Hirotake Uchikado

Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimers disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinsons disease, Picks disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.

Alzheimer disease with amygdala lewy bodies : A distinct form of α-synucleinopathy

Lewy bodies (LBs) are &agr;-synuclein-immunoreactive neuronal inclusions with a predilection for specific cortical and subcortical regions, including the amygdala. In this study, the presence of LBs was assessed in 347 cases of Alzheimer disease (AD). In 87 cases, LB pathology was diagnostic of brainstem (n = 3), transitional (n = 32), or diffuse (n = 52) Lewy body disease (LBD). The remaining 260 cases of AD were screened for amygdala LBs (AD/ALB) and 62 (24%) cases were found. If AD/LBD cases are included, LBs were detected in 149 (43%) cases of AD. The presence &agr;-synuclein pathology was assessed in multiple brain regions of the 62 cases of AD/ALB and 57 randomly selected cases of AD, and only sparse &agr;-synuclein pathology was detected in both. The burden of &agr;-synuclein pathology in brainstem nuclei, amygdala, and neocortex was significant lower in AD/ALB than in AD/LBD. In comparison to AD/LBD, AD/ALB did not differ in age at death, disease duration, male-to-female ratio, brain weight, Braak neurofibrillary tangle stage, average senile plaque density, or apolipoprotein E &egr;4 allele frequency. The results suggest that AD/ALB is pathologically different from AD/LBD, suggesting that it is a neuropathologically distinct and isolated &agr;-synucleinopathy.

Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia.

Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics.

Evidence in favor of Braak staging of Parkinson's disease†

Recently, Braak and coworkers proposed a pathologic staging scheme for Parkinson disease (PD). In this staging, scheme substantia nigra pathology occurs at midstage disease, while involvement of anterior olfactory nucleus, medulla, and pontine tegmentum occur earlier. In the last stages, Lewy bodies (LBs) involve cortical areas. The general principles of the proposed staging system have been confirmed in several studies of PD, but it does not appear to fit with all LB disorders. We studied the density and distribution of LBs with α‐synuclein immunohistochemistry in normal elderly with incidental LBs (N = 12); progressive supranuclear palsy (PSP) with incidental LBs (N = 18); Lewy body disease (LBD) with minimal or no Alzheimer type pathology (N = 52); LBD with concomitant Alzheimer disease (AD) (N = 84); and cases of AD with amygdala predominant LBs (N = 64). The proportion of cases that fit the PD staging scheme was 67% for incidental LBs; 86% for PSP with LBs; 86% for pure LBD; and 84% for LBD with AD; but only 6% for AD with amygdala predominant LBs. The PD staging scheme is valid, except in the setting of advanced AD. In this situation, LBs may be unrelated to PD and more likely related to factors inherent to AD and the selective vulnerability of the amygdala to both Alzheimer and α‐synuclein pathologies.

Neuropathology of Parkinson's disease dementia and dementia with Lewy bodies with reference to striatal pathology

Dementia is relatively common in Parkinsons Disease (PD). When dementia occurs in the setting of PD, it is referred to as Parkinsons disease dementia (PDD), which is distinguished from the clinical syndrome in which dementia precedes extrapyramidal features, dementia with Lewy bodies (DLB). In this report, the neuropathology of PDD and DLB is reviewed and preliminary findings are reported on striatal pathology in 28 brains, including 7 PD, 7 PDD and 14 DLB. Sections of putamen immunostained for a-synuclein and investigated with image analysis show that striatal pathology is common and that both cortical and striatal a-synuclein pathology is greater in PDD and DLB than PD. Most cases of PDD and DLB have Alzheimer-type pathology, particularly amyloid plaques, which may act in an additive or synergistic manner with a-synuclein pathology. There are few pathologic differences between PDD and DLB, despite differences in their clinical course.

Abnormal Localization of Leucine-Rich Repeat Kinase 2 to the Endosomal-Lysosomal Compartment in Lewy Body Disease

Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease and are also associated with diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We used immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. The immunoreactivity of LRRK2 was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions, or TAR-DNA-binding protein-43-positive inclusions. The immunoreactivity of LRRK2 frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala, and entorhinal cortex in patients with Parkinson disease or dementia with LBs. The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in dementia with LBs brains compared with age-matched control brains (p < 0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, the lysosomal-associated membrane protein 2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.

Serum ghrelin concentrations in patients receiving olanzapine or risperidone

RationaleAlthough enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanism is poorly understood.ObjectivesTo test the hypothesis that ghrelin, a gastrointestinal hormone that enhances appetite, is involved in increased food intake and weight gain during treatment with antipsychotics.MethodsSerum ghrelin concentrations were investigated in schizophrenic patients receiving olanzapine or risperidone, and in healthy volunteers.ResultsSerum ghrelin concentrations did not increase, but rather decreased, in patients treated with olanzapine or risperidone in comparison with healthy volunteers. No significant difference was found in serum ghrelin concentration between patients treated with olanzapine and risperidone.ConclusionsOur results indicate that ghrelin is not a direct cause of increased food intake and weight gain during treatment with olanzapine or risperidone, whereas ghrelin is associated with metabolic change in patients receiving these agents.

Co-localization of tau and α-synuclein in the olfactory bulb in Alzheimer's disease with amygdala Lewy bodies

We recently reported that Alzheimer’s disease (AD) with amygdala Lewy bodies (ALB) is a distinct form of α-synucleinopathy that occurs in advanced AD. In AD/ALB the α-synuclein pathology correlated with tau pathology, but not amyloid plaques, and there was often co-localization of tau and α-synuclein in the same neuron. Given the anatomical connectivity of the anterior olfactory nucleus and the amygdala, which receives axonal projections from the olfactory bulb, we hypothesized that there might be a relationship between tau and α-synuclein pathology in the olfactory bulb and the amygdala in AD. We screened for α-synuclein pathology in the olfactory bulb in AD with and without ALB, and investigated its relationship with tau pathology. In 38 of 41 (93%) AD/ALB cases and 4 of 21 (19%) AD cases without ALB (AD/non-ALB), α-synuclein pathology was detected in the olfactory bulb. Double immunolabeling at the light and electron microscopic levels revealed co-localization of tau and α-synuclein in the olfactory bulb neurons and neurites. The severity of tau pathology correlated with α-synuclein pathology in the olfactory bulb. In addition, α-synuclein pathology in the olfactory bulb correlated with α-synuclein pathology in amygdala. Tau pathology was greater in both the olfactory bulb and amygdala in AD/ALB than in AD/non-ALB, but there was no difference in tau pathology between the two groups in other brain regions assessed. The present study shows that in AD/ALB, the olfactory bulb is nearly equally vulnerable to tau and α-synuclein pathology as the amygdala and suggests that neurodegeneration in these two anatomical regions is linked.

Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.

Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0-I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia.

Serum adiponectin concentrations during treatment with olanzapine or risperidone: a pilot study

Adiponectin is a recently identified adipocyte-derived protein, which is associated with glucose metabolism, insulin sensitivity and adiposity. The aim of this study was to explore the alterations in serum adiponectin concentration during treatment with olanzapine orrisperidone. Serum concentrations of adiponectin were investigated in body mass index (BMI, kg/m2)- and age-matched groups of non-diabetic, non-obese schizophrenic patients receiving a stable dose of olanzapine (n=18) or risperidone (n=15) for 4 weeks or more, and of mentally and physically healthy volunteers (n=17). Patients undergoing treatment with olanzapine or risperidone had significantly higher adiponectin concentrations than the healthy volunteers, even after controlling for BMI. Adiponectin concentrations decreased with increasing BMI in patients taking olanzapine, while elevated levels were observed in patients taking risperidone, regardless of adiposity. This preliminary cross-sectional study indicates that adiponectin is involved in the regulation of glucose metabolism and weight in schizophrenic patients during treatment with olanzapine or risperidone, presumably showing a normalizing effect on metabolic abnormality.