Naoji Amano

Advanced Glycation End Products in Alzheimer’s Disease and Other Neurodegenerative Diseases

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimers disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimers disease and other neurodegenerative diseases (progressive supranuclear palsy, Picks disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimers brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimers disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Picks bodies in Picks disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimers disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimers disease.

Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy

Abstract Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are characterized by their unique clinical features and neuronal pathology. Although astrocytic plaques and tufts of abnormal fibers have been suggested to be specific histopathologic markers, recent studies have revealed significant clinicopathologic overlap between CBD and PSP. Based on the distinctive camera lucida profile of astrocytic inclusions on Gallyas-Braak silver staining, we found that astrocytic plaques and tufts of abnormal fibers did not coexist in the same patient among 30 cases of clinically diagnosed CBD, PSP and atypical Parkinson’s disease. Using Tau immunohistochemistry it was difficult to verify the absence of tufts of abnormal fibers. A morphometric analysis revealed that the two groups classified by the presence or absence of astrocytic plaques and tufts of abnormal fibers exhibited significant differences in the density of ballooned neurons and neurofibrillary tangles and degeneration of the subcortical nuclei. Assessment using the NINDS neuropathologic criteria revealed that the cases with astrocytic plaques and tufts of abnormal fibers closely correspond to CBD and typical PSP, respectively. In addition, the cases lacking either of these two astrocytic inclusions had atypical PSP according to the NINDS criteria, and were associated with novel tau-positive astrocytes (spiny astrocytes). We thus conclude that astrocytic plaques and tufts of abnormal fibers are highly characteristic structures for CBD and typical PSP, respectively. We emphasize the importance of strict differentiation between different astrocytic inclusions not only for diagnosis, but also for further studies for elucidation of their role in the disease mechanisms of CBD and PSP.

The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems

Abstract The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) were studied based on 30 cases of multiple system atrophy (MSA), including striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) and Shy-Drager syndrome. GCIs were widely spread throughout the central nervous system, including the striatonigral and olivopontocerebellar systems. Inclusion-bearing cells appeared to be oligodendrocytes which usually had larger and lighter nuclei than those of normal-looking oligodendrocytes. The distribution of GCIs was similar in all cases, irrespective of the degrees of OPCA and SND, but the frequency of GCIs varied from case to case. We classified all the cases into two categories based on the degree of neuropathological changes of SND (mild and severe) and, independently, into three groups based on that of OPCA (minimal, moderate, and severe), i.e., a total of six groups. An association between the frequency of GCIs and the severity of the lesions was obtained. For example, many GCIs exist in the cerebellar white matter in the cases in which OPCA was not histologically confirmed. More GCIs were seen in the cases with moderate OPCA. In the cases with severe OPCA, GCIs were rarer and smaller, in proportion to the devastation of fibers; no GCIs were seen in the cases with more severe OPCA. The incidence of GCIs showed a positive correlation to the severity of OPCA but not that of SND in the corticopontine tracts, of both OPCA and SND in the pyramidal tracts, and of SND but not of OPCA in the pencil fibers of the putamen. It is suggested that GCIs may represent either a change synchronous with neuronal degeneration or a phenomenon preceding neuronal changes, especially in the cerebellar white matter. Thus, they may represent the early changes in MSA and may be a useful neuropathological hallmark for diagnosis of MSA, even in cases with minimal OPCA and SND.

Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder

Elevated peripheral levels of interleukin-6 (IL-6) are common findings in schizophrenia and depression. However, previous studies that measured cerebrospinal fluid (CSF) IL-6 levels in these disorders reported controversial results. The present study examined whether CSF IL-6 levels are altered in patients with schizophrenia and those with depression. Lumbar punctures were performed in 32 patients with schizophrenia, 30 with major depressive disorder (MDD), and 35 healthy controls. Serum samples were simultaneously collected from all subjects in the patient groups and from 32 of the control group. CSF and serum IL-6 levels were determined by enzyme-linked immunosorbent assay. Both the patients with schizophrenia and MDD had significantly higher CSF IL-6 levels compared to the controls (schizophrenia: P = 0.0027; MDD: P = 0.012). IL-6 levels were significantly higher in the CSF than in the serum. No significant correlation was observed between CSF and serum IL-6 levels. The present findings suggest that IL-6 of central origin is associated with the pathophysiology of schizophrenia and MDD, although confounding effect of smoking status can not be entirely excluded.

Aberrant expression of bcl-2 gene family in Down's syndrome brains

Downs syndrome (DS) patient brains are known to develop prematurely the same degenerative changes as those seen in Alzheimers disease (AD). On the assumption that the apoptotic mechanism is involved in the neuronal loss in DS, we have investigated the expression of the bcl-2 gene family in DS brains and found marked alterations. The most prominent changes were in the temporal lobes where neuronal loss was greatest. Our findings suggest that a apoptotic process is involved in the neuronal loss in DS.

Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immunocytochemical and ultrastructural study

SummaryArgyrophilic intracytoplasmic inclusions in oligodendrocytes (AGCIs) were seen in all of 15 cases of multiple system atrophy (MSA), and none in other neurodegenerative diseases, including 9 cases of Menzel-type olivopontocerebellar atrophy and 4 cases of Josephs disease. The inclusions were widespread, not only in the olivopontocerebellar and striatonigral systems but also among fibers connecting their affecting lesions of MSA. Immunohistochemically, they were closely associated with tau, tubulins and microtubuleassociated protein 5. Ultrastructurally, they consisted of 30-to 50-nm filaments (not tubules) and electron-dense granules, in varying proportions, and their formation is discussed. The specific occurrence of AGCIs could be a key to approach the pathogenesis of MSA.

Negative correlation between cerebrospinal fluid oxytocin levels and negative symptoms of male patients with schizophrenia

BACKGROUND Accumulating evidence indicates that oxytocin plays an important role in social interactions. Previous studies also suggest altered oxytocin function in patients with schizophrenia and depression. However, few studies have examined the central oxytocin levels in these disorders. METHODS Cerebrospinal fluid (CSF) oxytocin levels were measured by ELISA in male participants consisting of 27 patients with schizophrenia, 17 with major depressive disorder (MDD), and 21 healthy controls. RESULTS CSF oxytocin levels of patients with schizophrenia or MDD did not differ significantly with healthy controls. The antidepressant dose or the Hamilton depression rating scale score did not significantly correlate with the oxytocin levels in MDD patients. CSF oxytocin levels in schizophrenic patients significantly negatively correlated with second generation antipsychotic dose (r=-0.49, P=0.010) but not with first generation antipsychotic dose (r=-0.13, P=0.50). A significant correlation was observed between oxytocin levels and negative subscale of PANSS (r=-0.38, P=0.050). This correlation remained significant even after controlling for second generation antipsychotic dose (r=-0.47, P=0.016). CONCLUSIONS We obtained no evidence of altered CSF oxytocin levels in patients with schizophrenia or those with MDD. However, lower oxytocin levels may be related to higher second generation antipsychotic dose and more severe negative symptoms in schizophrenia.

Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy.

SummaryThe fine structure of neurofibrillary tangles in the hippocampal gyrus, substantia nigra, pontine nuclei and locus coeruleus of the brain was postmortem studied in a case of progressive supranuclear palsy. Straight tubules and twisted tubules were observed in both the cortical and subcortical neurofibrillary tangles. Most tubules appeared separately in each neuron but a few straight tubules were mixed with the twisted tubules in the cortical tangles. The implication and possible significance of this findings are discussed.

Distribution of tangles and threads in the cerebral cortex in progressive supranuclear palsy

Recent studies have described silver‐ and tau‐positive glia and threads in the degenerating lesions of progressive supranuclear palsy. In this study, Gallyas‐Braak silver impregnation and several immunohistochemical techniques were employed to examine the distribution of tangles, abnormal glia and threads in the cerebral cortex of nine cases of progressive supranuclear palsy. In addition to neurofibrillary tangles, argentophilic glia and threads were impregnated exclusively by GaIIyas‐Braak technique. This technique demonstrated two types of glia profiles: tightly coiled intra‐cytoplasmic profiles surrounding nuclei (coiled profiles) and thorn‐like profiles with radial ramifications (thorn‐like profiles). Thorn‐like profiles are possibly in astrocytes and were detected in the cerebral cortex, while coiled profiles are possibly in oligodendroglia and were detected both in the cerebral cortex and subcortical white matter. Topographically, many neurofibrillary tangles were constantly seen in the frontal cortex and in the pre‐central gyrus. Numerous neurofibrillary tangles were detected in the entorhinal cortex of the two brains. Argentophilic glia and threads were also frequent both in the frontal cortex and the precentral gyrus: however, they were more frequent in the pre‐central gyrus that in the frontal cortex in four of the eight cases examined. In two brains, argentophilic threads were distributed widely in the cerebral cortex and white matter except for the temporal cortex. In immunohistochemical studies, argentophilic glia and threads were mostly positive for Tau 2, and a small number of them were weakly positive for ubiquitin and paired helical filament protein. The immunoproperties of these abnormal glia and threads seemed to be virtually identical to those of neurofibrillary tangles. These findings indicate that cytoskeletal abnormalities related with abnormal tau proteins may occur concordantly both in neuronal and glial cells, especially in the pre‐central gyrus. Cytoskeletal abnormalities occurring in the sub‐cortical nuclei may be involved in the primary motor cortex.

Neuroanatomical correlates of attention-deficit-hyperactivity disorder accounting for comorbid oppositional defiant disorder and conduct disorder

Aim:  An increasing number of neuroimaging studies have been conducted to uncover the pathophysiology of attention‐deficit–hyperactivity disorder (ADHD). The findings are inconsistent, however, at least partially due to methodological differences. In the present study voxel‐based morphometry (VBM) was used to evaluate brain morphology in ADHD subjects after taking into account the confounding effect of oppositional defiant disorder (ODD) and conduct disorder (CD) comorbidity.