Suzuka Ataka

A New Amyloid β Variant Favoring Oligomerization in Alzheimer's-Type Dementia

Soluble oligomers of amyloid β (Aβ), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimers disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question.

High Striatal Amyloid β-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types

BACKGROUND Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid beta-peptide (Abeta)-centric theory holds that Abeta is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Abeta levels before symptoms arise. OBJECTIVES To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Abeta burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. DESIGN Correlation analysis of positron emission tomography (PET) imaging studies. SETTING Academic research. PARTICIPANTS Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid beta-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. MAIN OUTCOME MEASURE Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. RESULTS All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Abeta burden was related to cognitive status. CONCLUSIONS Consistent with previous studies, the pattern of Abeta deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Abeta deposition were not associated with mutation type nor cognitive status.

Serum levels of albumin-amyloid beta complexes are decreased in Alzheimer's disease

Decreased amyloid β (Aβ) clearance from the brain to blood might play a key role in the development of Alzheimers disease (AD). Aβ is normally bound to and transported by albumin in blood, thus possibly maintaining constant concentration of free Aβ in the blood. We therefore hypothesized that decreased blood levels of albumin‐Aβ complexes could be associated with decreased Aβ removal from the brain to blood, resulting in Aβ accumulation in the brain.

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Background/Aims: Oligomeric amyloid β (Aβ) is currently considered to induce Alzheimer’s disease (AD). We examined 2 patients with familial AD who possessed the Osaka (E693Δ) mutation in amyloid precursor protein. To the best of our knowledge, these patients are the first AD cases presumably affected with Aβ oligomers in the absence of senile plaques, and they support the Aβ oligomer hypothesis. Methods: We evaluated the clinical course, neuropsychological data, cerebrospinal fluid biomarker levels, magnetic resonance imaging (MRI) scans, fluorodeoxyglucose-positron emission tomography (PET) scans, and Pittsburgh compound B (PiB)-PET images of these patients. Results: In the early stages, these patients developed memory disturbances in a similar rate to patients with sporadic AD. Despite their memory disturbances, both patients showed only limited brain atrophy on MRI and little amyloid accumulation on PiB-PET. Subsequent to the development of memory disturbances, both patients suffered from motor dysfunction, probably due to cerebellar ataxia, and, within a few years, the patients fell into an apallic state. Conclusions: Familial AD patients with Osaka (E693Δ) mutation show severe dementia, cerebellar ataxia, and gait disturbances.

Neuropsychological status of elderly patients with diabetes mellitus

AIM Diabetes mellitus (DM) is an important risk factor for Alzheimers disease (AD) but the relationship between DM and amnestic mild cognitive impairment (aMCI), characterized by isolated memory loss, is unclear. We studied the prevalence of MCI in DM patients. METHODS Neuropsychological status was evaluated using the Rivermead Behavioral Memory Test (RBMT) and the Mini Mental State Examination (MMSE). Subjects consisted of 103 consecutive diabetic patients hospitalized for diabetic education. Patients with severe diabetic complications or cerebrovascular accidents were excluded. RESULTS Neuropsychological evaluation of DM patients showed that 71% were normal (MMSE score > or =24 and RBMT score > or =15), 5% had amnestic MCI (aMCI) (MMSE score > or =24 and RBMT score <15) and the remaining 23% had dementia (MMSE score <24). The percentage of patients with dementia was significantly higher in the DM group than in the control group (p<0.04). RBMT score and HbA1c were mildly correlated in diabetic patients. CONCLUSION High blood sugar may cause deterioration in not only memory function but also other cognitive domains in elderly patients with DM. Monitoring the neuropsychological status of this patient population is important.

Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia.

AIMS To elucidate the role of cerebral serotonin neurotransmission in visceral perception in functional dyspepsia (FD), we observationally examined the regional expression level of the serotonin transporter (SERT) and its correlation with clinical symptoms. MAIN METHODS FD patients (Rome III criteria; N=9, age range: 36-76years) and healthy controls (N=8, age range: 25-61years) participated in this study. Positron emission tomography scanning with [(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB), which binds specifically to SERT, was used to quantify the binding potential (BPND) of [(11)C]DASB in the midbrain, thalamus, caudate, putamen, amygdala, and hippocampus with reference to co-registered magnetic resonance images. Clinical symptoms were assessed using the Gastrointestinal Symptoms Rating Scale (GSRS). Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI). KEY FINDINGS BPND of the midbrain (P=0.041) and thalamus (P=0.031) was higher in FD patients than in controls. The BPND values in the midbrain correlated with total GSRS (r=0.663, P=0.004) and abdominal pain (r=0.419, P=0.047) scores. Its values in the thalamus correlated with total GSRS (r=0.423, P=0.044), abdominal pain (r=0.502, P=0.022), and indigestion (r=0.476, P=0.028) scores. Its value in the hippocampus correlated with abdominal pain and state-STAI scores (r=0.528, P=0.017; r=0.428, P=0.043). SIGNIFICANCE Up-regulation of the SERT level in the midbrain and thalamus may underlie the pathogenesis of FD such as abdominal and psychological symptoms via a brain-gut interaction.

Two cases of dementias with motor neuron disease evaluated by Pittsburgh compound B-positron emission tomography

We described the cases of two patients with dementia associated with motor neuron disease, the former with frontotemporal dementia (FTD) and the latter with Alzheimer’s disease (AD), studied by the Pittsburgh compound B-positron emission tomography (PIB-PET). In the FTD patient, the PIB-PET revealed no amyloid accumulation in the cortex, whilst in the AD patient showed amyloid accumulation mainly in the frontal, parietal and lateral temporal lobes, besides the posterior cingulate gyrus and the precuneus. Thus, PIB-PET might facilitate the discrimination of different proteinopathies that cause neurodegenerative diseases, as dementia associated with ALS.

Clinical Features of Pittsburgh Compound-B-Negative Dementia

Background/Aims: We previously found that some cases of clinically diagnosed Alzheimer’s disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail. Methods: Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, 123I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM). Results: When examined by 123I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus. Conclusion: PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis.

A case of anti-N-methyl-D-aspartate receptor encephalitis with multiple sclerosis-like demyelinated lesions

OBJECTIVE To describe an unusual case of a male patient with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis who presented with multiple white matter lesions. Brain biopsy of the patient was performed, and follow-up evaluation of the cerebrospinal fluid (CSF) NMDAR antibody titer was implemented. DESIGN Case report. SETTING University hospital. PATIENT A 35-year-old man with anti-NMDAR encephalitis initially presented with fever and psychiatric symptoms. After an initial attack of anti-NMDAR encephalitis, 2 atypical relapses occurred, which presented with myelitis and multifocal white matter lesions; the lesions were open-ring-shaped and partially enhanced. INTERVENTION Analysis of the brain biopsy specimen revealed the presence of demyelinated lesions with discrete borders. Subsequent intravenous methylprednisolone therapy resulted in improvement in the brain lesions. Prednisolone and cyclophosphamide were orally administered thereafter. Clinical progression of the disease paralleled observed changes in the CSF NMDAR antibody titer. CONCLUSION The demyelinated lesions observed in this case were similar to lesions found in multiple sclerosis. On the basis of our finding that the clinical progression of the disease and the associated symptoms paralleled changes in the CSF NMDAR antibody titer, we speculate that the lesions formed as a result of anti-NMDAR encephalitis.

A second pedigree with amyloid-less familial Alzheimer's disease harboring an identical mutation in the amyloid precursor protein gene (E693delta).

A 59-year-old woman developed early-onset, slowly progressive dementia and spastic paraplegia. positron emission tomography (PET) imaging revealed a large reduction in the level of glucose uptake without amyloid deposition in the cerebral cortex. We identified a homozygous microdeletion within the amyloid β (Aβ) coding sequence in the amyloid precursor protein (APP) gene (c.2080_2082delGAA, p.E693del) in three affected siblings and a heterozygous microdeletion in an unaffected sibling. The identical mutation was previously reported in the first Alzheimers pedigree without amyloid deposits. Furthermore, an increase in high-molecular-weight Aβ-reactive bands was detected in the patients CSF. Our findings suggest that soluble Aβ-oligomers induce neuronal toxicity, independent of insoluble Aβ fibrils.