Differential diagnosis of MCI with Lewy bodies and MCI due to Alzheimer's disease by visual assessment of occipital hypoperfusion on SPECT images.

PURPOSE: Predicting progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) is important. We evaluated morphological and functional differences between MCI with Lewy bodies (MCI-LB) and MCI due to AD (MCI-AD), and a method for differentiating between these conditions using brain MRI and brain perfusion SPECT. METHODS: A continuous series of 101 subjects, who had visited our memory clinic and met the definition of MCI, were enrolled retrospectively. They were consisted of 60 MCI-LB and 41 MCI-AD subjects. Relative cerebral blood flow (rCBF) on SPECT images and relative brain atrophy on MRI images were evaluated. We performed voxel-based analysis and visually inspected brain perfusion SPECT images for regional brain atrophy, occipital hypoperfusion and the cingulate island sign (CIS), for differential diagnosis of MCI-LB and MCI-AD. RESULTS: MRI showed no significant differences in regional atrophy between the MCI-LB and MCI-AD groups. In MCI-LB subjects, occipital rCBF was significantly decreased compared with MCI-AD subjects (p < 0.01, family wise error [FWE]-corrected). Visual inspection of occipital hypoperfusion had sensitivity, specificity, and accuracy values of 100%, 73.2% and 89.1%, respectively, for differentiating MCI-LB and MCI-AD. Occipital hypoperfusion was offered higher diagnostic utility than the CIS. CONCLUSIONS: The occipital lobe was the region with significantly decreased rCBF in MCI-LB compared with MCI-AD subjects. Occipital hypoperfusion on brain perfusion SPECT may be a more useful imaging biomarker than the CIS for visually differentiating MCI-LB and MCI-AD.

Correlation between noise pareidolia test scores for visual hallucinations and regional cerebral blood flow in dementia with Lewy bodies.

OBJECTIVE: This study aimed at investigating the correlation between recurrent visual hallucinations (VHs) and regional cerebral blood flow (rCBF) in patients with dementia with Lewy bodies (DLB). METHODS: In 147 DLB patients, the correlation between noise pareidolia scores and rCBF in brain perfusion single photon emission computed tomography (SPECT) was evaluated. The 147 subjects comprised 52 probable and 95 possible DLB patients, of whom 107 did not have visual hallucinations and 40 had visual hallucinations. Brain perfusion SPECT was then performed, and memory impairment was assessed using the Mini-Mental State Examination (MMSE), while the optical illusion "pareidolia" (the tendency to see a specific image in a random visual pattern) was evaluated using noise pareidolia test. The correlations between rCBF and MMSE or noise pareidolia scores were then analyzed. RESULTS: The rCBF and MMSE scores were positively correlated, and rCBF was correlated with MMSE scores in a region that was consistent with a previously reported memory-related site. There was no correlation between noise pareidolia scores and occipital CBF, but there were weak correlations between noise pareidolia scores and rCBF in the bilateral frontal lobes (Brodmann area [BA]8 and BA9), left cingulate cortex (BA31), and left angular and supramarginal gyri (BA39 and BA40) in DLB patients. CONCLUSION: Weak correlation was found between noise pareidolia scores and rCBF in several sites (BA8, BA9, BA31, BA39 and BA40) other than in occipital lobe. These findings suggest that DLB hallucinations may be manifested by more complex brain network disorders, rather than by primary visual cortex disorders alone.

The AMPA Receptor Subunit GluA1 is Required for CA1 Hippocampal Long-Term Potentiation but is not Essential for Synaptic Transmission.

AMPA receptors mediate the majority of excitatory glutamatergic transmission in the mammalian brain and are heterotetramers composed of GluA1-4 subunits. Despite genetic studies, the roles of the subunits in synaptic transmission and plasticity remain controversial. To address this issue, we investigated the effects of cell-specific removal of GluA1 in hippocampal CA1 pyramidal neurons using virally-expressed GluA1 shRNA in organotypic slice culture. We show that this shRNA approach produces a rapid, efficient and selective loss of GluA1, and removed > 80% of surface GluA1 from synapses. This loss of GluA1 caused a modest reduction (up to 57%) in synaptic transmission and when applied in neurons from GluA3 knock-out mice, a similar small reduction in transmission occurred. Further, we found that loss of GluA1 caused a redistribution of GluA2 to synapses that may compensate functionally for the absence of GluA1. We found that LTP was absent in neurons lacking GluA1, induced either by pairing or by a theta-burst pairing protocol previously shown to induce LTP in GluA1 knock-out mice. Our findings demonstrate a critical role of GluA1 in CA1 LTP, but no absolute requirement for GluA1 in maintaining synaptic transmission. Further, our results indicate that GluA2 homomers can mediate synaptic transmission and can compensate for loss of GluA1.

Slow Progression of Cognitive Dysfunction of Alzheimer's Disease in Sexagenarian Women with Schizophrenia.

Although both schizophrenia (SCZ) and Alzheimer's disease (AD) are among the most common psychiatric diseases, the interaction of these two is not well-understood. We investigated three women with SCZ who developed AD in their 60s. The patients presented with cognitive dysfunction such as loss of recent memory, which was confirmed by both clinical observations and neuropsychological tests. Their magnetic resonance and functional imaging findings were consistent with AD. Their brain atrophy advanced significantly during a 6-year observation period. However, their global cognitive function did not deteriorate significantly during this period. Although the cognitive reserve model might account for this discrepancy, our results suggest some interactions between the neuropathology of SCZ and AD and warrant further research.

Computer-assisted system for diagnosing degenerative dementia using cerebral blood flow SPECT and 3D-SSP: a multicenter study.

PURPOSE: Due to increasing numbers of patients with dementia, more physicians who do not specialize in brain nuclear medicine are being asked to interpret SPECT images of cerebral blood flow. We conducted a multicenter study to determine whether a computer-assisted diagnostic system Z-score summation analysis method (ZSAM) using three-dimensional stereotactic surface projections (3D-SSP) can differentiate Alzheimer's disease (AD)/dementia with Lewy bodies (DLB) and non-AD/DLB in institutions using various types of gamma cameras. METHOD: We determined the normal thresholds of Z-sum (summed Z-score) within a template region of interest for each single photon emission computed tomography (SPECT) device and then compared them with the Z-sums of patients and calculated the accuracy of the differential diagnosis by ZSAM. We compared the diagnostic accuracy between ZSAM and visual assessment. PATIENTS: We enrolled 202 patients with AD (mean age, 76.8 years), 40 with DLB (mean age 76.3 years) and 36 with non-AD/DLB (progressive supranuclear palsy, n = 10; frontotemporal dementia, n = 20; slowly progressive aphasia, n = 2 and one each with idiopathic normal pressure hydrocephalus, corticobasal degeneration, multiple system atrophy and Parkinson's disease) who underwent N-isopropyl-p-[(123)I] iodoamphetamine cerebral blood flow SPECT imaging at each participating institution. RESULTS: The ZSAM sensitivity to differentiate between AD/DLB and non-AD/DLB in all patients, as well as those with mini-mental state examination scores of ≥24 and 20-23 points were 88.0, 78.0 and 88.4 %, respectively, with specificity of 50.0, 44.4 and 60.0 %, respectively. The diagnostic accuracy rates were 83.1, 72.9 and 84.2 %, respectively. The areas under receiver operating characteristics curves for visual inspection by four expert raters were 0.74-0.84, 0.66-0.85 and 0.81-0.93, respectively, in the same patient groups. The diagnostic accuracy rates were 70.9-89.2 %, 50.9-84.8 % and 76.2-93.1 %, respectively. CONCLUSION: The diagnostic accuracy of ZSAM to differentiate AD/DLB from other types of dementia or degenerative diseases regardless of severity was equal to that of visual assessment by expert raters even across several institutions. These findings suggested that ZSAM could serve as a supplementary tool to help expert evaluators who differentially diagnose dementia from SPECT images by visual assessment.

Myocardial scintigraphy may predict the conversion to probable dementia with Lewy bodies.

OBJECTIVE: To compare the usefulness of brain perfusion SPECT and (123)I-metaiodobenzylguanidine ((123)I-MIBG) in predicting the conversion of possible dementia with Lewy bodies (DLB) to probable DLB. METHODS: We examined 94 patients with possible DLB based on the Consensus Criteria for the Clinical Diagnosis of DLB by N-Isopropyl-p-(123)I-iodoamphetamine ((123)I-IMP) brain perfusion SPECT and (123)I-MIBG myocardial scintigraphy. After 1 year of follow-up, 33 of 94 patients met the criteria for probable DLB. (123)I-IMP brain perfusion SPECT and (123)I-MIBG myocardial scintigraphy were tested as predictors of the conversion from possible DLB to probable DLB. A receiver operating characteristic (ROC) analysis was performed. RESULTS: The areas under the ROC curves for SPECT for predicting the conversion to probable DLB from possible DLB based on the occipital/cerebellum and occipital/striatum cortex ratios of blood flow counts were 0.591 and 0.585, respectively. The areas under the ROC curves for (123)I-MIBG based on the early heart to mediastinum (H/M) ratio, delayed H/M ratio, and washout rate were 0.935, 0.936, and 0.884, respectively. CONCLUSION: (123)I-MIBG myocardial scintigraphy is a good predictor of the future conversion of possible DLB to probable DLB.

Automatic volumetry of the cerebrospinal fluid space in idiopathic normal pressure hydrocephalus.

OBJECTIVES: To measure the cerebrospinal fluid (CSF) space volume in idiopathic normal pressure hydrocephalus (INPH), we developed a software that allows us to automatically measure the regional CSF space and compared the volumes of the ventricle systems (VS), Sylvian fissures (SF) and sulci at high convexity and midline (SHM) among INPH patients, Alzheimer's disease (AD) patients and healthy volunteers (HVs). METHODS: Fifteen INPH patients, 15 AD patients and 15 HVs were retrospectively selected for this study. 3D-T1 MR images were obtained. We improved upon an automatic gray matter volume system to measure CSF spaces, adopting new regions for the template of INPH-characteristic CSF spaces and measured them. The VS, SF and SHM volumes were calculated relative to the intracranial volume. RESULTS: The relative SHM volume of the INPH group (0.0237 ± 0.0064) was the smallest among the 3 groups (AD: 0.0477 ± 0.0109, HV: 0.0542 ± 0.0045). The VS (0.0499 ± 0.0135) and SF (0.0187 ± 0.0037) volumes of the INPH group were significantly larger than those of the AD (VS: 0.0311 ± 0.0075, SF: 0.0146 ± 0.0026) and HV groups (VS: 0.0167 ± 0.0065, SF: 0.0111 ± 0.017). CONCLUSION: Automatic volume measurement can be used to delineate the characteristic changes in CSF space in patients with INPH and is useful in the diagnosis of INPH.

A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking.

Regulated exocytosis is essential for many biological processes and many components of the protein trafficking machinery are ubiquitous. However, there are also exceptions, such as SNAP-25, a neuron-specific SNARE protein that is essential for synaptic vesicle release from presynaptic nerve terminals. In contrast, SNAP-23 is a ubiquitously expressed SNAP-25 homolog that is critical for regulated exocytosis in non-neuronal cells. However, the role of SNAP-23 in neurons has not been elucidated. We found that SNAP-23 was enriched in dendritic spines and colocalized with constituents of the postsynaptic density, whereas SNAP-25 was restricted to axons. In addition, loss of SNAP-23 using genetically altered mice or shRNA targeted to SNAP-23 led to a marked decrease in NMDA receptor surface expression and NMDA receptor currents, whereas loss of SNAP-25 did not. SNAP-23 is therefore important for the functional regulation of postsynaptic glutamate receptors.

An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity.

PICK1 is a calcium-sensing, PDZ domain-containing protein that interacts with GluR2 and GluR3 AMPA receptor (AMPAR) subunits and regulates their trafficking. Although PICK1 has been principally implicated in long-term depression (LTD), PICK1 overexpression in CA1 pyramidal neurons causes a CaMK- and PKC-dependent potentiation of AMPAR-mediated transmission and an increase in synaptic GluR2-lacking AMPARs, mechanisms associated with NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here, we directly tested whether PICK1 participates in both hippocampal NMDAR-dependent LTP and LTD. We show that the PICK1 potentiation of AMPAR-mediated transmission is NMDAR dependent and fully occludes LTP. Conversely, blockade of PICK1 PDZ interactions or lack of PICK1 prevents LTP. These observations demonstrate an important role for PICK1 in LTP. In addition, deletion of PICK1 or blockade of PICK1 PDZ binding prevented NMDAR-dependent LTD. Thus, PICK1 plays a critical role in bidirectional NMDAR-dependent long-term synaptic plasticity in the hippocampus.

Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation.

Postnatal glutamatergic principal neuron synapses are typically presumed to express only calcium-impermeable (CI), GluR2-containing AMPARs under physiological conditions. Here, however, we demonstrate that long-term potentiation (LTP) in CA1 hippocampal pyramidal neurons causes rapid incorporation of GluR2-lacking calcium-permeable (CP)-AMPARs: CP-AMPARs are present transiently, being replaced by GluR2-containing AMPARs approximately 25 min after LTP induction. Thus, CP-AMPARs are physiologically expressed at CA1 pyramidal cell synapses during LTP, and may be required for LTP consolidation.

Eomesodermin is a localized maternal determinant required for endoderm induction in zebrafish.

In zebrafish, endoderm induction occurs in marginal blastomeres and requires Casanova (Cas), the first endoderm-specific factor expressed in the embryo. Whereas the transcription factors Gata5 and Bon are necessary and sufficient for cas expression in marginal blastomeres, Bon and Gata5 are unable to induce cas in animal pole cells, suggesting that cas expression requires an additional, unidentified factor(s). Here, we show that cas expression depends upon the T box transcription factor Eomesodermin (Eomes), a maternal determinant that is localized to marginal blastomeres. Eomes synergizes potently with Bon and Gata5 to induce cas, even in animal pole blastomeres. We show that Eomes is required for endogenous endoderm induction, acting via an essential binding site in the cas promoter. Direct physical interactions between Eomes, Bon, and Gata5 suggest that Eomes promotes endoderm induction in marginal blastomeres by facilitating the assembly of a transcriptional activating complex on the cas promoter.

Regulation of synaptic strength and AMPA receptor subunit composition by PICK1.

PICK1 (protein interacting with C kinase-1) regulates the surface expression of the AMPA receptor (AMPAR) GluR2 subunit, however, the functional consequences of this interaction are not well understood. Previous work has suggested that PICK1 promotes the internalization of AMPARs. However, we found that when PICK1 is virally expressed in the CA1 region of hippocampal slices, it causes an increase in AMPAR-mediated EPSC amplitude. This effect is associated with increased AMPAR rectification and sensitivity to polyamine toxin. These effects are blocked by PKC or calcium/calmodulin-dependent protein kinase II inhibitors, indicating that the virally expressed PICK1 signals through an endogenous kinase cascade. In contrast, blockade of interactions with GluR2 at the N-ethylmaleimide-sensitive factor site did not cause a change in subunit composition, suggesting that the effects of PICK1 are not simply a nonspecific consequence of removing AMPARs from the surface. Immunocytochemical and biochemical analyses in dissociated cultured hippocampal neurons show that PICK1 causes a decrease in endogenous GluR2 surface expression but no change in GluR1 surface levels. To address the physiological role of PICK1, we virally expressed C-terminal GluR2 peptides. Blockade of endogenous PICK1 PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain interactions produced opposite effects on synaptic strength and AMPAR rectification to those observed with PICK1 expression. This demonstrates that AMPAR subunit composition is physiologically regulated through a mechanism involving PICK1 PDZ domain interactions. These findings suggest that PICK1 acts to downregulate the GluR2 content of AMPARs at hippocampal CA1 synapses, thereby increasing synaptic strength at resting membrane potentials.

The Bh (black at hatch) gene that causes abnormal feather pigmentation maps to chromosome 1 of the Japanese quail.

Japanese quail embryos normally have longitudinal black and brown stripes formed by colored feather buds on their back whereas an autosomal dominant mutation, black at hatch (Bh), disrupts this pigmentation pattern by causing overall black and brown coating in heterozygotes and homozygotes, respectively. These phenotypes of the Bh mutant embryos suggest that the Bh locus plays an important role in the pigment pattern formation of plumage, but its genetic origin, including cloning of the responsible gene, has been insufficiently studied. In this study, we adapted genetically directed representational difference analysis with elimination of excessive clones (GDRDA-WEEC) to Bh quails and isolated two genetic markers linked to the Bh locus as DNA fragments. Cytogenetic study by fluorescence in situ hybridization (FISH) of the DNA fragments used as probes demonstrated that the marker loci were located in the same region on the long arm of chromosome 1. Close genetic linkage between the Bh and the marker loci, and the chromosomal location of the latter suggested that the Bh locus is located on the long-arm of chromosome 1 of the Japanese quail.

Nanomolar amyloid beta protein activates a specific PKC isoform mediating phosphorylation of MARCKS in Neuro2A cells.

Myristoylated alanine-rich C kinase substrate (MARCKS), a protein associated with cell growth, neurosecretion and macrophage activation, is activated by protein kinase C (PKC) phosphorylation. We reported that amyloid beta protein (Abeta) activated MARCKS through a tyrosine kinase and PKC-delta in rat cultured microglia. Here we report that Abeta signaling pathway through a specific PKC isoform is involved in the phosphorylation of MARCKS in Neuro2A cells. Selective PKC inhibitors but not tyrosine kinase inhibitors significantly inhibited the phosphorylation of MARCKS induced by Abeta. Abeta selectively activated PKC-alpha among the four PKC isoforms localized in Neuro2A cells. PKC-alpha activated by Abeta directly phosphorylated a recombinant MARCKS in vitro, Translocation of PKC-alpha from the cytoplasm to the membrane and accumulation of phospho-MARCKS in the cytoplasm were induced by Abeta. These results suggest involvement of a phosphoinositide signaling system through PKC-alpha in the phosphorylation of MARCKS in neurons, an event which may be associated with mechanisms underlying neurotrophic and neurotoxic effects of Abeta.

Crystal structures of 7-methylguanosine 5'-triphosphate (m(7)GTP)- and P(1)-7-methylguanosine-P(3)-adenosine-5',5'-triphosphate (m(7)GpppA)-bound human full-length eukaryotic initiation factor 4E: biological importance of the C-terminal flexible region.

The crystal structures of the full-length human eukaryotic initiation factor (eIF) 4E complexed with two mRNA cap analogues [7-methylguanosine 5'-triphosphate (m(7)GTP) and P(1)-7-methylguanosine-P(3)-adenosine-5',5'-triphosphate (m(7)GpppA)] were determined at 2.0 A resolution (where 1 A=0.1 nm). The flexibility of the C-terminal loop region of eIF4E complexed with m(7)GTP was significantly reduced when complexed with m(7)GpppA, suggesting the importance of the second nucleotide in the mRNA cap structure for the biological function of eIF4E, especially the fixation and orientation of the C-terminal loop region, including the eIF4E phosphorylation residue. The present results provide the structural basis for the biological function of both N- and C-terminal mobile regions of eIF4E in translation initiation, especially the regulatory function through the switch-on/off of eIF4E-binding protein-eIF4E phosphorylation.