants (for a review see [3]). Tyrosine hydroxylase is the rate limiting enzyme for dopamine synthesis, as well as for the synthesis of noradrenaline and adrenaline. However, several studies in primate species have showed that tyrosine hydroxylase and dopamine beta-hydroxylase (that is required for noradrenaline synthesis) are not colocalized in immunoreactive neurons. Tyrosine hydroxylase is therefore considered as a reliable marker for dopaminergic projections and neurons in primates [4]. Comparative analysis of tyrosin-hydroxylase-immunoreactive axon length density has revealed that humans and chimpanzees together deviated from macaques in having increased dopaminergic afferents in layers III and V/VI of Brodmann's areas 9 and 32 of PFC [5]. Such phylogenetic differences suggest a potential role for dopamine in the expansion of the neocortex and evolution of cognitive capabilities [4,6,7]. There are five subtypes of dopamine receptors, divided into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. These five dopamine receptors are all members of the superfamily of seven transmembrane domain, G-protein coupled receptors. The assignment of a cloned receptor to one of these families was based on shared pharmacological features, second messenger coupling, and conserved structural features among individual receptors. The D1-like dopamine receptors Abstract
In order to observe changes owing to aging and Alzheimer&#39;s disease (AD) in the volumes of... more In order to observe changes owing to aging and Alzheimer&#39;s disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 microns-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = -0.56, 2P &lt; 0.05), and a 32% mean reduction in the AD group compared with controls (P &lt; 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = -0.84, 2P &lt; 0.0001) and subiculum (r = -0.49, 2P &lt; 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P &lt; 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes.
Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events whi... more Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events which coincide with broadly defined phases of behavioral and cognitive development. During the early fetal period, early produced neurons make initial synapses which form the basis for the earliest electrical activity of the human brain. The overall immaturity of neuronal connections, in particularly in cortical areas, correlates with the absence of any behavioral pattern or goal-directed movements. In the late fetus and preterm infant, transient accumulation of major afferent pathways, the presence of transient layers (subplate zone) and transient pattern of transmitter-related organization form the neurological basis of cortical electric responses as well as transient behavioral states and sleep patterns. Parallel to the profound structural and chemical reorganization of the human cerebrum during the first 6 postnatal months there is a disappearance of transient behavioral and motor patterns. The previously close spatio-temporal correlation between these events becomes progressively looser. The overproduction of circuitry elements during the subsequent period peaks in associative cortex between 1 and 2 years of age, corresponding to the emergence of skilled actions and cognitive functions. After the elimination of some circuitry elements after the second year of life, the prolonged maturation of goal-directed behavior and the protracted emergence of different cognitive functions correlates with the developmental plateau of synapse production which can be seen up to 16 years of age. Parallel to the prolonged maturation of postsynaptic elements, there are well defined maturational changes in the chemical properties of associative pyramidal neurons of cortical layer III. These findings correspond to the prolonged maturation of movement-related brain macropotentials as well as other cognition-related potentials, where the last prominent changes were seen after 10 years of age. Although the coincidence of the developmental events does not necessarily mean a causal relationship, the combination of structural and physiological data opens new vistas for the further investigation of the neurobiological basis of goal-directed movement and cognitive behavior. l Corresponding author. Tel.: (041) 271-254. ment of voluntary,
The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was comp... more The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was compared with neuropathological changes and with cell death related DNA damage (as revealed by in situ end labeling, ISEL) in the hippocampal formation and entorhinal cortex of 12 age-matched control subjects and 12 Alzheimer's disease (AD) patients. Unlike controls, numerous nNOS-positive reactive astrocytes were found in AD patients around -amyloid plaques in CA1 and subiculum and at the places of clear and overt neuron loss, particularly in the entorhinal cortex layer II and CA4. This is the first evidence of nNOS-like immunoreactivity in reactive astrocytes in AD. In contrast to controls, in all but one AD subject, large numbers of ISEL-positive neuronal nuclei and microglial cells were found in the CA1 and CA4 regions and subiculum. Semiquantitative analysis showed that neuronal DNA fragmentation in AD match with the distribution of nNOS-expressing reactive astroglial cells in CA1 (r ؍ 0.74, P < 0.01) and CA4 (r ؍ 0.58, P < 0.05). A portion of the nNOS-positive CA2/CA3 pyramidal neurons was found to be spared even in the most affected hippocampi. A significant inverse correlation between nNOS expression and immunoreactivity to abnormally phosphorylated tau proteins (as revealed by AT8 monoclonal antibody) in perikarya of these CA2/3 neurons (r ؍ ؊0.85, P < 0.01) suggests that nNOS expression may provide selective resistance to neuronal degeneration in AD. In conclusion, our results imply that an upregulated production of NO by reactive astrocytes may play a key role in the pathogenesis of AD.
2009) Neuropathology and Applied Neurobiology 35, 532-554 Does Alzheimer's disease begin in the b... more 2009) Neuropathology and Applied Neurobiology 35, 532-554 Does Alzheimer's disease begin in the brainstem?
In a biological sense an individual's life is all about survival and reproduction. Beside the sel... more In a biological sense an individual's life is all about survival and reproduction. Beside the selection of a mate, the mutual commitment of a parent to sustain an infant through a period of dependency is amongst the most important aspects of natural selection. Here we review how the highly conserved circuitry of key midbrain and hypothalamic structures, and limbic and frontal cortical regions support these processes, and at the same time are involved in shaping the offspring's emotional development and behavior. Many recent studies provided new findings on how attachment behavior and parental bonding is promoted and maintained through genetic and epigenetic influences on synaptic plasticity of mirror neurons and various neuropeptide systems, particularly oxytocinergic, and how these systems serve to link social cues to the brain reward system. Most of this evidence suggests that stress, early parental deprivation and lack of care during the postnatal period leads to profound and lasting changes in the attachment pattern and motivational development with consequent increased vulnerability of the mesocortical and mesolimbic dopamine-associated reward reinforcement pathways to psychosocial stressors, abuse of stimulants and psychopathology later in life.
Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events whi... more Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events which coincide with broadly defined phases of behavioral and cognitive development. During the early fetal period, early produced neurons make initial synapses which form the basis for the earliest electrical activity of the human brain. The overall immaturity of neuronal connections, in particularly in cortical areas, correlates with the absence of any behavioral pattern or goal-directed movements. In the late fetus and preterm infant, transient accumulation of major afferent pathways, the presence of transient layers (subplate zone) and transient pattern of transmitter-related organization form the neurological basis of cortical electric responses as well as transient behavioral states and sleep patterns. Parallel to the profound structural and chemical reorganization of the human cerebrum during the first 6 postnatal months there is a disappearance of transient behavioral and motor patterns. The previously close spatio-temporal correlation between these events becomes progressively looser. The overproduction of circuitry elements during the subsequent period peaks in associative cortex between 1 and 2 years of age, corresponding to the emergence of skilled actions and cognitive functions. After the elimination of some circuitry elements after the second year of life, the prolonged maturation of goal-directed behavior and the protracted emergence of different cognitive functions correlates with the developmental plateau of synapse production which can be seen up to 16 years of age. Parallel to the prolonged maturation of postsynaptic elements, there are well defined maturational changes in the chemical properties of associative pyramidal neurons of cortical layer III. These findings correspond to the prolonged maturation of movement-related brain macropotentials as well as other cognition-related potentials, where the last prominent changes were seen after 10 years of age. Although the coincidence of the developmental events does not necessarily mean a causal relationship, the combination of structural and physiological data opens new vistas for the further investigation of the neurobiological basis of goal-directed movement and cognitive behavior. l Corresponding author. Tel.: (041) 271-254. ment of voluntary,
Proceedings of the National Academy of Sciences, 2011
The major mechanism for generating diversity of neuronal connections beyond their genetic determi... more The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by twoto threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders. association cortex | critical period | schizophrenia | synaptogenesis
The International journal of developmental biology, 1991
The aim of this paper was to offer for the first time a selective and systematic description of t... more The aim of this paper was to offer for the first time a selective and systematic description of the "Zabreb Neuroembryological Collection" of human brains and to illustrate the major results of our research team. Throughout these 16 years of continuous and systematic research, we have applied different techniques for demonstrating the cytoarchitectonics (Nissl staining), neuronal morphology (Golgi impregnation), synaptogenesis (EM analysis), growing pathways (acetylcholinesterase histochemistry) and transmitter-related properties of developing neuronal populations (immunocytochemistry and acetylcholinesterase histochemistry) on several hundred human brains ranging in age from the 5th week post-conception to 90 years. The combination of classical and modern research techniques applied to the constantly growing developmental collection, as well as the continuous evaluation of our data in the light of experimental work in non-human primates, has led to the discovery of an ear...
Sporadic Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Sporadic Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (sAD) is the most common form of dementia. Rats injected intracerebroventricularly with streptozotocin (STZ-icv) develop insulin-resistant brain state and represent a non-transgenic sAD model with a number of AD-like cognitive and neurochemical features. We explored cognitive, structural and ultrastructural changes in the brain of the STZ-icv rat model over a course of 9 months. Cognitive functions were measured in the STZ-icv- (0.3, 1 and 3 mg/kg) and age-matched control rats by passive avoidance test. Structural changes were assessed by Nissl and Bielschowsky silver staining. Immunohistochemistry and electron microscopy analysis were used to detect amyloid β- (Aβ1-42) and hyperphosphorylated tau (AT8) accumulation and ultrastructural changes in the brain. Memory decline was time- (≤3 months/acute, ≥3 months/progressive) and STZ-icv dose-dependent. Morphological changes were manifested as thinning of parietal cortex (≥1 month) and corpus callosum (9 months), and were more pronounced in the 3 mg/kg STZ group. Early neurofibrillary changes (AT8) were detected from 1 month onward in the neocortex, and progressed after 3 months to the hippocampus. Intracellular Aβ1-42 accumulation was found in the neocortex at 3 months following STZ-icv treatment, while diffuse Aβ1-42-positive plaque-like formations were found after 6 months in the neocortex and hippocampus. Ultrastructural changes revealed enlargement of Golgi apparatus, pyknotic nuclei, and time-dependent increase in lysosome size, number, and density. Our data provide a staging of cognitive, structural/ultrastructural, and neuropathological markers in the STZ-icv rat model that in many aspects seems to be generally comparable to stages seen in human sAD.
Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) represent an important diff... more Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) represent an important differential diagnostic problem in clinical practice. The identification for new biomarkers that would help establishing the diagnosis and primary cause of the dementia is therefore highly relevant. The aim of this study was to investigate the diagnostic accuracy of three potential CSF biomarkers, total tau protein (t-tau), tau protein phosphorylated at threonine 181 (p-tau181), and tau protein phosphorylated at serine 199 (p-tau199) in the differential diagnosis of AD and FTLD patients in relatively young age groups. The concentrations of the three CSF biomarkers were measured in 25 FTLD patients, 27 AD patients, and 25 non-demented (ND) subjects. The CSF concentrations of all three markers were significantly higher in AD than in FTLD cases (p < 0.001) or ND controls (p < 0.001). No difference was observed in FTLD compared to the ND group, except for p-tau181 (p = 0.028). When sensitivity was set at 85% or higher, specificity in differentiation between FTLD and AD patients reached 40% for t-tau, 37.5% for p-tau181 and 56% for p-tau199. Improvement of the diagnostic accuracy upon logistic regression analysis with t-tau and p-tau199 as independent variables showed that 22 out of 25 FTLD patients could be correctly classified. In conclusion, none of the markers per se fulfilled the criteria for the "ideal" marker (sensitivity and specificity higher than 85%). However, combination of t-tau and p-tau199 classified correctly 88% of FTLD patients, thus largely satisfying practical requirements.
The verrucae areae entorhinalis (VAE) are a characteristic feature of the human brain that occupy... more The verrucae areae entorhinalis (VAE) are a characteristic feature of the human brain that occupy the anterior and posterolateral parts of the parahippocampal gyri and correspond to the islands of layer II neurons. We analyzed VAE in 60 neurologically normal subjects ranging from 23 to 85 years of age using a casting method. In 10 of these subjects the total number of neurons in the entorhinal islands was estimated stereologically using the optical fractionator. The number and surface area of VAE were higher in the left hemisphere compared with the right, and this leftward asymmetry was highly significant. Regression analysis showed a negative correlation between average VAE area and age in both hemispheres, representing a rate loss of about 800 m 2 per year. The estimated number of neurons obtained with the optical fractionator showed no significant difference between the left and the right hemisphere (468,000؎144,000 vs. 405,000؎117,000). There was a highly significant negative correlation between neuron numbers and age in both sides. In addition, clusters of small, undifferentiated layer II neurons ('heterotopias') were frequently observed in the rostral part of the entorhinal cortex in young and elderly adults.
Amyloid β 1-42 (Aβ 1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) are the main cerebro... more Amyloid β 1-42 (Aβ 1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) are the main cerebrospinal fluid (CSF) biomarkers for early diagnosis of Alzheimer's disease (AD). Detection of AD is critically important in view of the growing number of potential new drugs that may influence the course of the disease in its early phases. However, cut-off levels for these CSF biomarkers have not yet been established. Variability in absolute concentrations of AD biomarkers is high among studies and significant differences were noticed even within the same datasets. Variability in biomarkers levels in these assays may be due to many aspects of operating procedures. Standardization of pre-analytical and analytical procedures in collection, treatment, and storage of CSF samples is crucial because differences in sample handling can drastically influence results. Multicenter studies showed that usage of ELISA kits from different manufacturers also affects outcome. So far only very few studies tested the efficiency of ELISA kits produced by different vendors. In this study, the performance of Innogenetics (Gent, Belgium) and Invitrogen (Camarillo, CA, USA) ELISA kits for t-tau and Aβ 1-42 was tested. Passing-Bablok analysis showed significant differences between Invitrogen and Innogenetics ELISA methods, making it impossible to use them interchangeably.
On the occasion of the launch of Translational Neuroscience, we extend a warm welcome to all the ... more On the occasion of the launch of Translational Neuroscience, we extend a warm welcome to all the readers and authors. We would also like to express our gratitude to the Editorial Board Members for their sustained support to make the launch of this new journal possible. We certainly could not publish an outstanding journal without the extraordinary efforts of our reviewers. The willingness and expertise of the professionals who serve as reviewers are essential to maintaining technical and editorial standards. So it is with great appreciation and gratitude that we express our thanks to each of the peer reviewers whose efforts help to ensure that this journal becomes one of the leading journals in the field of neuroscience.
The dopaminergic system subserves many aspects of normal human behavior and is involved in the pa... more The dopaminergic system subserves many aspects of normal human behavior and is involved in the pathogenesis of a number of psychiatric and neurological conditions, such as schizophrenia, drug abuse, and depression [1]. There is evidence that projections from midbrain dopaminergic neurons to limbic regions of the ventral striatum, amygdala, hippocampus and the prefrontal cortex (PFC) comprise the core of the universal brain reward system [2]. The firing frequency of these dopaminergic ventral tegmental area (VTA) neurons (mainly from the A10 group) increases during any naturally occurring pleasant experience of eating food, during sexual activity or while bonding with a child ("behavioral activation"), whereas long-term changes and alterations in synaptic plasticity of these projections that may result from lack of care during early postnatal period can lead to profound and lasting changes in emotional development, attachment behavior, and their increased responsiveness to stress and stimulants (for a review see [3]). Tyrosine hydroxylase is the rate limiting enzyme for dopamine synthesis, as well as for the synthesis of noradrenaline and adrenaline. However, several studies in primate species have showed that tyrosine hydroxylase and dopamine beta-hydroxylase (that is required for noradrenaline synthesis) are not colocalized in immunoreactive neurons. Tyrosine hydroxylase is therefore considered as a reliable marker for dopaminergic projections and neurons in primates [4]. Comparative analysis of tyrosin-hydroxylase-immunoreactive axon length density has revealed that humans and chimpanzees together deviated from macaques in having increased dopaminergic afferents in layers III and V/VI of Brodmann's areas 9 and 32 of PFC [5]. Such phylogenetic differences suggest a potential role for dopamine in the expansion of the neocortex and evolution of cognitive capabilities [4,6,7]. There are five subtypes of dopamine receptors, divided into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. These five dopamine receptors are all members of the superfamily of seven transmembrane domain, G-protein coupled receptors. The assignment of a cloned receptor to one of these families was based on shared pharmacological features, second messenger coupling, and conserved structural features among individual receptors. The D1-like dopamine receptors Abstract
In order to observe changes owing to aging and Alzheimer&#39;s disease (AD) in the volumes of... more In order to observe changes owing to aging and Alzheimer&#39;s disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 microns-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = -0.56, 2P &lt; 0.05), and a 32% mean reduction in the AD group compared with controls (P &lt; 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = -0.84, 2P &lt; 0.0001) and subiculum (r = -0.49, 2P &lt; 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P &lt; 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes.
Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events whi... more Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events which coincide with broadly defined phases of behavioral and cognitive development. During the early fetal period, early produced neurons make initial synapses which form the basis for the earliest electrical activity of the human brain. The overall immaturity of neuronal connections, in particularly in cortical areas, correlates with the absence of any behavioral pattern or goal-directed movements. In the late fetus and preterm infant, transient accumulation of major afferent pathways, the presence of transient layers (subplate zone) and transient pattern of transmitter-related organization form the neurological basis of cortical electric responses as well as transient behavioral states and sleep patterns. Parallel to the profound structural and chemical reorganization of the human cerebrum during the first 6 postnatal months there is a disappearance of transient behavioral and motor patterns. The previously close spatio-temporal correlation between these events becomes progressively looser. The overproduction of circuitry elements during the subsequent period peaks in associative cortex between 1 and 2 years of age, corresponding to the emergence of skilled actions and cognitive functions. After the elimination of some circuitry elements after the second year of life, the prolonged maturation of goal-directed behavior and the protracted emergence of different cognitive functions correlates with the developmental plateau of synapse production which can be seen up to 16 years of age. Parallel to the prolonged maturation of postsynaptic elements, there are well defined maturational changes in the chemical properties of associative pyramidal neurons of cortical layer III. These findings correspond to the prolonged maturation of movement-related brain macropotentials as well as other cognition-related potentials, where the last prominent changes were seen after 10 years of age. Although the coincidence of the developmental events does not necessarily mean a causal relationship, the combination of structural and physiological data opens new vistas for the further investigation of the neurobiological basis of goal-directed movement and cognitive behavior. l Corresponding author. Tel.: (041) 271-254. ment of voluntary,
The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was comp... more The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was compared with neuropathological changes and with cell death related DNA damage (as revealed by in situ end labeling, ISEL) in the hippocampal formation and entorhinal cortex of 12 age-matched control subjects and 12 Alzheimer's disease (AD) patients. Unlike controls, numerous nNOS-positive reactive astrocytes were found in AD patients around -amyloid plaques in CA1 and subiculum and at the places of clear and overt neuron loss, particularly in the entorhinal cortex layer II and CA4. This is the first evidence of nNOS-like immunoreactivity in reactive astrocytes in AD. In contrast to controls, in all but one AD subject, large numbers of ISEL-positive neuronal nuclei and microglial cells were found in the CA1 and CA4 regions and subiculum. Semiquantitative analysis showed that neuronal DNA fragmentation in AD match with the distribution of nNOS-expressing reactive astroglial cells in CA1 (r ؍ 0.74, P < 0.01) and CA4 (r ؍ 0.58, P < 0.05). A portion of the nNOS-positive CA2/CA3 pyramidal neurons was found to be spared even in the most affected hippocampi. A significant inverse correlation between nNOS expression and immunoreactivity to abnormally phosphorylated tau proteins (as revealed by AT8 monoclonal antibody) in perikarya of these CA2/3 neurons (r ؍ ؊0.85, P < 0.01) suggests that nNOS expression may provide selective resistance to neuronal degeneration in AD. In conclusion, our results imply that an upregulated production of NO by reactive astrocytes may play a key role in the pathogenesis of AD.
2009) Neuropathology and Applied Neurobiology 35, 532-554 Does Alzheimer's disease begin in the b... more 2009) Neuropathology and Applied Neurobiology 35, 532-554 Does Alzheimer's disease begin in the brainstem?
In a biological sense an individual's life is all about survival and reproduction. Beside the sel... more In a biological sense an individual's life is all about survival and reproduction. Beside the selection of a mate, the mutual commitment of a parent to sustain an infant through a period of dependency is amongst the most important aspects of natural selection. Here we review how the highly conserved circuitry of key midbrain and hypothalamic structures, and limbic and frontal cortical regions support these processes, and at the same time are involved in shaping the offspring's emotional development and behavior. Many recent studies provided new findings on how attachment behavior and parental bonding is promoted and maintained through genetic and epigenetic influences on synaptic plasticity of mirror neurons and various neuropeptide systems, particularly oxytocinergic, and how these systems serve to link social cues to the brain reward system. Most of this evidence suggests that stress, early parental deprivation and lack of care during the postnatal period leads to profound and lasting changes in the attachment pattern and motivational development with consequent increased vulnerability of the mesocortical and mesolimbic dopamine-associated reward reinforcement pathways to psychosocial stressors, abuse of stimulants and psychopathology later in life.
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Papers by Goran Simic