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Background: Aphasia often appears in persons living with dementia; however, aphasia and the mirror phenomenon are rarely present at the same time., Case Presentation: Here, we report a case of fluent conversation with a person in a mirror or a magazine, and examine the underlying mechanism using brain imaging and neuropsychological findings. We found that the appearance of the mirror phenomenon may be associated with a visuospatial dysfunction caused by a decreased function of the posterior region of the right temporal and parietal lobe. Moreover, active talking to a person in a mirror or a person in a magazine could be associated with disinhibition caused by a decline in bilateral frontal lobe function., Conclusions: This case represents a very valuable and interesting presentation because it is the first report of a long-term follow-up of the course of dementia using neurological imaging, and of the neuropsychological analysis of the mechanism of conversation with a mirror image combined with aphasia.

Brain extraction represents an important step in numerous neuroimaging analyses. The brain extraction tool (BET)2 is a widely used deformable model-based approach for extraction of intracranial volume (ICV). The aim of this study is to estimate the ICV extraction accuracy using synthetic MR(SyMRI) method and BET2 in healthy adult participants and patients with Sturge-Weber Syndrome (SWS), including infants. 'Quantification of relaxation times and proton density by multi-echo acquisition of saturation recovery with turbo-spin-echo readout' (QRAPMASTER) with a 3.0 T magnetic resonance image (MRI) system was used for data acquisition. Statistical evaluations were performed with linear regression analysis and the Jaccard similarity coefficient (J). ICV extraction accuracy with synthetic MR method is found to be higher than BET2, for both aged healthy participants and SWS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: The aim of this study was to examine the mechanisms of cognitive impairment and reversibility in elderly patients with severe aortic stenosis (AS) after transcatheter aortic valve implantation (TAVI) with special reference to cerebral blood flow (CBF)., Methods and Results: We examined 15 elderly patients with severe AS (mean age 83.2±4.5 years, 12 female) who underwent TAVI. Before and three months after TAVI, we evaluated cognitive function with the Logical Memory II test (LM II), cardiac output (CO) with echocardiography, and CBF with 99mTc single-photon emission computed tomography (SPECT). LM II score and CO were significantly increased after TAVI compared with baseline (p<0.01 for LM II, p<0.005 for CO). Notably, CBF in the local regions, including that in the right hippocampus, was significantly increased after TAVI (p<0.005 at each voxel). The patients with increased CO after TAVI also showed significantly increased CBF in the right hippocampus compared with those without it (p<0.01). Importantly, CBF in the right hippocampus was positively correlated with LM II scores (p<0.05)., Conclusions: These results provide the first evidence that TAVI may improve cognitive functions associated with increased cerebral perfusion especially in the hippocampus in elderly patients with severe AS.

Quantitative magnetic resonance imaging (MRI) with multislice, multi-echo, and multi-delay acquisition enables simultaneous quantification of R 1 and R 2 relaxation rates, proton density, and the B 1 field in a single acquisition, and requires only about 6 minutes for full-head coverage. Using dedicated SyMRI software, radiologists can generate any contrast-weighted image by manipulating the acquisition parameters, including repetition time, echo time, and inversion time. Moreover, automatic brain tissue segmentation, volumetry, and myelin measurement can also be performed. Using the SyMRI approach, a shorter scan time, an objective examination, and personalized MR imaging parameters can be obtained in daily clinical pediatric imaging. Here we summarize and review the use of SyMRI in imaging of the pediatric brain, including the basic principles of MR quantification along with its features, clinical applications, and limitations., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions., Methods: DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks., Results: The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice., Conclusions: The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We aimed to identify modularized structural atrophy of brain regions with a high degree of connectivity and its longitudinal changes associated with the progression of Alzheimer's disease (AD) using weighted gene co-expression network analysis (WGCNA), which is an unsupervised hierarchical clustering method originally used in genetic analysis., Methods: We included participants with late mild cognitive impairment (MCI) at baseline from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study. We imputed normalized and Z-transformed structural volume or cortical thickness data of 164 parcellated brain regions/structures based on the calculations of the FreeSurfer software. We applied the WGCNA to extract modules with highly interconnected structural atrophic patterns and examined the correlation between the identified modules and clinical AD progression., Results: We included 204 participants from the baseline dataset, and performed a follow-up with 100 in the 36-month dataset of MCI cohort participants from the J-ADNI. In the univariate correlation or variable importance analysis, baseline atrophy in temporal lobe regions/structures significantly predicted clinical AD progression. In the WGCNA consensus analysis, co-atrophy modules associated with MCI conversion were first distributed in the temporal lobe and subsequently extended to adjacent parietal cortical regions in the following 36 months., Conclusions: We identified coordinated modules of brain atrophy and demonstrated their longitudinal extension along with the clinical course of AD progression using WGCNA, which showed a good correspondence with previous pathological studies of the tau propagation theory. Our results suggest the potential applicability of this methodology, originating from genetic analyses, for the surrogate visualization of the underlying pathological progression in neurodegenerative diseases not limited to AD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Idiopathic normal pressure hydrocephalus (iNPH) is a dementia-inducing disorder. Primary cause of iNPH is speculated to be a reduction of cerebrospinal fluid (CSF) absorption, which secondarily induces hydrocephalus, compression of brain, and reduction of CSF production. Patients are treated by surgically inserting a shunt to deliver excess CSF to the abdominal cavity. The prognosis for cognitive improvement after shunt surgery has been difficult to predict. We therefore investigated various CSF proteins, hoping to find a biomarker predictive of cognitive performance one to two years after shunt surgery. CSF proteins of 34 iNPH and 15 non-iNPH patients were analysed by Western blotting, revealing two glycan isoforms of transferrin (Tf); 'brain-type' Tf with N-acetylglucosaminylated glycans and 'serum-type' Tf with α2, 6-sialylated glycans. Brain-type Tf levels decreased in iNPH but rapidly returned to normal levels within 1-3 months after shunt surgery. This change was positively correlated with recovery from dementia, per Mini-Mental State Examination and Frontal Assessment Battery scores at 11.8 ± 7.7 months post-operation, suggesting that brain-type Tf is a prognostic marker for recovery from dementia after shunt surgery for iNPH. Histochemical staining with anti-Tf antibody and an N-acetylglucosamine-binding lectin suggests that brain-type Tf is secreted from choroid plexus, CSF-producing tissue.

Background: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies., Methods: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting., Results: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%., Conclusion: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH., General Significance: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF., (Copyright © 2018. Published by Elsevier B.V.)

Content-based image retrieval (CBIR) is a technology designed to retrieve images from a database based on visual features. While the CBIR is highly desired, it has not been applied to clinical neuroradiology, because clinically relevant neuroradiological features are swamped by a huge number of noisy and unrelated voxel information. Thus, effective dimension reduction is the key to successful CBIR. We propose a novel dimensional compression method based on 3D convolutional autoencoders (3D-CAE), which was applied to the ADNI2 3D brain MRI dataset. Our method succeeded in compressing 5 million voxel information to only 150 dimensions, while preserving clinically relevant neuroradiological features. The RMSE per voxel was as low as 8.4%, suggesting a promise of our method toward the application to the CBIR.

Background and Purpose: Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy (PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [ 18 F]THK-5351, which we have recently developed., Methods: Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [ 3 H]THK-5351 and immunohistochemistry. Nine healthy controls, 13 patients with Alzheimer's disease and three patients with PSP participated in this PET study with [ 18 F]THK-5351. To detect amyloid-β deposition, PET imaging with Pittsburgh compound B was also performed., Results: Autoradiography in the brain sections of patients with PSP demonstrated [ 3 H]THK-5351 binding to tau deposits with a high selectivity. Although patients with PSP exhibited no remarkable [ 18 F]THK-5351 retention in the temporal cortex, significantly higher tracer retention was observed in the globus pallidus and midbrain. In contrast, amyloid imaging with Pittsburgh compound B showed no remarkable accumulation in the cerebral cortex of PSP., Conclusions: We conclude that [ 18 F]THK-5351 PET can potentially be used to detect the regional brain distribution of tau lesions in PSP, thereby facilitating the differential diagnosis of neurodegenerative disorders associated with tau protein., (© 2016 EAN.)

Objective: To determine whether 18 F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS)., Methods: We evaluated the in vitro binding of 3 H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, 18 F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD)., Results: 3 H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher 18 F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher 18 F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism., Conclusions: 18 F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. 18 F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS., (© 2016 American Academy of Neurology.)

It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age-related neurological disorders such as stroke, Alzheimer's disease, and Parkinson's disease. Therefore, it is very important to understand the relationship between functional age-related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age-related cerebral change and associated neurological disorders using neuroimaging techniques. In this special issue of Ageing Research Reviews, we focus on cerebral- and neuro-imaging, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. In addition, we summarize several review articles about the history, present values, and future perspectives of neuroimaging modalities., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Cerebral cavernous malformations (CCMs) are a distinct cerebrovascular disease. A fraction of CCMs present as diffuse manifestations distributed over the cerebral hemispheres, cerebellum, and brainstem. The purpose of the present study was to explore the clinical picture of such CCMs., Methods: This study assessed the appearance of CCMs on magnetic resonance (MR) images, the presence of genetic mutations using the polymerase chain reaction method, and disease course over long-term follow-up in a total of 10 patients with diffuse CCMs., Results: The 10 patients were Japanese and comprised 5 males and 5 females with a mean age of 48.7years. Three of them presented with seizures, two with headache and intracerebral hemorrhage, two with numbness, and one with dizziness, while the remaining two were asymptomatic. Genetic analysis revealed CCM1 mutations in four patients, CCM2 mutations in three, and a CCM3 mutation in one. In a family with 2 CCM2 patients, the appearance of sustained diffuse CCMs on MR images significantly differed between the 2 patients despite the mutation being identical. During the mean follow-up period of 13.7years, none of the 10 patients showed evidence of neurological deterioration or symptomatic hemorrhage. The appearance of their CCMs on MRI did not show significant changes. Eight patients maintained normal neurological function., Conclusions: CCMs with diffuse manifestation is a hereditary disease with satisfactory prognosis. Unrecognized genomic mutations may be involved in the genesis of these CCMs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

OBJECT The authors' goal in this paper is to provide the first clinical, radiological, and genetic studies of panventriculomegaly (PaVM) defined by a wide foramen of Magendie and large cisterna magna. METHODS Clinical and brain imaging data from 28 PaVM patients (including 10 patients from 5 families) were retrospectively studied. Five children were included. In adult patients, the age at onset was 56.0 ± 16.7 years. Tetraventricular dilation, aqueductal opening with flow void on T2-weighted images, and a wide foramen of Magendie and large cisterna magna (wide cerebrospinal fluid space at the fourth ventricle outlet) were essential MRI findings for PaVM diagnosis. 3D fast asymmetrical spin echo sequences were used for visualization of cistern membranes. Time-spatial labeling inversion pulse examination was performed to analyze cerebrospinal fluid movement. Copy number variations were determined using high-resolution microarray and were validated by quantitative polymerase chain reaction with breakpoint sequencing. RESULTS Adult patients showed gait disturbance, urinary dysfunction, and cognitive dysfunction. Five infant patients exhibited macrocranium. Patients were divided into 2 subcategories, those with or without downward bulging third ventricular floors and membranous structures in the prepontine cistern. Patients with bulging floors were successfully treated with endoscopic third ventriculostomy. Genetic analysis revealed a deletion in DNAH14 that encodes a dynein heavy chain protein associated with motile cilia function, and which co-segregated with patients in a family without a downward bulging third ventricular floor. CONCLUSIONS Panventriculomegaly with a wide foramen of Magendie and a large cisterna magna may belong to a subtype of congenital hydrocephalus with familial accumulation, younger age at onset, and symptoms of normal pressure hydrocephalus. In addition, a family with PaVM has a gene mutation associated with dysfunction of motile cilia.

Objective: Almost two-thirds of patients with Sturge-Weber syndrome (SWS) have epilepsy, and half of them require surgery for it. However, it is well known that scalp electroencephalography (EEG) does not demonstrate unequivocal epileptic discharges in patients with SWS. Therefore, we analyzed interictal and ictal discharges from intracranial subdural EEG recordings in patients treated surgically for SWS to elucidate epileptogenicity in this disorder., Methods: Five intractable epileptic patients with SWS who were implanted with subdural electrodes for presurgical evaluation were enrolled in this study. We examined the following seizure parameters: seizure onset zone (SOZ), propagation speed of seizure discharges, and seizure duration by visual inspection. Additionally, power spectrogram analysis on some frequency bands at SOZ was performed from 60 s before the visually detected seizure onset using the EEG Complex Demodulation Method (CDM)., Results: We obtained 21 seizures from five patients for evaluation, and all seizures initiated from the cortex under the leptomeningeal angioma. Most of the patients presented with motionless staring and respiratory distress as seizure symptoms. The average seizure propagation speed and duration were 3.1 ± 3.6 cm/min and 19.4 ± 33.6 min, respectively. Significant power spectrogram changes at the SOZ were detected at 10-30 Hz from 15 s before seizure onset, and at 30-80 Hz from 5 s before seizure onset., Significance: In patients with SWS, seizures initiate from the cortex under the leptomeningeal angioma, and seizure propagation is slow and persists for a longer period. CDM indicated beta to low gamma-ranged seizure discharges starting from shortly before the visually detected seizure onset. Our ECoG findings indicate that ischemia is a principal mechanism underlying ictogenesis and epileptogenesis in SWS.

Objectives: It is well known that Alzheimer's disease (AD)-type pathology is commonly present in dementia with Lewy bodies (DLB) brains and that the degree of AD-type pathology has an influence on the clinical characteristics of DLB. Although significant hypometabolism in the temporoparietal/precuneus on [(18)F]fluoro-d-glucose ((18)F-FDG) positron emission tomography (PET) scans is considered to support a diagnosis of AD, some DLB patients also exhibit this metabolic pattern. The clinical significance of the metabolic pattern on DLB remains unknown., Methods: Twenty-three DLB patients, 10 AD patients, and 11 controls underwent (18)F-FDG PET scans. According to the degree of hypometabolism in the parietal/precuneus regions, representing the AD-like metabolic pattern, 12 patients were placed in the DLB-AD(+) group and 11 patients were placed in the DLB-AD(-) group. The demographics and clinical variables were compared among the four groups., Results: In addition to the parietal/precuneus regions, the DLB-AD(+) group exhibited significantly greater posterior cingulate hypometabolism than the DLB-AD(-) group, although occipital metabolism did not differ. The prevalence of visual hallucinations and extracampine hallucinations, and the Bender-Gestalt test score were significantly higher in the DLB-AD(+) group than the DLB-AD(-) group, although there were no differences in the demographics and other examined clinical variables between the two DLB groups. These clinical differences were absent in the DLB-AD(-) group, AD group, and controls., Conclusions: Parietal/precuneus hypometabolism may be associated with clinical characteristics in DLB patients. Further multiple imaging modalities that are sensitive to AD-type pathology are needed to reveal the neurobiological basis of the AD-like metabolic pattern., (Copyright © 2014 John Wiley & Sons, Ltd.)

Genetic analysis of familial forms of Alzheimer's disease (AD) causally links the proteolytic processing of the amyloid precursor protein (APP) and AD. However, the specific type of amyloid and mechanisms of amyloid pathogenesis remain unclear. We conducted a detailed analysis of intracellular amyloid with an aggregation specific conformation dependent monoclonal antibody, M78, raised against fibrillar Aß42. M78 immunoreactivity colocalizes with Aß and the carboxyl terminus of APP (APP-CTF) immunoreactivities in perinuclear compartments at intermediate times in 10month 3XTg-AD mice, indicating that this represents misfolded and aggregated protein rather than normally folded APP. At 12months, M78 immunoreactivity also accumulates in the nucleus. Neuritic plaques at 12months display the same spatial organization of centrally colocalized M78, diffuse chromatin and neuronal nuclear NeuN staining surrounded by peripheral M78 and APP-CTF immunoreactivity as observed in neurons, indicating that neuritic plaques arise from degenerating neurons with intracellular amyloid immunoreactivity. The same staining pattern was observed in neuritic plaques in human AD brains, showing elevated intracellular M78 immunoreactivity at intermediate stages of amyloid pathology (Braak A and B) compared to no amyloid pathology and late stage amyloid pathology (Braak 0 and C, respectively). These results indicate that intraneuronal protein aggregation and amyloid accumulation is an early event in AD and that neuritic plaques are initiated by the degeneration and death of neurons by a mechanism that may be related to the formation of extracellular traps by neutrophils., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Hypocretin (Hcrt) is a neuropeptide synthesized in the lateral hypothalamus (LHT) that plays a key role in maintaining arousal state. In Parkinson's disease (PD), a narcolepsy-like syndrome is commonly seen, and a previous study showed substantial Hcrt neuronal loss in accordance with PD severity. In the present study, we quantitatively examined Hcrt immunoreactivity and α-synuclein and tau pathologies in the LHT and locus coeruleus (LC) in dementia with Lewy bodies (DLB) (n=15), Alzheimer's disease (AD) (n=14), and controls (n=7). In the LHT, substantial Hcrt-positive neurons were detected in controls. In contrast, in DLB and AD, the numbers of both total neurons and Hcrt-positive neurons were significantly reduced. The reduction of the latter was significantly severer in DLB than in AD. In the LC of controls, many Hcrt-positive axonal terminals were found. In contrast, the amount of Hcrt immunoreactivity was significantly reduced both in DLB and AD. In DLB, some Lewy body (LB)-bearing neurons were detected in the LHT, but the Hcrt-positive neurons did not have any LBs. Meanwhile, some tau-positive neurofibrillary tangle (NFT)-bearing neurons were detected in the LHT, and Hcrt-positive neurons occasionally contained NFTs. We observed a significant negative correlation between the number of Hcrt-positive neurons in the LHT and the neurofibrillary stage (r=-0.67, p=0.0067), whereas no significant correlation was found between the number of Hcrt-positive neurons and the Lewy stage (r=-0.47, p=0.077). This is the first report clarifying the substantial loss of Hcrt neurons in the LHT and of Hcrt axonal terminals in the LC in DLB and the correlation between the severity of Hcrt neuronal loss and progression of neurofibrillary pathology., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We validated the utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy (1H MRS) as an adjunct screening technique for dementia due to Alzheimer's disease (AD). We examined the posterior cingulate gyri of 228 subjects using VSRAD and 1H MRS in addition to conventional cerebrospinal fluid biomarkers at baseline. At the 3-year follow-up, the 228 subject were classified as follows: 93 healthy subjects, 42 MCI-non-converters (MCI-NC), 25 MCI-converters to AD (MCI-C), 44 AD, 8 dementia with Lewy bodies (DLB), 5 normal pressure hydrocephalus, and 11 patients with other neurological diseases. Our results demonstrated that subjects with increased medial temporal atrophy (MTA) severity on VSRAD, increased Cho/Cr, MI/Cr ratio, and decreased NAA/Cr and NAA/MI ratio on 1H MRS at baseline were at risk of dementia due to AD. Receiver operating characteristic analysis showed that severity of MTA and the NAA/MI ratio distinguished patients with AD and MCI-C from controls. Furthermore, the 118 subjects without dementia and MTA showing only a decreased NAA/MI ratio at baseline developed to MCI-C, AD, and DLB 3 years later. 1H MRS detected biochemical abnormalities preceding brain atrophy and cognitive decline. VSRAD combined with 1H MRS may be routinely applied to screen for MCI/AD and prodromal AD in clinical practice.

Aim: Falls are common in patients with cognitive disorder. The purpose of this study was to determine whether global brain atrophy is associated with cognitive function, physical performance and fall incidents in older adults with mild cognitive disorder., Methods: A total of 31 older adults with mild cognitive disorders (mean age 78.9 ± 7.3 years) were studied, and 10 of them had experienced falls and the others had not in the past 1 year. Cognitive function and physical performance were measured in these patients. Global brain atrophy was determined by the Voxel-Based Specific Regional Analysis System for Alzheimer's Disease software., Results: Fallers showed significantly worse scores than the non-fallers in the Global Brain Atrophy Index, Clock Drawing Test (CDT), Verbal Fluency Test (animal), maximum walking time and Timed Up & Go (TUG) Test. The Global Brain Atrophy Index was correlated with the Verbal Fluency Test (animal; r = -0.522), the Verbal Fluency Test with letter (ka; r = -0.337), CDT (r = -0.547), TUG (r = 0.276) and Five Chair Stands Test (r = 0.303) by age-adjusted correlation analyses. Stepwise regression analysis showed that the Global Brain Atrophy Index (β = 1.265, 95% CI 1.022-1.567) was a significant and independent determinant of falls (R(2) = 0.356, P = 0.003)., Conclusion: Global brain atrophy might be indicated as one of the risk factors for falls in older adults with mild cognitive disorders., (© 2012 Japan Geriatrics Society.)

Phosphodiesterase (PDE) exists in the cardiovascular system, adipose tissue and platelets, and its inhibition increases the cellular levels of cAMP, which could activate cAMP-responsive element binding protein (pCREB). The present study was designed to map the expression of PDE3A/B in the forebrain and define the time course of PDE3 expression in the ischemic boundary zone after ischemia. The number of PDE3A-positive cells (neurons and endothelial cells) remained unchanged, while PDE3B-positive cells gradually increased after ischemia/reperfusion. In the corpus callosum, PDE3B was expressed in oligodendrocytes, oligodendrocyte progenitor cells, and astrocytes. PDE3B-expressing astrocytes showed gradual increase after ischemia/reperfusion. In the cortex, the majority of PDE3B-expressing cells before ischemia were neurons, though few were astrocytes. Ischemic insult resulted in gradual increase in PDE3B-expressing astrocytes and neurons, with larger increase in astrocytes. Expression of brain derived neurotrophic factor (BDNF) and B-cell leukemia/lymphoma 2 protein (Bcl-2) was detected in pCREB-positive cells, not in PDE3B-positive cells. Our results demonstrated that ischemic insult increased PDE3B expression, but not PDE3A, and changed the number and type of cells in a time-dependent manner. The variation of PDE3B-expression in the brain might play a crucial pathophysiological role, and regulation of PDE3B production might protect against ischemic brain damage., (Copyright © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Objectives: We have previously reported that the level of leucine-rich alpha-2-glycoprotein (LRG) expression is specifically increased in cerebrospinal fluid (CSF) of idiopathic normal pressure hydrocephalus (INPH). The objective of this study is to examine the localization of LRG - the cerebral areas where it is expressed., Method: The histological sections of autopsied brain specimens from ten subjects, five adult cases (mean age 43.6 years; range 34-50 years) and five senile cases (mean age 76.0 years; range 67-88 years) were prepared, multistained with antibodies against human LRG, glial fibrillary acidic protein (GFAP), CD31, and aquaporin-4 (AQP4), and reviewed for the expression sites of LRG., Results: Immunostains of GFAP and LRG were compared in standard brain specimens from elderly patients. The results indicated that LRG is distributed throughout the entire brain, with especially high expression in the deep cerebral cortex. In addition, the cells that express LRG showed similar morphology to astrocytes. Double staining of CD31 and LRG revealed a significant expression of LRG in the pericapillary regions. The expression was observed in resident astrocytes, as well as in the capillary vessel to which astrocytic processes grow and adhere. When age-related comparisons were made between senile and adult specimens, LRG expression increased with age., Conclusion: LRG expression in resident astrocytes increased with age.

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.

Noninvasive detection of amyloid-β (Aβ) deposits in the brain would be beneficial for an early and presymptomatic diagnosis of Alzheimer's disease (AD). We developed THK-265 as a candidate near-infrared fluorescence (NIRF) probe for the in vivo detection of amyloid deposits in the brain. The maximal emission wavelength of THK-265 was greater than 650nm and it showed high quantum yield and molar absorption coefficients. A fluorescence binding assay showed its high binding affinity to Aβ fibrils (Kd = 97 nM). THK-265 clearly stained amyloid plaques in AD neocortical brain sections and showed a moderate log p value (1.8). After intravenous administration of THK-265 in amyloid-β protein precursor (AβPP) transgenic mice, amyloid deposits in the brain were clearly labeled with THK-265. Furthermore, in vivo NIRF imaging demonstrated significantly higher fluorescence intensity in the brains of AβPP transgenic mice than in those of wild-type mice. As THK-265 showed profound hyperchromic effect upon binding to Aβ fibrils, good discrimination between AβPP transgenic and wild-type mice was demonstrated even early after THK-265 administration. Furthermore, the fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of AβPP transgenic mice. These findings strongly support the usefulness of THK-265 as an NIRF imaging probe for the noninvasive measurement of brain amyloid load.

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 Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0-I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Mutations of the CASK gene are associated with X-linked mental retardation with microcephaly and disproportionate brain stem and cerebellar hypoplasia in females. The areas of the cerebrum, corpus callosum, pons, midbrain, and cerebellar vermis and hemisphere and a ratio of cerebrum/corpus callosum areas were measured in 5 female patients with CASK mutations, 67 female controls, and 5 patients with pontine hypoplasia. MR imaging in patients with CASK mutations revealed a normal size of the corpus callosum and a low ratio of the cerebrum/corpus callosum with a reduced area of the cerebrum, pons, midbrain, and cerebellar vermis and hemispheres. The 5 patients with pontine hypoplasia showed thinning of the corpus callosum and a high ratio of the cerebrum/corpus callosum, irrespective of the size of the cerebrum. The normal size of the corpus callosum, which gives an impression of callosal thickening at first glance, may be an imaging clue to detect patients with CASK mutations.

Due to a change in disease spectrum in aged countries, the primary role of geriatricians should be directed to an appropriate management and prevention of 1) cognitive decline and dementia, 2) swallowing and aspiration pneumonia and 3) falls and fractures. Management of dementia constitutes a central part in the practice of geriatric medicine in order to support independence of life in elderly people. The current paradigm of cognitive function-based testing for the diagnosis and treatment of Alzheimer's disease (AD) is going to drastically shift to a biomarker-based test approach, a shift that will correspond to the emergence of disease-modifying drugs. In addition, a new molecular imaging technique that visualizes neuronal protein deposits or pathological features has been developed in Japan and the U.S.A. Based on these achievements, the Alzheimer's Disease Neuroimaging Initiative (ADNI) was proposed and initiated in 2005. The ADNI is a long-term observational study being conducted in the U.S.A., Europe, Australia, and Japan using identical protocols. The objectives of ADNI are: 1) to establish methodology which will allow standard values related to long-term changes in imaging data, such as MRI and PET, in patients with AD and mild cognitive impairment and normal elderly persons; 2) to obtain clinical indices, psychological test data, and blood/cerebrospinal fluid biomarkers to demonstrate the validity of image-based surrogate markers; and 3) to establish optimum methods to monitor the therapeutic effects of disease-modifying drugs for AD. Patient enrollment in the Japanese ADNI has begun in July 2008. Imaging of AD pathology not only acts as a reliable biomarker with which to assay curative drug development by novel pharmaceutical companies, but it also helps health promotion toward AD prevention.

The histopathological hallmark of multiple system atrophy is the appearance of intracellular inclusion bodies, named glial cytoplasmic inclusions, which are mainly composed of alpha-synuclein fibrils. In vivo visualization of alpha-synuclein deposition should be used for the diagnosis and assessment of therapy and severity of pathological progression in multiple system atrophy. Because 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole could stain alpha-synuclein-containing glial cytoplasmic inclusions in post-mortem brains, we compared the carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole positron emission tomography findings of eight multiple system atrophy cases to those of age-matched normal controls. The positron emission tomography data demonstrated high distribution volumes in the subcortical white matter (uncorrected P < 0.001), putamen and posterior cingulate cortex (uncorrected P < 0.005), globus pallidus, primary motor cortex and anterior cingulate cortex (uncorrected P < 0.01), and substantia nigra (uncorrected P < 0.05) in multiple system atrophy cases compared to the normal controls. They were coincident with glial cytoplasmic inclusion-rich brain areas in multiple system atrophy and thus, carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole positron emission tomography is a promising surrogate marker for monitoring intracellular alpha-synuclein deposition in living brains.

Introduction: The aim of the present study was to determine the brain areas associated with fibromyalgia, and whether pretreatment regional cerebral blood flow (rCBF) can predict response to gabapentin treatment., Methods: A total of 29 women with fibromyalgia and 10 healthy women (without pain) matched for age were finally enrolled in the study. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography ((99m)Tc-ECD SPECT) was performed in the fibromyalgia patients and controls. A voxel-by-voxel group analysis was performed using Statistic Parametric Mapping 5 (SPM5). After treatment with gabapentin, 16 patients were considered 'responders', with decrease in pain of greater than 50% as evaluated by visual analogue scale (VAS). The remaining 13 patients were considered 'poor responders'., Results: We observed rCBF abnormalities, compared to control subjects, in fibromyalgia including hypoperfusion in the left culmen and hyperperfusion in the right precentral gyrus, right posterior cingulate, right superior occipital gyrus, right cuneus, left inferior parietal lobule, right middle temporal gyrus, left postcentral gyrus, and left superior parietal lobule. Compared to responders, poor responders exhibited hyperperfusion in the right middle temporal gyrus, left middle frontal gyrus, left superior frontal gyrus, right postcentral gyrus, right precuneus, right cingulate, left middle occipital gyrus, and left declive. The right middle temporal gyrus, left superior frontal gyrus, right precuneus, left middle occipital gyrus, and left declive exhibited high positive likelihood ratios., Conclusions: The present study revealed brain regions with significant hyperperfusion associated with the default-mode network, in addition to abnormalities in the sensory dimension of pain processing and affective-attentional areas in fibromyalgia patients. Furthermore, hyperperfusion in these areas was strongly predictive of poor response to gabapentin.

Background: Adiponectin, an adipocyte-derived bioactive protein, provides vascular protection. Recent clinical studies have suggested that plasma adiponectin plays a role in cerebrovascular disease (CVD). The present study was designed to determine the serial changes in adiponectin expression in the brain and plasma after transient focal cerebral ischemia in mice., Methods: C57BL/6 mice (n=100) were subjected to 60 min of middle cerebral artery occlusion followed by 1, 3, 6, 12, 24, 48, 72 h and 7-day reperfusion. Plasma adiponectin levels were determined by ELISA kit, and expression of adiponectin was assessed by immunohistochemistry, western blot analysis, and reverse transcription-polymerase chain reaction., Results: Cerebral ischemia-reperfusion injury resulted in a transient rise in the acute phase and decrease in the late phase, in plasma adiponectin levels (P<0.05). The same insult resulted in upregulation of adiponectin expression, with two peaks at 3 and 24 h after reperfusion (P<0.05). Adiponectin protein was negligible in nonischemic contralateral hemispheres, but relatively high levels of the protein were detected in the ischemic hemisphere. Adiponectin mRNA was detected in neither nonischemic nor ischemic hemisphere. Adiponectin accumulated only in endothelial cells of ischemic brain in response to cerebral ischemia., Conclusions: Our results indicate that ischemic insult results in a transient rise in plasma adiponectin level during the acute phase, and that circulating adiponectin then accumulates in damaged vessels in the ischemic brain during the late phase. These findings suggest that time-targeting administration of adiponectin could be potentially useful in the treatment of stroke.

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.

Abnormal metabolism of essential polyunsaturated fatty acids (EPUFAs), a component of phospholipids in neural membranes, has been suggested to be related to the pathophysiology of schizophrenia. The purpose of this study was to examine the relationship between EPUFA concentrations in erythrocyte membranes, a peripheral measure of phospholipid composition in the brain, and clinical variables, such as cognitive performance relevant to social functions, in patients with schizophrenia. Erythrocyte membrane levels of EPUFAs, saturated fatty acids, and monounsaturated acids were measured in 25 patients with schizophrenia and 32 age- and gender-matched 32 normal volunteers. The script tasks, a measure of social cognition, and the Brief Psychiatric Rating Scale were administered to the patients. The levels of EPUFAs, but not those of saturated or monosaturated fatty acids, were significantly lower in patients than in normal controls. The degree of a decrease in EPUFA levels was positively correlated with severity of positive symptoms and impairment of frequency judgment performance on the script tasks, while no such correlations were found with negative symptoms, attention as measured by the Wechsler Adult Intelligence Scale-Revised-Digit Span, or verbal memory as measured by the Auditory Verbal Learning Test. These results provide the first suggestion for a contribution of decreased levels of EPUFAs to impaired social cognition, as represented by event schema, in patients with schizophrenia.

Mutations in the LRRK2 gene cause autosomal dominant, late-onset parkinsonism, which presents with pleomorphic pathology including alpha-synucleopathy. To promote our understanding of the biological role of LRRK2 in the brain we examined the distribution of LRRK2 mRNA and protein in postmortem human brain tissue from normal and neuropathological subjects. In situ hybridization and immunohistochemical analysis demonstrate the expression and localization of LRRK2 to various neuronal populations in brain regions implicated in Parkinson's disease (PD) including the cerebral cortex, caudate-putamen and substantia nigra pars compacta. Immunofluorescent double labeling studies additionally reveal the prominent localization of LRRK2 to cholinergic-, calretinin- and GABA(B) receptor 1-positive, dopamine-innervated, neuronal subtypes in the caudate-putamen. The distribution of LRRK2 in brain tissue from sporadic PD and dementia with Lewy bodies (DLB) subjects was also examined. In PD brains, LRRK2 immunoreactivity localized to nigral neuronal processes is dramatically reduced which reflects the disease-associated loss of dopaminergic neurons in this region. However, surviving nigral neurons occasionally exhibit LRRK2 immunostaining of the halo structure of Lewy bodies. Moreover, LRRK2 immunoreactivity is not associated with Lewy neurites or with cortical Lewy bodies in sporadic PD and DLB brains. These observations indicate that LRRK2 is not a primary component of Lewy bodies and does not co-localize with mature fibrillar alpha-synuclein to a significant extent. The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.

Background and Aim: In Alzheimer's disease (AD), regional cerebral blood flow (rCBF) in the posterior cingulate gyrus and precuneus has been reported to decrease even at a very early stage. We performed a multicentre SPECT study to evaluate the discrimination ability of an easy Z-score imaging system (eZIS) by detecting an rCBF decrease in this area with a common normal database between very early AD patients at the stage of mild cognitive impairment and age-matched healthy volunteers., Methods: Brain perfusion SPECT images of 40 Alzheimer's disease patients and 40 healthy volunteers were acquired from four gamma camera systems in different institutions. Systematic differences of SPECT images between different gamma cameras were corrected using conversion maps calculated from the SPECT images of the same brain phantom. Ten observers with various degrees of expertise graded eZIS results for receiver operating characteristic (ROC) curves. ROC curves for a positive Z-score in the volume of interest (VOI) of the posterior cingulate gyrus and precuneus were also analysed., Results: An area under the ROC curve value (AZ) for ten observers showed the highest value of 0.866 on average with the smallest standard deviation of 0.027 in the condition of the lower threshold of a Z-score map of 2 without superimposition of VOI. Automated analysis of a Z-score in the VOI showed an AZ value of 0.895., Conclusion: Since the degree of expertise of the observers with respect to reading eZIS did not influence the performance and an eZIS can use a common normal database by converting site-specific SPECT data to the core data, the eZIS was considered to be very useful for diagnosing early AD in routine studies in many institutions.

We investigated cerebrospinal fluid (CSF) samples from 21 patients with idiopathic normal pressure hydrocephalus (INPH) and 14 controls without neurological disease. The concentrations of leucine-rich alpha-2-glycoprotein (LRG), transforming growth factor (TGF)-beta1, 2, 3 and TGF-beta type II receptor (TbetaR-II) in CSF were measured using ELISA. TGF-beta1, TbetaR-II and LRG CSF levels of patients with INPH were significantly higher than controls, whereas no significant differences in TGF-beta2 levels were found between INPH patients and controls. The present study suggests that TGF-betas expressions may be modulated differently in patients with INPH. These results also indicate that the CSF level assay of TGF-beta1, TbetaR-II and LRG is useful for the diagnosis of patients with INPH, and TGF-beta1, TbetaR-II and LRG may be involved in the pathogenesis of the disease.

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have been identified as the cause of familial Parkinson's disease (PD) at the PARK8 locus. To begin to understand the physiological role of LRRK2 and its involvement in PD, we have investigated the distribution of LRRK2 mRNA and protein in the adult mouse brain. In situ hybridization studies indicate sites of mRNA expression throughout the mouse brain, with highest levels of expression detected in forebrain regions, including the cerebral cortex and striatum, intermediate levels observed in the hippocampus and cerebellum, and low levels in the thalamus, hypothalamus and substantia nigra. Immunohistochemical studies demonstrate localization of LRRK2 protein to neurones in the cerebral cortex and striatum, and to a variety of interneuronal subtypes in these regions. Furthermore, expression of LRRK2 mRNA in the striatum of VMAT2-deficient mice is unaltered relative to wild-type littermate controls despite extensive dopamine depletion in this mouse model of parkinsonism. Collectively, our results demonstrate that LRRK2 is present in anatomical brain regions of direct relevance to the pathogenesis of PD, including the nigrostriatal dopaminergic pathway, in addition to other regions unrelated to PD pathology, and is likely to play an important role in the normal function of telencephalic forebrain neurones and other neuronal populations.

The aim of this study was to evaluate the change in the distribution for the P300 generator, as demonstrated by Low Resolution Electromagnetic Tomography (LORETA) images, in patients with schizophrenia during treatment with olanzapine. Data were obtained from five right-handed patients treated with olanzapine for 6 months. Five right-handed normal volunteers also participated in the study. LORETA images of P300 in response to the odd-ball auditory discrimination task revealed a left dominant lateralized high current source density in the temporal lobes in all control subjects. Although this pattern of brain activation was not evident in patients at baseline, 6-month treatment with olanzapine recovered the left dominant pattern of the electrical density in the temporal regions, such as the Heschl gyrus, and improved performance on a test of verbal learning and memory. Scores of the Brief Psychiatric Rating Scale and the Global Assessment of Functioning Scale also improved during treatment. These results provide the first suggestion that enhancement of verbal memory and the functional status by treatment with some antipsychotic drugs may be associated with modulations of the anatomical configuration of electrical brain activity in patients with schizophrenia.

We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmann's area 17), secondary visual pathway (pulvinar, Brodmann's areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.

A newly developed quantitative near-infrared spectroscopy (NIRS) system was used to measure changes in cortical hemoglobin oxygenation during the Verbal Fluency Task in 32 healthy controls, 15 subjects with mild cognitive impairment (MCI), and 15 patients with Alzheimer's disease (AD). The amplitude of changes in the waveform, which was quantitatively calculated by a signal processing method, was significantly lower in the frontal, and the bilateral parietal areas in the AD group, whereas that in the MCI group was significantly lower only in the right parietal area. The NIRS system may be a potential tool for the primary screening of AD.

Recently, we confirmed the presence of enhanced neural reconstruction in Parkinson's disease and in an animal model of Parkinson's disease based on increased polysialic acid-like immunoreactivity. Changes in neurogenesis often appear parallel to changes in angiogenesis. Moreover, both these processes share similar modulating factors, like vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1). Using immunohistochemistry, we identified in this study upregulation of VEGF in the substantia nigra but not in the striatum of patients with Parkinson's disease by enzyme-linked immunosorbent assay. Such overexpression may participate in vascular remodeling and neurogenesis in the substantia nigra of Parkinson's disease.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimer's disease (AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to beta-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using 11C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty-five autopsied DLB cases were examined using alpha-synuclein-immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem-predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex-predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/ pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico-pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.

We report an autopsy case showing neuropathologically abundant Lewy bodies and argyrophilic grains. A Japanese woman without hereditary burden developed parkinsonian gait at the age of 74, following by insomnia, memory disturbance, delirium, resting tremor, rigidity, and retropulsion. About 8 months later, a visual hallucination, concerning small worms, children, and so on, became obvious. About 16 months later, malignant lymphoma was detected. About 17 months later, she died of pneumonia. The total duration of illness was approximately one year and five months. The weight of the brain was 1153 g before fixation. Depigmentation of the substantia nigra and locusceruleus was prominent. Many argyrophilic grains were seen in the temporal lobe (T3, T4), amygdala, and hippocampal CA1. Some ballooned neurons were found in the amygdala. Many Lewy bodies were encountered in the transentorhinal region and cingulated gyrus. A few Lewy bodies were seen in the temporal, frontal, and parietal lobes. In this case, neuropathological examination is compatible for dementia of Lewy bodies and argyrophilic grain dementia, and clinical course is consistent with dementia of Lewy bodies. This report may contribute to the elucidation of the clinicopathological hallmarks of argyrophilic grain dementia and dementia with Lewy bodies.

Driving is a complex behavior involving multiple cognitive domains. To identify neural correlates of driving performance, [15O]H2O positron emission tomography was performed using a simulated driving task. Compared with the resting condition, simulated driving increased regional cerebral blood flow (rCBF) in the cerebellum, occipital, and parietal cortices. Correlations between rCBF and measurements of driving performance were evaluated during simulated driving. Interestingly, rCBF in the thalamus, midbrain, and cerebellum were positively correlated with time required to complete the course and rCBF in the posterior cingulate gyrus was positively correlated with number of crashes during the task. These brain regions may thus play roles in the maintenance of driving performance.

Repeated administration of phencyclidine (PCP) induces behavioral sensitization to dopaminergic neural transmission. This phenomenon has been implicated in the pathophysiology of schizophrenia. Recently, GABAergic agonists have been shown to reduce behavioral activity induced by enhanced dopaminergic neural transmission, which is mediated by the GABA(A)/benzodiazepine (BZD) receptor complex. Thus, to investigate the role of BZD receptors during induction and expression of behavioral sensitization in PCP-sensitized animals, the effects of both single and repeated PCP administration on BZD receptors in rat brain were examined using in vitro quantitative autoradiography. Repeated PCP administration failed to significantly alter levels of [3H]flunitrazepam (FNZ) binding in any of the regions examined. However, significant increases in levels of [3H]FNZ binding were found in the nucleus accumbens and ventral pallidum 1 h after single administration of PCP. These results suggest that BZD binding sites may not play important roles in the development of PCP-induced sensitization at several sites of GABA(A)/BZD receptor complex, while changes in GABA function in the nucleus accumbens differ from other areas following single administration of N-methyl-D-aspartate (NMDA) antagonist.

Background: Mild cognitive impairment (MCI) may be a heterogeneous condition rather than a uniform disease entity., Objective: To develop reliable tools that aid in identifying patients at risk of developing Alzheimer disease (AD) among heterogeneous populations with MCI to maximize the benefits of emerging therapies for AD., Design: A 2-year prospective study., Setting: Clinical follow-up in an outpatient memory clinic., Patients: Seventy-two consecutive older patients with memory complaints., Main Outcome Measures: Cerebrospinal fluid tau levels, severity of periventricular and deep white matter lesions, silent brain infarction on magnetic resonance imaging, plasma homocysteine levels, apolipoprotein E genotype, and other vascular risk factors were assessed at baseline., Results: Fifty-seven patients were diagnosed as having amnestic MCI. Forty-one patients with (AD-converted MCI group) or without (progressive MCI group) conversion to dementia and AD progressed over time, whereas the other 16 patients remained cognitively stable (stable MCI group). The stable MCI group was characterized by normal cerebrospinal fluid tau levels and a high grade of periventricular white matter lesions (PWMLs). The progressive MCI and AD-converted MCI groups had increased cerebrospinal fluid tau levels and low grades of PWMLs. A logistic regression model showed that age was significantly associated with developing PWMLs (P =.03; odds ratio, 1.15; 95% confidence interval, 1.0-1.3)., Conclusions: Tau-related AD pathologic conditions and possibly ischemic PWMLs represent 2 major etiologies in the development of MCI, reflecting heterogeneity in the clinical progression. Because the progressive type of MCI may be a primary target of clinical trials that aim at secondary prevention of dementia, these patients should be identified by appropriate biomarkers and neuroimaging techniques.