Mihovil Mladinov

Does Alzheimer's disease begin in the brainstem?

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimers disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high‐order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake–sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging – Reagan Institute (NIA‐RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, β‐amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD‐related neuropathological changes.

Astrocyte expression of D2-like dopamine receptors in the prefrontal cortex

The dopaminergic system is of crucial importance for understanding human behavior and the pathogenesis of many psychiatric and neurological conditions. The majority of studies addressing the localization of dopamine receptors (DR) examined the expression of DR in neurons, while its expression, precise anatomical localization and possible function in glial cells have been largely neglected. Here we examined the expression of D2-like family of DR in neuronal and glial cells in the normal human brain using immunocytochemistry and immunofluorescence. Tissue samples from the right orbitomedial (Brodmann’s areas 11/12), dorsolateral (areas 9/46) and dorsal medial (area 9) prefrontal cortex were taken during autopsy from six subjects with no history of neurological or psychiatric disorders, formalin-fixed, and embedded in paraffin. The sections were stained using novel anti-DRD2, anti-DRD3, and anti-DRD4 monoclonal antibodies. Adjacent sections were labeled with an anti-GFAP (astroglial marker) and an anti-CD68 antibody (macrophage/microglial marker). The pyramidal and non-pyramidal cells of all three regions analyzed had strong expression of DRD2 and DRD4, whereas DRD3 were very weakly expressed. DRD2 were more strongly expressed in layer III compared to layer V pyramidal neurons. In contrast, DRD4 receptors had a stronger expression in layer V neurons. The most conspicuous finding was the strong expression of DRD2, but not DRD3 or DRD4, receptors in the white matter fibrous astrocytes and in layer I protoplasmic astrocytes. Weak DRD2-immunoreactivity was also observed in protoplasmic astrocytes in layers III and V. These results suggest that DR-expressing astrocytes directly participate in dopaminergic transmission of the human prefrontal cortex.

CSF tau proteins in differential diagnosis of dementia

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.

Annotation - Does Alzheimer's disease begin in the brainstem?

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimers disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high‐order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake–sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging – Reagan Institute (NIA‐RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, β‐amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD‐related neuropathological changes.

Does Alzheimer's disease begin in the brainstem? - Annotation

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimers disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high‐order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake–sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging – Reagan Institute (NIA‐RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, β‐amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD‐related neuropathological changes.

Gene expression profiling of the dorsolateral and medial orbitofrontal cortex in schizophrenia.

Abstract Schizophrenia is a complex polygenic disorder of unknown etiology. Over 3,000 candidate genes associated with schizophrenia have been reported, most of which being mentioned only once. Alterations in cognitive processing - working memory, metacognition and mentalization - represent a core feature of schizophrenia, which indicates the involvement of the prefrontal cortex in the pathophysiology of this disorder. Hence we compared the gene expression in postmortem tissue from the left and right dorsolateral prefrontal cortex (DLPFC, Brodmanns area 46), and the medial part of the orbitofrontal cortex (MOFC, Brodmanns area 11/12), in six patients with schizophrenia and six control brains. Although in the past decade several studies performed transcriptome profiling in schizophrenia, this is the first study to investigate both hemispheres, providing new knowledge about possible brain asymmetry at the level of gene expression and its relation to schizophrenia. We found that in the left hemisphere, twelve genes from the DLPFC and eight genes from the MOFC were differentially expressed in patients with schizophrenia compared to controls. In the right hemisphere there was only one gene differentially expressed in the MOFC. We reproduce the involvement of previously reported genes TARDBP and HNRNPC in the pathogenesis of schizophrenia, and report seven novel genes: SART1, KAT7, C1D, NPM1, EVI2A, XGY2, and TTTY15. As the differentially expressed genes only partially overlap with previous studies that analyzed other brain regions, our findings indicate the importance of considering prefrontal cortical regions, especially those in the left hemisphere, for obtaining disease-relevant insights.