Sleep Disorders in Alzheimer’s Disease: from Clinical Presentation to Neurobiological Findings

Poremećaji spavanja su učestali rani simptom Alzheimerove bolesti (AB) i vodeći uzrok smanjene kvalitete života bolesnika s AB. S neurobiološke strane poremećaji spavanja su iznimno važni jer omogućuju uvid u rane mehanizme i neurodegenerativne procese specifične za AB. Mnoga istraživanja ukazuju da su poremećaji spavanja u AB uzrokovani selektivnom degeneracijom jezgara koje potiču budnost i spavanje, a koje se nalaze u moždanom deblu i hipotalamusu. Od posebne je važnosti poremećaj sporovalnog spavanja koji dovodi do porasta razine tau proteina i beta amiloida u mozgu, što vjerojatno ima važnu ulogu u patofiziologiji AB. Osmišljavanje prospektivnih istraživanja koja kombiniraju opsežne kliničke podatke s modernim neuropatološkim metodama obećavajući su pristup za bolje razumijevanje biološke podloge poremećaja spavanja i razvoja terapije učinkovite u ranim stadijima AB.Sleep disorders are common early symptoms of Alzheimer’s disease (AD) and the leading cause of quality of life impairment in AD patients. In terms of neurobiology, sleep disorders are of exceptional importance as they may provide insight into early mechanisms and neurodegenerative processes specific to AD. Growing data indicate that sleep disruption in AD is caused by selective degeneration of sleep- and wake-promoting nuclei in the brain stem and hypothalamus. Disruption of slow-wave sleep increases the concentration of tau and amyloid-beta in the brain, which may represent an important part of the pathophysiology of AD. Designing prospective studies that combine comprehensive clinical data with modern neuropathological analyses is a promising strategy to elucidate the biological basis of sleep disorders, and open new avenues for early treatments of AD

Raspodjela i izraženost dopaminskih D2 receptora u prefrontalnoj moždanoj kori čovjeka i miša [Localization and expression of the dopamine D2 receptors in the prefrontal cortex of man and mouse]

The brain dopamine systems are of key importance for understanding human behavior as well as various psychiatric and neurological disorders. The existing studies showed inconclusive evidence for the expression of D2 dopaminergic receptors (DR2) using specific monoclonal antibodies in the human prefrontal cortex. Additionally, there have been contradictory reports in relation to the expression pattern of D2R in glial cells and subcellular localization of the long (D2L) and short (D2S) mRNA isoforms of DR2 have not been elucidated in the human brain. In this study we investigated the layer- and cell-specific localization and distribution of DR2 in the dorsolateral, orbitomedial and medial prefrontal human cortex. Dopamine DR2 and DR4 receptors had stronger expression than DR3 in all regions. DR2 and DR4 showed a bilaminar distribution pattern and were particularly expressed in the pyramidal cortical layers III and V. However, DR2 had stronger expression in layer III, whereas DR4 in layer V-VI. At the cellular level, DR2 were predominantly expressed in pyramidal neurons, although some interneurons also showed DR2-immunopositivity. Suprisingly, astrocytes localized in layer I and subcortical white matter showed significant DR2 expression. Contrary to previous findings, which localize DR2 to the cell membrane, we found a more distinct vesicular localization in the cytoplasm. This finding was repeadly confirmed through experiments on mouse primary cortical cultures, as well as SY5Y and NT2 cell cultures. Moreover, transfection of D2L and D2S into primary neuronal cultures showed a dynamic trafficking of these receptors. The mRNA expression of the long and short isoform of DR2 in the human dorsolateral and orbitomedial prefrontal cortex was assessed by using microarray chips. Although the expression of mRNA for both isoforms was not detectable, we analyzed various mouse brain regions (cortex, striatum, thalamus, hippocampus, brain stem) with qRT-PCR and showed that D2L had a stronger expression than D2S in all brain regions. However, D2S had a relatively stronger expression in brain stem and thalamus, indicating its presynaptic function. In conclusion, these results suggest an active role of astrocytes expressing dopaminergic receptors in the human PFC. Consequently, alterations of not only neuronal, but also glial DR expression may have clinical implications with respect to function of PFC and its disturbances in schizophrenia, drug abuse, depression and other psychopathological states

Brain asymmetries related to language with emphasis on entorhinal cortex and basal forebrain

Anatomical asymmetries of the human brain are important in at least four respects: 1) they can serve as potential indicators of the evolutionary foundations of language, 2) they can be used for comparative analysis of neural specializations for communication in primates, 3) they may provide underlying structural correlates for functional imaging (fMRI, PET) and genetic studies, and finally 4) they can be used for studying disorders which are suspected to result from either disturbed development of cerebral asymmetry or asymmetric damage to the brain. In the first part of this review, we give a general framework of this field through the brief descriptions of the milestone discoveries and major conceptual advances as they emerged throughout the last 150 years. In the second part, we provide a more detailed view on the functional relevance that asymmetries of the entorhinal cortex and basal forebrain may have on the language

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

The role of heterotopic (migratory) motoneurons (HMN) in the pathogenesis of spinal muscular atrophy (SMA) is still controversial. We examined the occurrence and amount of HMN in spinal cord tissue from eight children with SMA (six with SMA-I and two with SMA-II). All affected subjects were carrying a homozygous deletion of exon 7 in the SMN1 gene. Unlike controls, virtually free from HMN, all SMA subjects showed a significant number of HMN at all levels of the spinal cord. Heterotopic neurons were hyperchromatic, located mostly in the ventral white matter and had no axon or dendrites. More than half of the HMN were very undifferentiated, as judged from their lack of immunoreactivity for NeuN and MAP2 proteins. Small numbers of more differentiated heterotopic neurons were also found in the dorsal and lateral white matter region. As confirmed by ultrastructural analysis, in situ end labeling (ISEL) and CD68 immunoreactivity, HMN in the ventral outflow were found to have no synapses, to activate microglial cells, and to eventually die by necrosis. An unbiased quantitative analysis showed a significant negative correlation between age of SMA subjects (a reflection of the clinical severity) and the number of HMN. Subjects who died at older ages had increased number of GFAP-positive astrocytes. Complementing our previous report on motoneuron apoptosis within the ventral horns in SMA, we now propose that abnormal migration, differentiation, and lack of axonal outgrowth may induce motoneuron apoptosis predominantly during early stages, whereas a slower necrosis-like cell death of displaced motoneurons which "escaped" apoptosis characterizes later stages of SMA

Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in Down syndrome

Amyloid beta (Aβ) is thought to play a critical role in the pathogenesis of Alzheimer’s disease (AD). Prion-like Aβ polymorphs, or “strains”, can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aβ that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and Aβ strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various Aβ and tau species and used conformation-sensitive fluorescent probes to detect differences in Aβ strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of Aβ emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sporadic AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01298-0

Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia

Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied NLRP1 expression and content in the postmortem brain tissue of 10 schizophrenia and 10 control subjects. In the medial orbitofrontal cortex (Brodmann’s area 11/12) and dorsolateral prefrontal cortex (area 46) from both hemispheres of six schizophrenia subjects, the NLRP1 mRNA expression was significantly higher than in six control brains (p < 0.05). As the expression difference was highest for the medial orbitofrontal cortex in the right hemisphere, we assessed NLRP1-immunoreactive pyramidal neurons in layers III, V, and VI in the medial orbitofrontal cortex in the right hemisphere of seven schizophrenia and five control brains. Compared to controls, we quantified a significantly higher number of NLRP1-positive pyramidal neurons in the schizophrenia brains (p < 0.01), suggesting NLRP1 inflammasome activation in schizophrenia subjects. Layer III pyramidal neuron dysfunction aligns with working memory deficits, while impairments of pyramidal neurons in layers V and VI likely disrupt predictive processing. We propose NLRP1 inflammasome as a potential biomarker and therapeutic target in schizophrenia

Localization and expression of the dopamine D2 receptors in the prefrontal cortex of man and mouse

Istraživanje dopaminskog sustava ključno je za razumijevanje normalnog ljudskog ponašanja, kao i mnogih psihijatrijskih i neuroloških bolesti. Međutim, podatci o raspodjeli dopaminskih D2 receptora (DR2) u neuronima prefrontalnog korteksa čovjeka su nepotpuni, a rezultati izražaja DR2 u potpornim (glija) stanicama su oprečni. Nadalje, izraženost i stanična i subcelularna lokalizacija dugog (D2L) i kratkog (D2S) izo-oblika DR2 u moždanom tkivu čovjeka i miša te u staničnim modelima do sada još nisu istražene. U ovom doktorskom radu imunohistokemijskom i imunofluorescentnom metodom prikazana je slojevna i stanična raspodjela D2 skupine receptora u dorzolateralnoj, orbitomedijalnoj i medijalnoj prefrontalnoj moždanoj kori čovjeka. Dopaminski DR2 i DR4 receptori su bili značajno jače izraženi u odnosu na DR3 u svim regijama. Što se tiče slojevne raspodjele, DR2 i DR4 su pokazali bilaminarnu raspodjelu i bili posebno izraženi u piramidnim slojevima korteksa. Pritom su DR2 bili nešto izraženiji u III, a DR4 u V-VI kortikalnom sloju. Na staničnoj razini, DR2 su bili pretežno izraženi na piramidnim neuronima, a značajno manje interneuronima. Od glija stanica, astrociti prvog sloja i subkortikalne bijele tvari su pokazali značajnu DR2-imunoreaktivnost. Nasuprot uobičajenom mišljenju da su neurotransmitorski receptori pretežno izraženi na staničnoj membrani, ovdje se pokazalo da se DR2 u velikoj mjeri nalaze u citoplazmatskim vezikulama. Navedeni je nalaz potvrđen i proširen pokusima na primarnim kulturama kortikalnih neurona miša i staničnim kulturama SY5Y i NT2. Nadalje, transfekcijom primarnih neuronskih kultura genskim konstruktom za fluorescentno obilježene D2L i D2S pokazalo se da je kretanje navedenih receptora vrlo dinamičan proces. Osim toga, razina mRNA za D2L i D2S kvantitativno je istražena metodom mikropostroja u dorzolateralnoj i orbitomedijalnoj regiji korteksa čovjeka. Tom metodom razina mRNA za navedene receptore nije bila mjerljiva. Pokusi provedeni na uzorcima mišjeg mozga pomoću qRT-PCR pokazali su da je u svim analiziranim regijama (korteks, strijatum, talamus, hipokampus, moždano deblo) D2L jače izražen u odnosu na D2S. Međutim, D2S je u moždanom deblu i talamusu relativno jače izražen u odnosu na ostale regije, što ukazuje na njegovu presinaptičku funkciju. Zaključno, ovi rezultati ukazuju na aktivnu ulogu astrocita 62 koji izražavaju receptore za DR u PFC. Shodno tome, može se zaključiti da izraženost DR ne samo na neuronima, nego i na glija stanicama može imati kliničke implikacije s obzirom na djelovanje PFC i njegove poremećaje u shizofreniji, bolestima ovisnosti, depresiji i drugim psihopatološkim stanjima.The brain dopamine systems are of key importance for understanding human behavior as well as various psychiatric and neurological disorders. The existing studies showed inconclusive evidence for the expression of D2 dopaminergic receptors (DR2) using specific monoclonal antibodies in the human prefrontal cortex. Additionally, there have been contradictory reports in relation to the expression pattern of D2R in glial cells and subcellular localization of the long (D2L) and short (D2S) mRNA isoforms of DR2 have not been elucidated in the human brain. In this study we investigated the layer- and cell-specific localization and distribution of DR2 in the dorsolateral, orbitomedial and medial prefrontal human cortex. Dopamine DR2 and DR4 receptors had stronger expression than DR3 in all regions. DR2 and DR4 showed a bilaminar distribution pattern and were particularly expressed in the pyramidal cortical layers III and V. However, DR2 had stronger expression in layer III, whereas DR4 in layer V-VI. At the cellular level, DR2 were predominantly expressed in pyramidal neurons, although some interneurons also showed DR2-immunopositivity. Suprisingly, astrocytes localized in layer I and subcortical white matter showed significant DR2 expression. Contrary to previous findings, which localize DR2 to the cell membrane, we found a more distinct vesicular localization in the cytoplasm. This finding was repeadly confirmed through experiments on mouse primary cortical cultures, as well as SY5Y and NT2 cell cultures. Moreover, transfection of D2L and D2S into primary neuronal cultures showed a dynamic trafficking of these receptors. The mRNA expression of the long and short isoform of DR2 in the human dorsolateral and orbitomedial prefrontal cortex was assessed by using microarray chips. Although the expression of mRNA for both isoforms was not detectable, we analyzed various mouse brain regions (cortex, striatum, thalamus, hippocampus, brain stem) with qRT-PCR and showed that D2L had a stronger expression than D2S in all brain regions. However, D2S had a relatively stronger expression in brain stem and thalamus, indicating its presynaptic function. In conclusion, these results suggest an active role of astrocytes expressing dopaminergic receptors in the human PFC. Consequently, alterations of not only neuronal, but also glial DR expression may have clinical implications with respect to function of PFC and its disturbances in schizophrenia, drug abuse, depression and other psychopathological states

Localization and expression of the dopamine D2 receptors in the prefrontal cortex of man and mouse

Istraživanje dopaminskog sustava ključno je za razumijevanje normalnog ljudskog ponašanja, kao i mnogih psihijatrijskih i neuroloških bolesti. Međutim, podatci o raspodjeli dopaminskih D2 receptora (DR2) u neuronima prefrontalnog korteksa čovjeka su nepotpuni, a rezultati izražaja DR2 u potpornim (glija) stanicama su oprečni. Nadalje, izraženost i stanična i subcelularna lokalizacija dugog (D2L) i kratkog (D2S) izo-oblika DR2 u moždanom tkivu čovjeka i miša te u staničnim modelima do sada još nisu istražene. U ovom doktorskom radu imunohistokemijskom i imunofluorescentnom metodom prikazana je slojevna i stanična raspodjela D2 skupine receptora u dorzolateralnoj, orbitomedijalnoj i medijalnoj prefrontalnoj moždanoj kori čovjeka. Dopaminski DR2 i DR4 receptori su bili značajno jače izraženi u odnosu na DR3 u svim regijama. Što se tiče slojevne raspodjele, DR2 i DR4 su pokazali bilaminarnu raspodjelu i bili posebno izraženi u piramidnim slojevima korteksa. Pritom su DR2 bili nešto izraženiji u III, a DR4 u V-VI kortikalnom sloju. Na staničnoj razini, DR2 su bili pretežno izraženi na piramidnim neuronima, a značajno manje interneuronima. Od glija stanica, astrociti prvog sloja i subkortikalne bijele tvari su pokazali značajnu DR2-imunoreaktivnost. Nasuprot uobičajenom mišljenju da su neurotransmitorski receptori pretežno izraženi na staničnoj membrani, ovdje se pokazalo da se DR2 u velikoj mjeri nalaze u citoplazmatskim vezikulama. Navedeni je nalaz potvrđen i proširen pokusima na primarnim kulturama kortikalnih neurona miša i staničnim kulturama SY5Y i NT2. Nadalje, transfekcijom primarnih neuronskih kultura genskim konstruktom za fluorescentno obilježene D2L i D2S pokazalo se da je kretanje navedenih receptora vrlo dinamičan proces. Osim toga, razina mRNA za D2L i D2S kvantitativno je istražena metodom mikropostroja u dorzolateralnoj i orbitomedijalnoj regiji korteksa čovjeka. Tom metodom razina mRNA za navedene receptore nije bila mjerljiva. Pokusi provedeni na uzorcima mišjeg mozga pomoću qRT-PCR pokazali su da je u svim analiziranim regijama (korteks, strijatum, talamus, hipokampus, moždano deblo) D2L jače izražen u odnosu na D2S. Međutim, D2S je u moždanom deblu i talamusu relativno jače izražen u odnosu na ostale regije, što ukazuje na njegovu presinaptičku funkciju. Zaključno, ovi rezultati ukazuju na aktivnu ulogu astrocita 62 koji izražavaju receptore za DR u PFC. Shodno tome, može se zaključiti da izraženost DR ne samo na neuronima, nego i na glija stanicama može imati kliničke implikacije s obzirom na djelovanje PFC i njegove poremećaje u shizofreniji, bolestima ovisnosti, depresiji i drugim psihopatološkim stanjima.The brain dopamine systems are of key importance for understanding human behavior as well as various psychiatric and neurological disorders. The existing studies showed inconclusive evidence for the expression of D2 dopaminergic receptors (DR2) using specific monoclonal antibodies in the human prefrontal cortex. Additionally, there have been contradictory reports in relation to the expression pattern of D2R in glial cells and subcellular localization of the long (D2L) and short (D2S) mRNA isoforms of DR2 have not been elucidated in the human brain. In this study we investigated the layer- and cell-specific localization and distribution of DR2 in the dorsolateral, orbitomedial and medial prefrontal human cortex. Dopamine DR2 and DR4 receptors had stronger expression than DR3 in all regions. DR2 and DR4 showed a bilaminar distribution pattern and were particularly expressed in the pyramidal cortical layers III and V. However, DR2 had stronger expression in layer III, whereas DR4 in layer V-VI. At the cellular level, DR2 were predominantly expressed in pyramidal neurons, although some interneurons also showed DR2-immunopositivity. Suprisingly, astrocytes localized in layer I and subcortical white matter showed significant DR2 expression. Contrary to previous findings, which localize DR2 to the cell membrane, we found a more distinct vesicular localization in the cytoplasm. This finding was repeadly confirmed through experiments on mouse primary cortical cultures, as well as SY5Y and NT2 cell cultures. Moreover, transfection of D2L and D2S into primary neuronal cultures showed a dynamic trafficking of these receptors. The mRNA expression of the long and short isoform of DR2 in the human dorsolateral and orbitomedial prefrontal cortex was assessed by using microarray chips. Although the expression of mRNA for both isoforms was not detectable, we analyzed various mouse brain regions (cortex, striatum, thalamus, hippocampus, brain stem) with qRT-PCR and showed that D2L had a stronger expression than D2S in all brain regions. However, D2S had a relatively stronger expression in brain stem and thalamus, indicating its presynaptic function. In conclusion, these results suggest an active role of astrocytes expressing dopaminergic receptors in the human PFC. Consequently, alterations of not only neuronal, but also glial DR expression may have clinical implications with respect to function of PFC and its disturbances in schizophrenia, drug abuse, depression and other psychopathological states

Localization and expression of the dopamine D2 receptors in the prefrontal cortex of man and mouse

Istraživanje dopaminskog sustava ključno je za razumijevanje normalnog ljudskog ponašanja, kao i mnogih psihijatrijskih i neuroloških bolesti. Međutim, podatci o raspodjeli dopaminskih D2 receptora (DR2) u neuronima prefrontalnog korteksa čovjeka su nepotpuni, a rezultati izražaja DR2 u potpornim (glija) stanicama su oprečni. Nadalje, izraženost i stanična i subcelularna lokalizacija dugog (D2L) i kratkog (D2S) izo-oblika DR2 u moždanom tkivu čovjeka i miša te u staničnim modelima do sada još nisu istražene. U ovom doktorskom radu imunohistokemijskom i imunofluorescentnom metodom prikazana je slojevna i stanična raspodjela D2 skupine receptora u dorzolateralnoj, orbitomedijalnoj i medijalnoj prefrontalnoj moždanoj kori čovjeka. Dopaminski DR2 i DR4 receptori su bili značajno jače izraženi u odnosu na DR3 u svim regijama. Što se tiče slojevne raspodjele, DR2 i DR4 su pokazali bilaminarnu raspodjelu i bili posebno izraženi u piramidnim slojevima korteksa. Pritom su DR2 bili nešto izraženiji u III, a DR4 u V-VI kortikalnom sloju. Na staničnoj razini, DR2 su bili pretežno izraženi na piramidnim neuronima, a značajno manje interneuronima. Od glija stanica, astrociti prvog sloja i subkortikalne bijele tvari su pokazali značajnu DR2-imunoreaktivnost. Nasuprot uobičajenom mišljenju da su neurotransmitorski receptori pretežno izraženi na staničnoj membrani, ovdje se pokazalo da se DR2 u velikoj mjeri nalaze u citoplazmatskim vezikulama. Navedeni je nalaz potvrđen i proširen pokusima na primarnim kulturama kortikalnih neurona miša i staničnim kulturama SY5Y i NT2. Nadalje, transfekcijom primarnih neuronskih kultura genskim konstruktom za fluorescentno obilježene D2L i D2S pokazalo se da je kretanje navedenih receptora vrlo dinamičan proces. Osim toga, razina mRNA za D2L i D2S kvantitativno je istražena metodom mikropostroja u dorzolateralnoj i orbitomedijalnoj regiji korteksa čovjeka. Tom metodom razina mRNA za navedene receptore nije bila mjerljiva. Pokusi provedeni na uzorcima mišjeg mozga pomoću qRT-PCR pokazali su da je u svim analiziranim regijama (korteks, strijatum, talamus, hipokampus, moždano deblo) D2L jače izražen u odnosu na D2S. Međutim, D2S je u moždanom deblu i talamusu relativno jače izražen u odnosu na ostale regije, što ukazuje na njegovu presinaptičku funkciju. Zaključno, ovi rezultati ukazuju na aktivnu ulogu astrocita 62 koji izražavaju receptore za DR u PFC. Shodno tome, može se zaključiti da izraženost DR ne samo na neuronima, nego i na glija stanicama može imati kliničke implikacije s obzirom na djelovanje PFC i njegove poremećaje u shizofreniji, bolestima ovisnosti, depresiji i drugim psihopatološkim stanjima.The brain dopamine systems are of key importance for understanding human behavior as well as various psychiatric and neurological disorders. The existing studies showed inconclusive evidence for the expression of D2 dopaminergic receptors (DR2) using specific monoclonal antibodies in the human prefrontal cortex. Additionally, there have been contradictory reports in relation to the expression pattern of D2R in glial cells and subcellular localization of the long (D2L) and short (D2S) mRNA isoforms of DR2 have not been elucidated in the human brain. In this study we investigated the layer- and cell-specific localization and distribution of DR2 in the dorsolateral, orbitomedial and medial prefrontal human cortex. Dopamine DR2 and DR4 receptors had stronger expression than DR3 in all regions. DR2 and DR4 showed a bilaminar distribution pattern and were particularly expressed in the pyramidal cortical layers III and V. However, DR2 had stronger expression in layer III, whereas DR4 in layer V-VI. At the cellular level, DR2 were predominantly expressed in pyramidal neurons, although some interneurons also showed DR2-immunopositivity. Suprisingly, astrocytes localized in layer I and subcortical white matter showed significant DR2 expression. Contrary to previous findings, which localize DR2 to the cell membrane, we found a more distinct vesicular localization in the cytoplasm. This finding was repeadly confirmed through experiments on mouse primary cortical cultures, as well as SY5Y and NT2 cell cultures. Moreover, transfection of D2L and D2S into primary neuronal cultures showed a dynamic trafficking of these receptors. The mRNA expression of the long and short isoform of DR2 in the human dorsolateral and orbitomedial prefrontal cortex was assessed by using microarray chips. Although the expression of mRNA for both isoforms was not detectable, we analyzed various mouse brain regions (cortex, striatum, thalamus, hippocampus, brain stem) with qRT-PCR and showed that D2L had a stronger expression than D2S in all brain regions. However, D2S had a relatively stronger expression in brain stem and thalamus, indicating its presynaptic function. In conclusion, these results suggest an active role of astrocytes expressing dopaminergic receptors in the human PFC. Consequently, alterations of not only neuronal, but also glial DR expression may have clinical implications with respect to function of PFC and its disturbances in schizophrenia, drug abuse, depression and other psychopathological states

Cerebrospinal fluid markers in differential diagnosis of Alzheimer's disease and vascular dementia

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common causes of dementia in old people. They remain difficult to differentiate in practice because of lack of sensitivity and specificity of current clinical diagnostic criteria. Recent molecular and cellular advancements indicate that the use of cerebrospinal fluid markers may improve early detection and differential diagnosis of AD. Our objective in this study was to determine diagnostic accuracy of three cerebrospinal (CSF) markers: total tau protein (t-tau), tau protein phosphorylated on threonine 181 (p-tau181) and tau protein phosphorylated on serine 199 (p-tau199). Using commercially available ELISA kits concentrations of t-tau, p-tau181 and p-tau199 were analyzed in 12 patients with probable AD, 9 patients with VaD and 12 NC subjects. The median levels of all three markers were significantly higher in AD group versus VaD and NC groups. However, when the sensitivity levels were set to 85% or higher, only t-tau and p-tau199 satisfied consensus recommendations (specificity more than 75%) when differentiating AD from VaD. In conclusion, our preliminary data on a small group of selected subjects suggest that the CSF t-tau and p-tau199 levels are useful markers for differentiating AD from VaD