Pure psychiatric presentation of the Lewy body disease is depression--an analysis of 60 cases verified with myocardial meta-iodobenzylguanidine study.

OBJECTIVE: Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) were collectively termed Lewy body disease (LBD). Pure psychiatric presentation (PPP) of the LBD may be the fourth subtype in which psychiatric symptoms without definite parkinsonism and cognitive disturbance lasted for many years. The aim of this study is to localize the presence of the PPP in subjects with low uptake of myocardial meta-iodobenzylguanidine (MIBG). METHODS: Sixty MIBG-verified patients (28 women and 32 men) were classified into three psychiatric pictures; depression (Group D: 27 patients), isolated visual hallucinations (Group V: 16 patients) and psychosis (Group P: 17 patients). Fifty six cases were examined with single photon emission tomography (SPECT) study of the brains in which hypoperfusion lobes were identified in 37 cases and 19 cases showed no abnormality. After that, we determined final diagnoses; PD, PDD, DLB and PPP with an aid of the DSM-IV, the unified Parkinson's disease rating scale (UPDRS) and Mini-mental state examination (MMSE). RESULTS: Of Group D patients 40% remained depressive without parkinsonism and about 50% had or developed typical parkinsonism. Most Group P patients developed clinical pictures of PDD or DLB. Statistics provided four combinations: Group V-DLB-occipital lobe hypoperfusion, Group D-PD without SPECT abnormality, Group P-PDD with temporal lobe hypoperfusion and Group D-PPP without SPECT abnormality. CONCLUSIONS: PPP featured major depressive disorder and can be preparative of incidental LBD and prodromal depression of PD. Psychosis and dementia were of the same quality that characterizes the PDD.

Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT†R406W mutation presenting with a broad distribution of abundant senile plaques.

We report the autopsy results of a patient with familial dementia who was diagnosed as having frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with an R406W mutation in the microtubule-associated protein tau (MAPT) gene. This patient showed Alzheimer's disease (AD)-like clinical manifestations from the age of 59, with reduced ß-amyloid1-42 (Aß42 ) and elevated total and phosphorylated tau levels in the cerebrospinal fluid. He did not present with any apparent parkinsonism throughout the disease course. His autopsy at age 73 showed atrophy and neurodegeneration in many brain regions, particularly in the antero-medial temporal cortex and hippocampus, followed by the frontal lobes, with abundant neurofibrillary tangles. In addition, a diffuse distribution of Aß-positive senile plaques, including many neuritic plaques, was observed and classified as stage C according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. These results suggest that analyzing of the MAPT gene is essential for diagnosing familial dementia, even if amyloid markers such as Aß42 in the cerebrospinal fluid and amyloid imaging are positive, or if neuropathological findings indicate a diagnosis of AD.

Clinical Presentation and Imaging Findings of Irreversible Cerebral Amyloid Angiopathy-Related Inflammation (CAA-ri): A Case Report and Literature Review.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare condition primarily driven by an autoimmune reaction against cerebrovascular amyloid beta protein. Accurate diagnosis hinges on recognizing characteristic clinical symptoms and imaging features, such as asymmetric cerebral white matter lesions often linked to angioedema. We report the case of a woman in her 70s with progressive, irreversible CAA-ri who initially presented with left homonymous hemianopia and experienced significant psychiatric and neurological deterioration following an epileptic seizure. Despite initiating corticosteroid therapy seven months after onset, her condition continued to worsen, ultimately leading to her death in the 11th month due to general decline. This report reviews the clinical progression and imaging findings of the case, discusses the diagnostic process for CAA-ri, differentiates it from related conditions, and evaluates the timing of corticosteroid treatment.

Detection of Lewy body disease in patients with late-onset depression, anxiety and psychotic disorder with myocardial meta-iodobenzylguanidine scintigraphy.

PURPOSE: Lewy body disease (LBD) is comprised of a spectrum of diseases that includes Parkinson's disease (PD), PD dementia (PDD) and dementia with LBD (DLBD), an array of dementia, and motor symptoms. Low uptake of myocardial meta-iodobenzylguanidine (MIBG) validates diagnosis of LBD. Psychiatric symptoms sometimes precede atypical Parkinsonian syndromes in LBD. Of 34 patients with low MIBG uptake, late-onset depressive, anxiety, or psychotic symptoms were analyzed in term of clinical profiles. METHOD: Thirty-four patients were classed into three groups according to three main symptoms, 11 patients with visual hallucination (VH), 13 with depression-anxiety (DA), and 10 with psychosis with cognitive disturbance (PCD). Cutoff values of heart-to-mediastinum (HM) ratio of MIBG were set at 1.78 in early phase or 1.68 in late phase. RESULTS: Group VH patients showed a trend toward higher age at onset and occipital lobe hypoperfusion. Group DA patients lacked central and core features of DLBD and five of them showed frontal lobe hypoperfusion. Group PCD patients had the highest frequencies of suggestive symptoms and UPDRS scores and showed temporal lobe hypoperfusion. HM ratio was not associated with clinical profiles of three groups. Cognitive function was more severely disturbed in atypical Parkinsonian syndrome cases at an initial visit. CONCLUSION: Group VH was considered to DLBD, and Group PCD was regarded as PDD or DLBD with early psychotic presentation. Group DA has a possibility of early depression or anxiety disorder of LBD although it lacked DLBD criteria. Atypical Parkinsonian syndromes are associated with cognitive disturbance irrespective of psychiatric profiles.

Subcortical neurofibrillary tangles and argyrophilic grains in a case of familial frontotemporal dementia with parkinsonism.

A case of familial frontotemporal dementia with parkinsonism (FTDP) similar to progressive supranuclear palsy (PSP) was reported. A 58-year-old man developed personality change followed by parkinsonism and dementia. Three family members showed similar symptoms. Cerebral atrophy was marked on the anterior frontotemporal lobes. The substantia nigra, hippocampus, peri-aqueductal gray matter and pontine nucleus were affected with globose neurofibrillary tangles (NFT) and glial tangles. Argyrophilic grains were distributed in the CA1-CA2. NFT, glial tangles and argyrophilic grains expressed four-repeat microtubule-associated protein tau (MAPT). MAPT gene had no mutation. Familial occurrence of FTDP with PSP-like tauopathy is rare.

Correlation between astrocyte apoptosis and Alzheimer changes in gray matter lesions in Alzheimer's disease.

The relationships between astrocytic apoptosis and both senile plaques and neurofibrillary tangles (NFT) in gray matter lesions were examined quantitatively in Alzheimer's disease (AD) brains. Seven cortical regions were examined in seven AD brains by terminal dUTP nick end-labeling and immunolabeling with antibodies to glial fibrillary acidic protein, phosphorylated tau protein (AT180), apoptosis-related proteins (caspase-3, bcl-2, and CD95), and beta amyloid protein. Senile plaques showed the lowest density in the cornu ammonis. The density of apoptotic astrocytes was significantly correlated with the density of uncored and cored senile plaques. Neuronal caspase-3 and CD95 expression levels were too low to allow statistical assessment, but Bcl-2 was expressed strongly in the astrocytes and neurons with and without NFT. The correlation of the density of apoptotic astrocytes with apoptotic neurons and NFT was not statistically significant. The density of Bcl2-positive neurons correlated significantly with those of NFT and cored senile plaques, but Bcl2-positive astrocyte density showed no correlation with density of senile plaques or apoptotic astrocytes. These observations suggest that senile plaques may be a cause of astrocytic apoptosis in the gray matter, and that Bcl-2 protein is associated with NFT formation.

Severe delirium due to basal forebrain vascular lesion and efficacy of donepezil.

A severe intractable delirium caused by the basal forebrain vascular lesion and its dramatic recovery after donepezil administration were reported. A 68-year-old man had suffered for a month from delirium of mixed type caused by the right basal forebrain vascular lesion after surgery for craniopharyngioma. Magnetic resonance imaging (MRI) showed hemorrhagic infarcts in the head of the right caudate nucleus and the right basal forebrain of the medial septal nucleus, diagonal band of Broca and nucleus basalis of Meynert. He had been treated with anti-psychotics, anti-depressants and hypnotics, which resulted in little improvement. Donepezil administration dramatically improved his intractable delirium at the 19th post-donepezil administration day, but this was followed by amnestic symptoms. Clinical correlates of delirium with the basal forebrain lesion and efficacy of donepezil support the hypocholinergic theory of delirium.

Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease.

In addition to neuritic changes and amyloid deposits, neuronal and glial cell apoptosis is an important pathological feature of Alzheimer's disease (AD). Several factors have been postulated as causes or triggers of cellular apoptotic change. This study focused on a quantifiable relationship between phosphorylation sites of tau protein in the neurofibrillary tangles (NFT) and neuronal apoptosis. Five monoclonal anti-tau antibodies (AT180, AT8, HT7, Tau2 and Tau5) for NFT labeling and TdT-mediated UTP nick-end labeling (TUNEL) for localizing apoptotic change were employed. TUNEL-stained neuronal nuclei showed significantly high density in the entorhinal cortex, cornu ammonis (CA) and the parietal cortex. In all regions, density of TUNEL-stained neuronal nuclei showed significantly direct correlation with that of AT8-, AT180- and Tau2-positive neurons. Correlation of TUNEL-stained neuronal nuclei with tau-positive neurons differed depending on the cerebral regions. Density of TUNEL-stained neuronal nuclei showed inverse correlation with that of both AT8-positive and Gallyas-stained NFT in the CA and showed significantly direct correlation with AT8- and HT7-positive neurons in the frontal cortex. Density of tau-positive and Gallyas-stained NFT was higher than that of TUNEL-stained nuclei. We conclude that phosphorylation sites of tau, 159-163 and 202-205, are probably associated with neuronal apoptosis and apoptotic change follows abnormal phosphorylation of tau.

14-3-3 protein beta isoform is associated with 3-repeat tau neurofibrillary tangles in Alzheimer's disease.

14-3-3 proteins play roles in phosphorylation of tau proteins in neurofibrillary tangles (NFT) in Alzheimer's disease (AD). Tau is phosphorylated at serine (pSer) and threonine (pThr) in NFT, and NFT morphology varies according to phosphorylated sites and tau isoform. The roles of 14-3-3 proteins in NFT morphology remain unknown. This study was performed to examine the relationships between 14 and 3-3 proteins and tau phosphorylation of NFT. NFT were labeled with Gallyas impregnation, tau and 14-3-3 immunohistochemistry in paraffin-embedded hippocampal sections from seven AD and three control brains. Anti-tau antisera included monoclonal antisera that recognize pSer262 (pSer262), pSer422 (pSer422), pSer202/pThr205 (AT8), Thr231 (AT180), three-repeat (RD3) and four-repeat (RD4) tau isoform. Anti-14-3-3 protein isoform antisera included polyclonal antisera to beta, gamma, zeta, epsilon, tau, mu and sigma isoforms and monoclonal antiserum to beta antiserum (H8-beta). NFT density was obtained by counting labeled NFT in cornu ammonis (CA) 1-CA4, subiculum and entorhinal cortex. H8-beta and zeta isoforms were strongly expressed in NFT. Regional densities of NFT positive for pSer262, AT8, AT180, and Gallyas impregnation were similar to RD3-positive NFT density with high densities in CA1 and entorhinal cortex. NFT positive for pSer422 showed a similar regional distribution to RD4-positive NFT with high NFT density in CA2-CA4. H8-beta-positive NFT showed a similar regional distribution to RD3-positive NFT. In contrast, zeta isoform-positive NFT showed no specific distribution. In conclusion, H8-beta isoform is associated with development of 3-repeats NFT but a role of 14-3-3 zeta isoform in NFT could not be specified.

Association of minimal thickness of the medial temporal lobe with hippocampal volume, maximal and minimal hippocampal length: volumetric approach with horizontal magnetic resonance imaging scans for evaluation of a diagnostic marker for neuroimaging of Alzheimer's disease.

A 3-D volumetric study of the medial temporal lobe (MTL) was performed to evaluate how a minimum thickness of the MTL (mtMTL), a visually estimated measure, is associated with other MTL measures, maximal and minimal hippocampal length (max-HL, min-HL) and hippocampal volume, all measured with a 3-D device, Neurolucida, in 33 patients with Alzheimer's disease (AD), seven patients with mild cognitive impairment (MCI), and 20 age-matched controls. Cognitive impairment was evaluated with Mini-Mental State examination (MMSE). The T1-weighted horizontal magnetic resonance imaging (MRI) scans with slices 5 mm thick were analyzed with Neurolucida and the mtMTL was measured with visual estimation. The MTL was divided into the amygdala and hippocampus. Max-HL on both sides was longer in controls than in AD and MCI, whereas min-HL and mtMTL were longer in controls than in AD, and no difference was observed between MCI and controls. Similarly hippocampal volume was larger in controls than in AD, and no differences were seen within the MCI and controls. No difference in amygdala and midbrain volumes was observed among AD, MCI and controls. Correlation of MMSE score with min-HL and mtMTL was higher than that with max-HL. Although hippocampal and MTL measures examined here failed to show significant difference between AD and MCI, max-HL could be a diagnostic neuroimaging sign of AD. The high correlation of MMSE with mtMTL as well as with min-HL compared with that with max-HL, also will support neuroimaging diagnosis of AD.

Leptomeningeal carcinomatosis from urinary bladder adenocarcinoma: a clinicopathological case study.

We report a 73-year-old male patient with leptomeningeal metastasis from urinary bladder adenocarcinoma. He was presented with prominent hyperactive delirium during the course of the disease. Meningeal carcinomatosis was detected 5 days before his death, but the primary site of the malignant tumor could not be determined. Necropsy revealed leptomeningeal infiltration of many adenocarcinoma cells that covered the cerebrum. The leptomeninges of the right middle frontal gyrus, superior temporal gyrus, precentral gyrus and inferior parietal lobe were most severely affected by tumor cell infiltration. Cerebral edema was found to extensively cover the basal part of the temporal lobe. In the cerebrum, tumor cells were clustered in the perivascular spaces and had invaded localized areas of the frontal lobe. Vascular cell adhesion molecule (VCAM)-1 expression was detected in the small vessels of the cerebral upper cortical layers and of temporal subcortical u-fibers. Numerous astrocytes positive for cytokeratin AE1/AE3 were found in the frontal and temporal lobes. Meningeal carcinomatosis from urinary bladder adenocarcinoma is extremely rare and up-regulation of the adhesion molecules in the meningeal adenocarcinoma was confirmed.

Immunohistochemical study of neuronal intranuclear and cytoplasmic inclusions in Machado-Joseph disease.

Machado-Joseph disease (MJD) is a dominantly inherited spinocerebellar disorder, and expansions of trinucleotide (CAG) at chromosome 14 have been shown to be the locus of this disorder. Polyglutamine CAG stretches in the neuronal cytoplasms and nuclei were studied with immunolabeling using 1C2, a monoclonal antibody recognizing polyglutamine stretches, and polyclonal antiubiquitin antibody in six genetically verified cases of MJD. 1C2 clearly labeled two types of neuronal intranuclear inclusions (NII) and neuronal cytoplasmic inclusions (NCI) in the substantia nigra, pontine nucleus, dentate nucleus and spinal anterior horn where NII and NCI were also positive for ubiquitin, as were extracellular dot-like structures and oligodendroglial inclusions. 1C2-positive NII and NCI had a lesion-specific distribution. While the spinal motoneurons contained only 1C2-positive NCI and lacked 1C2-positive NII, the ventral pontine nucleus neurons had many 1C2-positive NII and few 1C2-positive NCI. Semi-quantitative examination of NII and NCI positive for 1C2 or ubiquitin demonstrated that there were more 1C2-positive NII and NCI than ubiquitin-positive ones. It is noteworthy that the nuclei of the spinal motoneurons lacked 1C2-positive immunoreactivity, so that ubiquitination of 1C2-positive structures is presumed to occur late in the course of the disease.

Regional analysis of differently phosphorylated tau proteins in brains from patients with Alzheimer's disease.

Neurofibrillary tangles (NFT) in Alzheimer's disease (AD) are composed of abnormally phosphorylated tau proteins. Many phosphorylation sites have been reported in the AD brain, and NFT distribution was now roughly classified into 3 stages by Braak stage; this classification is based on pathological studies using the specific silver impregnation technique. The aim of our study was to examine the regional distribution of differently phosphorylated tau proteins with 5 site-specific monoclonal antibodies against the tau proteins, AT8, AT180, HT7, Tau2 and Tau5. We then compared our findings with those obtained from silver-stained NFT in an attempt to clarify the relationship between abnormal phosphorylation sites of the tau protein and NFT development. AT180 and AT8 labeled the highest and Tau2 the lowest density of NFT in any regions, while Tau5 and HT7 showed inconsistent distribution. In the limbic cortex, cornu ammonis, entorhinal cortex and cingulate cortex, silver-stained NFT density significantly correlated with density of NFT labeled with the 5 anti-tau antibodies, but cerebral isocortices showed heterogenous patterns of tau-positive NFT. Quantification of tau-positive regional NFT density showed that the AD-associated phosphorylation process progresses from the C-terminal to the N-terminal of the amino acid sequence, and correlation of Gallyas-stained NFT density with tau-labeled NFT density was more significant in the limbic cortices than the cerebral isocortices, which implies that stereotypical phosphorylation occurs in the limbic structures.

Pick's disease pathology of a missense mutation of S305N of frontotemporal dementia and parkinsonism linked to chromosome 17: another phenotype of S305N.

We report the second phenotype of frontotemporal dementia and parkinsonism linked to chromosome 17 with S305N similar to Pick's disease pathology in two brothers. The brain of the older brother showed macroscopic atrophy compatible with Pick's disease, and subsequent tau gene analysis revealed heterozygous S305N mutation in exon 10 of the tau gene. Round-shaped neuronal inclusions similar to Pick's bodies were positive for phosphorylated serine 262 as well as other anti-tau antisera, which is different from immunoexpression of Pick's bodies. Ultrastructurally, these neuronal inclusions consisted of straight, randomly orientated fibrils measuring approximately 10-20 nm in width and 60-600 nm in length. This ultrastructural profile is similar to that of the first case of S305N. S305N reported here can cause another phenotype closely resembling Pick's disease.