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1.
Dement Geriatr Cogn Dis Extra ; 8(1): 85-97, 2018.
Article in English | MEDLINE | ID: mdl-29706985

ABSTRACT

BACKGROUND: In this study, we examined the construct validity, concurrent validity concerning other standard scales, intrarater reliability, and changes in scores at 12 weeks of the previously developed ABC Dementia Scale (ABC-DS), a novel assessment tool for Alzheimer's disease (AD). METHODS: Data were obtained from 312 patients diagnosed with either AD or mild cognitive impairment. The scores on the ABC-DS and standard scales were compared. RESULTS: The 13 items of the ABC-DS are grouped into three domains, and the domain-level scores were highly correlated with the corresponding conventional scales. Statistically significant changes in assessment scores after 12 weeks were observed for the total ABC-DS scores. CONCLUSION: Our results demonstrate the ABC-DS to have good validity and reliability, and its usefulness in busy clinical settings.

2.
Am J Neurodegener Dis ; 2(4): 266-75, 2013.
Article in English | MEDLINE | ID: mdl-24319644

ABSTRACT

The clinical features of the genetically determined forms of familial Parkinson's disease (PD) have been described in multiple reports, but there have been few comparative neuropathologic studies. Five familial PD cases, with mutations in SNCA, were matched for age, sex, and Alzheimer type pathology with sporadic PD cases. Immunohistochemistry for phospho-tau and α-synuclein was performed in 8 brain regions. The frequency of tau pathology and the morphologic features of α-synuclein pathology in familial PD were compared with sporadic PD using semi-quantitative methods. In familial PD, there were significantly more tau positive extra-perikaryal spheroid-like and thread-like lesions than in the sporadic PD. There was no significant difference in the amount of α-synuclein positive neuronal perikaryal pathology between familial PD and sporadic PD, but α-synuclein positive oligodendroglial and neuritic lesions were significantly greater in familial PD compared to sporadic PD. In the substantia nigra, familial PD had more marked neuronal loss and fewer residential neurons with Lewy bodies than the sporadic PD, suggesting a close relationship between the severity of neuronal loss and Lewy body formation. The results show a diversity of pathological features of genetically determined familial PD, and they draw attention to the possible role of tau protein in neurodegeneration. Moreover, the presence of oligodendroglial inclusions at the light and electron microscopic levels in familial PD suggests that PD and multiple system atrophy form a continuum of α-synuclein pathology.

3.
J Neurol Neurosurg Psychiatry ; 83(4): 424-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22291217

ABSTRACT

PURPOSE: The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies. METHODS: A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented. RESULTS: MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology. CONCLUSION: This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Apolipoproteins E/genetics , Lewy Body Disease/genetics , Lewy Body Disease/pathology , alpha-Synuclein/genetics , tau Proteins/genetics , Aged, 80 and over , Brain/pathology , Female , Haplotypes , Humans , Lewy Bodies/pathology , Male , Organ Size , Parkinson Disease/genetics , Parkinson Disease/pathology , Polymorphism, Single Nucleotide
4.
Neuropathology ; 32(3): 272-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21978320

ABSTRACT

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD-tau) and FTLD with TDP-43 accumulation (FTLD-TDP) both cause PNFA. We reviewed clinical records of 29 FTLD-TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81-year-old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP-43-immunoreactive neuronal cytoplasmic inclusions and round or irregular-shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD-TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.


Subject(s)
Frontotemporal Lobar Degeneration/pathology , Primary Progressive Nonfluent Aphasia/pathology , Aged, 80 and over , Atrophy , Brain/pathology , Disease Progression , Fatal Outcome , Frontotemporal Lobar Degeneration/psychology , Functional Laterality/physiology , Humans , Inclusion Bodies/pathology , Japan , Magnetic Resonance Imaging , Male , Neurites/pathology , Neurons/pathology , Neuropsychological Tests , Primary Progressive Nonfluent Aphasia/psychology , TDP-43 Proteinopathies/pathology , Tissue Fixation , Ubiquitin/metabolism
5.
J Neurol Sci ; 314(1-2): 111-9, 2012 Mar 15.
Article in English | MEDLINE | ID: mdl-22041339

ABSTRACT

We performed a quantitative neuropathological examination of the hypometabolic regions on FDG PET in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and control cases. When the DLB cases were divided into two groups according to concomitant AD pathology (ADP), neuronal loss in the temporo-parietal association area was milder in the DLB groups than in the AD group, although there were no differences between the two DLB groups. Tau and Aß immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aß immunoreactivities as well as numbers of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) were more common in the AD group than in the DLB group with ADP. There was no difference in neuronal loss in the occipital area among the three groups. α-Synuclein immunoreactivity was observed in the DLB groups but not in the AD group. There were no differences in α-synuclein immunoreactivity and number of Lewy bodies (LBs) between the two DLB groups. These findings indicate that the neuropathological bases of the hypometabolic regions in the temporo-parietal association and occipital area in DLB may be AD pathology and Lewy pathology, respectively.


Subject(s)
Lewy Body Disease/diagnostic imaging , Lewy Body Disease/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Autopsy , Brain/diagnostic imaging , Brain/pathology , Cell Count , Data Interpretation, Statistical , Disease Progression , Female , Fluorodeoxyglucose F18 , Humans , Immunohistochemistry , Lewy Body Disease/pathology , Male , Middle Aged , Neurofibrillary Tangles/pathology , Neurons/pathology , Positron-Emission Tomography , Radiopharmaceuticals , alpha-Synuclein/metabolism , tau Proteins/metabolism
6.
Psychiatry Clin Neurosci ; 65(5): 529-32, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21851463

ABSTRACT

The present study sought to determine whether the co-occurrence of problem drinking heightens suicide risk in individuals with depression in Japan, using a sample of 784 outpatients (287 men and 497 women) with depressive disorder. Female subjects with at least a moderate problem drinking showed significantly more severe depression and suicidality than those without, but no such difference was identified in men.


Subject(s)
Alcoholism/psychology , Depressive Disorder/psychology , Diagnosis, Dual (Psychiatry)/psychology , Suicide/psychology , Adult , Alcoholism/complications , Cross-Sectional Studies , Depressive Disorder/complications , Diagnosis, Dual (Psychiatry)/adverse effects , Female , Humans , Male , Psychiatric Status Rating Scales/statistics & numerical data , Risk Factors , Self Report
7.
J Neuropathol Exp Neurol ; 70(4): 264-80, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21412173

ABSTRACT

There is emerging evidence implicating a role for the autophagy-lysosome pathway in the pathogenesis of Lewy body disease. We investigated potential neuropathologic and biochemical alterations of autophagy-lysosome pathway-related proteins in the brains of patients with dementia with Lewy bodies (DLB), Alzheimer disease (AD), and control subjects using antibodies against Ras-related protein Rab-7B (Rab7B), lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1A/1B light chain 3 (LC3). In DLB, but not in control brains, there were large Rab7B-immunoreactive endosomal granules. LC3 immunoreactivity was increased in vulnerable areas of DLB brains relative to that in control brains; computerized cell counting analysis revealed that LC3 levels were greater in the entorhinal cortex and amygdala of DLB brains than in controls. Rab7B levels were increased, and LAMP2 levels were decreased in the entorhinal cortex of DLB brains. In contrast, only a decrease in LAMP2 levels versus controls was found in AD brains. LC3 widely colocalized with several types of Lewy pathology; LAMP2 localized to the periphery or outside of brainstem-type Lewy bodies; Rab7B did not colocalize with Lewy pathology. Immunoblot analysis demonstrated specific accumulation of the autophagosomal LC3-II isoform in detergent-insoluble fractions from DLB brains. These results support apotential role for the autophagy-lysosome pathway in the pathogenesis of DLB.


Subject(s)
Brain/pathology , Lewy Bodies/metabolism , Lewy Bodies/pathology , Lewy Body Disease/pathology , Microtubule-Associated Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Adult , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Autophagy , Blotting, Western , Cell Count , Entorhinal Cortex/pathology , Female , Fluorescent Antibody Technique , HEK293 Cells , Humans , Immunohistochemistry , Lysosomal-Associated Membrane Protein 2 , Lysosomal Membrane Proteins/genetics , Lysosomal Membrane Proteins/physiology , Male , Middle Aged , Neurofibrillary Tangles/pathology , Plasmids/genetics , rab GTP-Binding Proteins/genetics , rab GTP-Binding Proteins/physiology , rab7 GTP-Binding Proteins
8.
Neuropathology ; 31(2): 135-43, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20880319

ABSTRACT

Nasu-Hakola disease is an autosomal recessively inherited disease characterized by lipomembranous polycystic osteodysplasia and sclerosing leukoencephalopathy. While white matter lesions prominent in the brain have been reported in the literature, gray matter lesions have not received particular attention. In this study, we examined three autopsy cases of Nasu-Hakola disease in order to focus specifically on gray matter lesions. The ages at onset of the three cases were 20, 23 and 29 years, and the disease durations were 29, 19 and 8 years, respectively. In addition to characteristic degeneration in the cerebral white matter, such as demyelination with conspicuous fibrillary gliosis and axonal changes, all three cases showed overt pathology in the gray matter. Neuronal loss with gliosis in the thalamus (particularly in the dorsomedial nucleus and anterior nucleus), caudate nucleus, putamen and substantia nigra was prominent in all cases, and the severity corresponded to the disease duration. The cerebral cortices were relatively preserved in all cases. One case showed neuronal loss and gliosis in the gray matter of the hippocampus, possibly due to repeated episodes of epileptic convulsions. These gray matter pathologies are considered to be responsible for some of the clinical manifestations of the disease, including extrapyramidal symptoms.


Subject(s)
Brain/pathology , Adult , Age of Onset , Autopsy , Female , Humans , Lipodystrophy/pathology , Lipodystrophy/physiopathology , Male , Middle Aged , Osteochondrodysplasias/pathology , Osteochondrodysplasias/physiopathology , Subacute Sclerosing Panencephalitis/pathology , Subacute Sclerosing Panencephalitis/physiopathology , Young Adult
9.
Neurosci Lett ; 486(1): 19-23, 2010 Dec 03.
Article in English | MEDLINE | ID: mdl-20851165

ABSTRACT

Parkinson's 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 Aß-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 Aß-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.


Subject(s)
Amyloid beta-Peptides/metabolism , Brain/metabolism , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Parkinson Disease/metabolism , Parkinson Disease/pathology , Aged , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Biomarkers/metabolism , Brain/pathology , Diagnosis, Differential , Female , Humans , Lewy Bodies/metabolism , Male , Neurofibrillary Tangles/metabolism , alpha-Synuclein/metabolism , tau Proteins/metabolism
10.
Mov Disord ; 25 Suppl 1: S78-82, 2010.
Article in English | MEDLINE | ID: mdl-20187227

ABSTRACT

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 alpha-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 alpha-synuclein pathologies.


Subject(s)
Lewy Bodies/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Severity of Illness Index , alpha-Synuclein/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Female , Humans , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Male , Supranuclear Palsy, Progressive/metabolism , Supranuclear Palsy, Progressive/pathology
11.
J Neuropathol Exp Neurol ; 68(9): 994-1005, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19680143

ABSTRACT

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.


Subject(s)
Brain/pathology , Endosomes/pathology , Lewy Body Disease/pathology , Lysosomes/pathology , Neurons/pathology , Protein Serine-Threonine Kinases/metabolism , Aged , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Brain/metabolism , Dementia/metabolism , Dementia/pathology , Endosomes/metabolism , Female , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Lewy Body Disease/metabolism , Lysosomes/metabolism , Male , Middle Aged , Neurons/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Pick Disease of the Brain/metabolism , Pick Disease of the Brain/pathology , Supranuclear Palsy, Progressive/metabolism , Supranuclear Palsy, Progressive/pathology
12.
Dement Geriatr Cogn Disord ; 27(3): 214-23, 2009.
Article in English | MEDLINE | ID: mdl-19225235

ABSTRACT

BACKGROUND/AIMS: Semantic dementia is a subtype of frontotemporal lobar degeneration, of which an initial symptom is semantic aphasia. Semantic dementia pathologically corresponds to atypical Pick's disease (aPiD), showing ubiq- uitin-positive inclusions similar to those in dementia with motor neuron disease (D-MND). Previous studies have not clarified the regions responsible for semantic aphasia in aPiD, and there have been no reported neuropathological studies concerning its pathomechanism. METHODS: We neuropathologically investigated aPiD and D-MND cases with and without semantic aphasia. RESULTS: We determined that the regions involved in the early stage of the disease course of semantic dementia were more restricted to the anterior and inferior portion of the temporal lobe on the side of the dominant hemisphere. CONCLUSION: Degeneration of the temporal pole is most likely to participate in the pathomechanism of SA in semantic dementia.


Subject(s)
Aphasia/pathology , Aphasia/psychology , Dementia/pathology , Dementia/psychology , Aged , Aged, 80 and over , Aphasia/etiology , Brain/pathology , Dementia/complications , Female , Gliosis/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Motor Neuron Disease/pathology , Pick Disease of the Brain/pathology
13.
Acta Neuropathol ; 117(2): 151-8, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19039597

ABSTRACT

To determine whether TAR-DNA binding protein 43 (TDP-43) immunoreactivity was present in brains of argyrophilic grain disease (AGD), we immunohistochemically examined 15 cases of AGD (mean age at death: 84 years) using a panel of anti-TDP-43 antibodies, including both phosphorylation-independent and -dependent ones. Nine AGD cases (60%) showed TDP-43 immunoreactivities mainly in the limbic regions and lateral occipitotemporal cortex. TDP-43 positive structures included neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, grain-like dot-shaped structures, and neurofibrillary tangle (NFT)-like structures. The distribution of these TDP-43 positive structures was largely consistent with that of argyrophilic grains. Double-labeling confocal microscopy revealed, however, that many of phospho-TDP-43 positive structures were not colocalized with phospho-tau staining. Colocalization of phospho-TDP-43 and phospho-tau was observed only in part of neuronal cytoplasmic inclusions, grain-like structures and NFT-like structures. There were no differences in demographics, disease duration, brain weight, NFT Braak stage, or severity of amyloid burden between AGD cases with and without TDP-43-immunoreactivity. However, cases of AGD with TDP-43-immunoreactivity were assigned to higher AGD stages than those without TDP-43-immunoreactivity (P < 0.05). Furthermore, the TDP-43 pathology tended to be prominent in cases with severe grain pathology. The results of the present study indicate for the first time a high frequency of concomitant TDP-43 pathology in AGD, and suggest that abnormal accumulation of TDP-43 may be involved in the pathological process and disease progression of AGD.


Subject(s)
Brain/metabolism , DNA-Binding Proteins/metabolism , Dementia/metabolism , Aged , Aged, 80 and over , Brain/pathology , Dementia/pathology , Female , Humans , Immunohistochemistry , Inclusion Bodies/metabolism , Male , Microscopy, Confocal , Neurofibrillary Tangles/metabolism , Neuroglia/metabolism , Neuroglia/pathology , Neurons/metabolism , Neurons/pathology , Organ Size , Phosphorylation , tau Proteins/metabolism
14.
Int J Clin Exp Pathol ; 1(5): 403-8, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18787622

ABSTRACT

Cerebral amyloid angiopathy (CAA) affects both leptomeningeal and parenchymal blood vessels and is common in Alzheimer's disease (AD). In some vessels, CAA is accompanied by localized neuritic dystrophy around the affected blood vessel. The aim of this study was to assess the distribution and severity of perivascular neuritic dystrophy in primary visual and visual association cortices. The severity of perivascular neuritic dystrophy and Abeta deposition was scored in an association cortex (Brodmann area 18) and a primary cortex (Brodmann area 17) with double labeling immunohistochemistry for tau and Abeta in 31 cases of AD with severe CAA. The perivascular tau neuritic dystrophy score was significantly worse in visual association cortex than in primary visual cortex. On the other hand, there was no difference in the perivascular Abeta score between the two cortices. There were positive correlations between the severity of perivascular tau and perivascular Abeta scores for both primary and association cortices. The results suggest that the local neuronal environment determines the severity and nature of the perivascular neuritic pathology more than the severity of the intrinsic vascular disease and suggest a close association between perivascular amyloid deposits, so-called dyshoric angiopathy, and perivascular neuritic dystrophy.

15.
Acta Neuropathol ; 116(1): 17-24, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18446351

ABSTRACT

We recently reported that Alzheimer's disease (AD) with amygdala Lewy bodies (ALB) is a distinct form of alpha-synucleinopathy that occurs in advanced AD. In AD/ALB the alpha-synuclein pathology correlated with tau pathology, but not amyloid plaques, and there was often co-localization of tau and alpha-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 alpha-synuclein pathology in the olfactory bulb and the amygdala in AD. We screened for alpha-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), alpha-synuclein pathology was detected in the olfactory bulb. Double immunolabeling at the light and electron microscopic levels revealed co-localization of tau and alpha-synuclein in the olfactory bulb neurons and neurites. The severity of tau pathology correlated with alpha-synuclein pathology in the olfactory bulb. In addition, alpha-synuclein pathology in the olfactory bulb correlated with alpha-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 alpha-synuclein pathology as the amygdala and suggests that neurodegeneration in these two anatomical regions is linked.


Subject(s)
Alzheimer Disease/pathology , Amygdala/pathology , Lewy Bodies/pathology , Olfactory Bulb/pathology , alpha-Synuclein/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Humans , Immunohistochemistry , Lewy Bodies/metabolism , Microscopy, Fluorescence , Microscopy, Immunoelectron , Neurofibrillary Tangles/pathology , Olfactory Bulb/metabolism
16.
J Alzheimers Dis ; 13(1): 53-66, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18334757

ABSTRACT

BACKGROUND: Protein cross-linking and aggregation are important molecular processes in Alzheimer's disease (AD), and tissue transglutaminase (tTG) catalyzes protein cross-linking. OBJECTIVES: To measure tTG, tTG enzyme activity and isopeptide, which is the product of tTG, in brain and to relate them to cognitive scores. METHODS: tTG and isopeptide levels were measured in frontal gray matter of 10 normal (NCI), 10 mild cognitive impairment (MCI) and 9 AD brains from the Religious Orders Study. tTG enzymatic activity was measured with a fluorescence assay. RESULTS: tTG protein and enzyme activity were highest in AD, but not significantly greater than MCI or NCI. In contrast, isopeptide immunoreactivity in formic acid extracts was significantly greater in AD than NCI and MCI. The level of insoluble formic acid extractable isopeptide correlated with several measures of cognitive function, including word generation and perceptual speed. Multiple linear regression analyses indicated that insoluble isopeptide immunoreactivity could be accounted for by a combination of factors in the formic acid extract, including Abeta, ubiquitin and tau. CONCLUSIONS: Accumulation of insoluble proteins with isopeptide bonds correlates with cognitive impairment. The relationship of isopeptide to other proteins that are also enriched in formic acid extracts suggests that several substrates of tTG may play a role in the pathogenesis of AD.


Subject(s)
Alzheimer Disease/enzymology , Alzheimer Disease/epidemiology , Carbon-Nitrogen Lyases/metabolism , Cerebral Cortex/immunology , Cerebral Cortex/metabolism , Cognition Disorders/epidemiology , Alzheimer Disease/pathology , Amyloid/metabolism , Antibodies, Monoclonal , Cerebral Cortex/pathology , Cognition Disorders/diagnosis , Frontal Lobe/immunology , Frontal Lobe/metabolism , Frontal Lobe/pathology , GTP-Binding Proteins , Humans , Neuropsychological Tests , Protein Glutamine gamma Glutamyltransferase 2 , Severity of Illness Index , Transglutaminases/metabolism , Ubiquitin/metabolism , tau Proteins/metabolism
17.
Prog Neuropsychopharmacol Biol Psychiatry ; 32(3): 755-60, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18226436

ABSTRACT

Adherence to antipsychotic treatment is particularly important in the long-term management of schizophrenia and other related psychotic disorders since poor adherence to medication is associated with poor health outcomes. Although the patients' subjective satisfaction with the medication is crucial for adherence to medication, few studies have examined the relationship between subjective satisfaction with antipsychotics and adherence. In this study, we investigated subjective satisfaction with antipsychotics in patients with schizophrenia by using the Treatment Satisfaction Questionnaire for Medication (TSQM), a self-reporting instrument to assess the major dimensions of patients' satisfaction with their medication. The subjects included 121 clinically stabilized outpatients who met the following criteria: 1) patients between 20 and 65 years of age, diagnosed with schizophrenia or other psychotic disorders as defined by DSM-IV, 2) patients undergoing oral antipsychotic monotherapy or taking only an antiparkinsonian agent as an adjuvant remedy, and 3) patients who had received a stable dose of an antipsychotic for more than four weeks. Patients were asked to answer the TSQM questions, and their clinical symptoms were also evaluated by the Brief Psychiatric Rating Scale (BPRS). Satisfaction with regard to side-effects (p=0.015) and global satisfaction (p=0.035) were significantly higher in patients taking second-generation antipsychotics (SGAs, n=111) than those taking first-generation antipsychotics (FGAs, n=10), whereas no significant difference was found between the two groups in clinical symptoms according to BPRS (p=0.637) or the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS, p=0.209). In addition, correlations were not significant between the subjective satisfactions and clinician-rated objective measures of the symptoms. These findings suggest that SGAs have more favorable subjective satisfaction profiles than FGAs in the treatment of schizophrenia. Since it is often difficult to detect the difference by a traditional objective assessment of the patients, it is desirable that physicians pay attention to the patients' subjective satisfaction in conjunction with their own objective clinical assessment.


Subject(s)
Antipsychotic Agents/therapeutic use , Patient Satisfaction , Schizophrenia/drug therapy , Schizophrenic Psychology , Adult , Analysis of Variance , Antipsychotic Agents/classification , Chi-Square Distribution , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Psychotic Disorders/drug therapy , Psychotic Disorders/psychology , Surveys and Questionnaires
18.
Acta Neuropathol ; 115(5): 561-75, 2008 May.
Article in English | MEDLINE | ID: mdl-18080129

ABSTRACT

While both neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD) show frontotemporal lobar degeneration and/or motor neuron disease, it remains unclear whether, and how, these diseases differ from each other. Here, we compared the clinicopathological characteristics of four BIBD and two NIFID cases. Atypical initial symptoms included weakness, dysarthria, and memory impairment in BIBD, and dysarthria in NIFID. Dementia developed more than 1 year after the onset in some BIBD and NIFID cases. Upper and lower motor neuron signs, parkinsonism, and parietal symptoms were noted in both diseases, and involuntary movements in BIBD. Pathologically, severe caudate atrophy was consistently found in both diseases. Cerebral atrophy was distributed in the convexity of the fronto-parietal region in NIFID cases. In both BIBD and NIFID, the frontotemporal cortex including the precentral gyrus, caudate nucleus, putamen, globus pallidus, thalamus, amygdala, hippocampus including the dentate gyrus, substantia nigra, and pyramidal tract were severely affected, whereas lower motor neuron degeneration was minimal. While alpha-internexin-positive inclusions without cores were found in both NIFID cases, one NIFID case also had alpha-internexin- and neurofilament-negative, but p62-positive, cytoplasmic spherical inclusions with eosinophilic p62-negative cores. These two types of inclusions frequently coexisted in the same neuron. In three BIBD cases, inclusions were tau-, alpha-synuclein-, alpha-internexin-, and neurofilament-negative, but occasionally p62-positive. These findings suggest that: (1) the clinical features and distribution of neuronal loss are similar in BIBD and NIFID, and (2) an unknown protein besides alpha-internexin and neurofilament may play a pivotal pathogenetic role in at least some NIFID cases.


Subject(s)
Brain/pathology , Inclusion Bodies/pathology , Intermediate Filaments/pathology , Neurodegenerative Diseases/pathology , Adult , Aged , Brain/metabolism , Female , Humans , Inclusion Bodies/metabolism , Intermediate Filaments/metabolism , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neurodegenerative Diseases/classification , Neurodegenerative Diseases/metabolism , Neurofilament Proteins/metabolism
19.
Brain Res ; 1184: 284-94, 2007 Dec 12.
Article in English | MEDLINE | ID: mdl-17963732

ABSTRACT

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 Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's 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.


Subject(s)
Alzheimer Disease/pathology , DNA-Binding Proteins/metabolism , Lewy Body Disease/pathology , alpha-Synuclein/metabolism , tau Proteins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Female , Humans , Lewy Body Disease/metabolism , Male , Middle Aged , Postmortem Changes , Ubiquitin/metabolism
20.
Neurosci Lett ; 419(3): 213-8, 2007 Jun 04.
Article in English | MEDLINE | ID: mdl-17507161

ABSTRACT

TAR-DNA-binding protein 43 (TDP-43) was identified as a major component of ubiquitin-positive intracellular inclusions from brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Here, we immunohistochemically investigated the appearance pattern of TDP-43 to compare the distribution of TDP-43-positive structures with that of ubiquitin-positive structures in brains of seven patients with Japanese FTLD-U, five of atypical Pick's disease (aPiD) and two of dementia with motor neuron disease (D-MND), as well as two patients with PiD as control. TDP-43-immunoreactivity generally colocalized to ubiquitin-immunoreactivity in both neuronal cytoplasmic inclusions and neurites in FTLD-U brains, but TDP-43-immunoreactivity alone or ubiquitin-immunoreactivity alone was also observed. In five aPiD cases, double-immunostaining with TDP-43 and ubiquitin demonstrated that diffuse neuronal cytoplasmic immunostaining for ubiquitin did not always display TDP-43-immunoreactivity. In contrast, ubiquitin-positive neuronal cytoplasmic inclusions usually displayed TDP-43-immunoreactivity in two D-MND cases, although most glial inclusions in one of two cases were immunostained only for TDP-43. TDP-43-positive structures were not detected in two PiD cases. Thus, the ratio in the appearance pattern of TDP-43 and ubiquitin was different between aPiD and D-MND, leading to the hypothesis that this difference may be associated with the two pathogenic variants related to clinical and pathological heterogeneity in FTLD-U.


Subject(s)
DNA-Binding Proteins/metabolism , Dementia/metabolism , Dementia/pathology , Inclusion Bodies/pathology , Ubiquitin/metabolism , Aged , Aged, 80 and over , Asian People , Brain/metabolism , Brain/pathology , Female , Humans , Immunohistochemistry , Inclusion Bodies/metabolism , Male , Middle Aged
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