Akihiko Shiino

Cortical and subcortical vestibular response to caloric stimulation detected by functional magnetic resonance imaging

The posterior insula, central sulcus, and inferior parietal lobule including the intraparietal sulcus have been considered the vestibular cortex based on functional brain mapping in humans as well as experiments in lower primates. The same regions receive optokinetic, visual, and proprioceptive projections. We examined the cortical and subcortical projection of vestibular activity with visual and proprioceptive input eliminated during caloric stimulation (CS), using functional magnetic resonance imaging (fMRI). Single-shot gradient-echo echoplanar image (EPI) volumes were sensitive to BOLD contrast in oblique orientation. We adopted a pharmacokinetic model for analysis of imaging data from 10 subjects as a group. The insular gyrus, intraparietal sulcus, superior temporal gyrus, hippocampus, cingulate gyrus, and thalamus showed activation by CS. Cortical and subcortical activation during CS in the present study was observed within regions less precisely delineated by other methods. As intraparietal sulcus activation showed right hemispheric dominance, this region may have an oculomotor projection as well as the vestibular input.

Four subgroups of Alzheimer's disease based on patterns of atrophy using VBM and a unique pattern for early onset disease.

To clarify the involvement of the posterior cingulate cortex (PCC) in Alzheimers disease (AD), we analyzed brain volume loss by voxel-based morphometry. Forty patients with non-familial AD and 20 patients with mild cognitive impairment (MCI) were recruited and compared to 88 elderly volunteers and 40 young volunteers. Local atrophy with aging was observed bilaterally in the perisylvian opercula, anterior cingulate cortex, caudate head, dorsomedial thalamus and parahippocampal cortex. In addition to those, atrophy in AD patients was observed in the amygdala, hippocampus, subcallosal region, posterior-associated cortices and PCC. We classified AD into four subgroups according to the atrophy pattern; atrophy in the amygdala/hippocampal formations (Hipp), in the Hipp and posterior cortices, in the Hipp and PCC and in the PCC and posterior cortices (PCC/-TOPa). As a result, the probability of PCC/-TOPa was 90% for ages <65 years, whereas that of the Hipp was 100% for disease duration >36 months. PCC atrophy was found in 16 of 40 AD patients and eight of 20 MCI patients. There seemed to be two subgroups with atrophy of the PCC, the one with disease progression and the other without. The latter had characteristic features of early onset and no significant atrophy in the amygdala/anterior hippocampus. There are at least four atrophy patterns that raise doubts about a single disease entity or progression in AD. This may reflect a different hierarchical pattern of progression in patients who have atrophy in PCC and posterior cortices when compared to the Braak staging scheme.

Proton magnetic resonance spectroscopy with dementia.

To provide new insights into metabolic changes in the brain of patients with dementia, we performed in vivo localized proton magnetic resonance spectroscopy in nine patients with primary degenerative dementia and in three patients with normal-pressure hydrocephalus. We compared the results with those in 26 healthy volunteers. Measurements of regional cerebral blood flow were performed in seven patients by means of single photon emission computed tomography with amphetamine I 123 as a tracer. The magnetic resonance spectra constantly showed three major peaks corresponding to N-acetylaspartate (NAA), creatine and phosphocreatine (Cr), and choline-containing compounds. There were no age-related changes in the mean area ratio of NAA to Cr in neurologically normal volunteers. The NAA/Cr ratio was significantly reduced in patients with primary degenerative dementia. The reduction of the NAA/Cr ratio was observed even in dementia patients with no significant brain atrophy or reduction in regional cerebral blood flow. No significant reduction of the NAA/Cr ratio was seen in patients with normal-pressure hydrocephalus. The NAA/Cr ratio might reflect the number and/or activity of neuronal cells in the brain. Proton magnetic resonance spectroscopy may well provide a useful tool for early detection of, and further pathophysiological study of, primary degenerative dementia.

Stereopsis-processing regions in the human parieto-occipital cortex.

We performed fMRI on the human parieto-occipital cortex in order to identify the neural processing regions of stereopsis. Visual stimulation for stereopsis was performed with a random-dot stereogram displayed in the image guides of a new binocular visual stimulation device that we developed. Interestingly, regions from the dorsal portion of the occipital lobe to the superior parietal lobule were activated by binocular disparity, while the inferior parietal lobule was not activated. Moreover, these regions were shown as dominant in the right hemisphere. Functional brain mapping revealed that the processing regions of stereopsis were dorsally located in parieto-occipital cortex, and that the superior parietal lobule is an important region for neural processing of human stereopsis.

In vivo detection of amyloid β deposition using 19F magnetic resonance imaging with a 19F-containing curcumin derivative in a mouse model of Alzheimer's disease

Amyloid β (Aβ) deposition in the brain is considered the initiating event in the progression of Alzheimers disease (AD). Amyloid imaging is widely studied in diagnosing AD and evaluating the disease stage, with considerable advances achieved in recent years. We have developed a novel ¹⁹F-containing curcumin derivative (named FMeC1) as a potential imaging agent. This compound can exist in equilibrium between keto and enol tautomers, with the enol form able to bind Aβ aggregates while the keto form cannot. This study investigated whether FMeC1 is suitable as a ¹⁹F magnetic resonance imaging (MRI) probe to detect Aβ deposition in the Tg2576 mouse, a model of AD. In ¹⁹F nuclear magnetic resonance (NMR) spectra obtained from the whole head, a delayed decreased rate of F ¹⁹F signal was observed in Tg2576 mice that were peripherally injected with FMeC1 in comparison to wild-type mice. Furthermore, ¹⁹F MRI displayed remarkable levels of ¹⁹F signal in the brain of Tg2576 mice after the injection of FMeC1. Histological analysis of FMeC1-injected mouse brain showed penetration of the compound across the blood-brain barrier and binding to Aβ plaques in peripherally injected Tg2576 mice. Moreover, the distribution of Aβ deposits in Tg2576 mice was in accordance with the region of the brain in which the ¹⁹F signal was imaged. FMeC1 also exhibited an affinity for senile plaques in human brain sections. These findings suggest the usefulness of FMeC1 as a ¹⁹F MRI probe for the detection of amyloid deposition in the brain. Furthermore, the properties of FMeC1 could form the basis for further novel amyloid imaging probes.

Absolute Quantification in Proton Magnetic Resonance Spectroscopy Is Useful to Differentiate Amnesic Mild Cognitive Impairment from Alzheimer's Disease and Healthy Aging

Background/Aims: Amnesic mild cognitive impairment (aMCI) is thought to represent a transitional state between healthy aging and very mild Alzheimer’s disease (AD). It is very important to diagnose aMCI for early treatment. In order to investigate biochemical changes in aMCI, we measured metabolite concentrations using proton magnetic resonance spectroscopy (1H-MRS) from patients with aMCI and compared the results with healthy controls (HCs) and patients with AD. Methods: The subjects were 52 HCs, 70 AD patients and 47 aMCI patients. 1H-MR spectra with single-voxel point-resolved spectroscopy at a short echo time (TE) were acquired from 8 volumes of interest in the brain. Results: The bilateral hippocampal N-acetylaspartate (NAA) concentrations from aMCI patients showed intermediate values, which were lower than those from HC subjects but higher than those from AD patients. The patients with aMCI also had lower concentrations of NAA than HCs in the bilateral posterior periventricular and deep white matters (PDWM) and posterior cingulate gyrus and had lower levels of choline compounds in the left posterior PDWM. Conclusion: Using a single-voxel 1H-MRS at a short TE, we revealed that absolute quantification is useful to detect the characteristic patterns of metabolite concentrations in patients with aMCI as compared with AD patients and HCs.

Shunt-responsive parkinsonism and reversible white matter lesions in patients with idiopathic NPH

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable dementia and gait disorder with abnormal CSF dynamics.ObjectiveTo investigate and characterize the changes in motor symptoms and CT and MRI features of iNPH before and after a shunt operation using specific evaluation criteria.MethodsWe studied 17 definitive iNPH patients, diagnosed according to the clinical guidelines of both the Japanese Society of NPH and the International NPH Consultant Group, with ventricular enlargement (Evan’s index > 0.3) and narrowed CSF spaces at the high convexity on CT scan and /or MRI. The pre- and post-operative evaluation criteria for the gait and motor disturbances included the Japanese NPH Grading Scale-Revised (JNPHGSR), the Timed “Up and Go” test and the motor sections of the Unified Parkinson Disease Rating Scale. For cognitive impairments, the JNPHGSR, Mini Mental State Examination, Frontal Assessment Battery and Trail Making Test were used. White matter lesions were rated from the CT and/or MRI using a validated visual rating scale.ResultsAll patients showed specific CT and MRI findings, consisting of diffusely-dilated Sylvian fissure, as well as narrowed CSF space at the high convexity. Fifteen patients (88 %) showed white matter lesions on their CT or MRI images. These signs were ameliorated in all patients after the shunt operation. Evan’s index and the mean total scores on the visual scale for white matter lesions also improved significantly. Clinically, the patients had frequent parkinsonism (71 %), but relatively few had a history of either small-vessel diseases (29 %), hypertension (41 %) or diabetes (35 %). All patients showed gait disturbances, and these symptoms, including postural instability and body bradykinesia, improved significantly after the operation. Over half also showed signs of cognitive impairment and urinary incontinence, and all such symptoms and signs improved significantly.ConclusioniNPH often appears as a shunt-responsive type of parkinsonism and reversible white matter lesions among the geriatric population.

Estimation of Cerebral Perfusion Reserve by Blood Oxygenation Level—Dependent Imaging: Comparison with Single-Photon Emission Computed Tomography

Measurement of cerebrovascular reserve capacity predicts the risk of ischemic insult in patients with major vessel occlusion. Blood oxygenation level-dependent (BOLD) imaging has the potential to estimate reserve capacity of the cerebral circulation noninvasively based on changes in the signal that reflect differences in the magnetic susceptibility of intravascular oxyhemoglobin and deoxyhemoglobin. The authors examined the feasibility of using the BOLD technique to assess cerebrovascular reserve capacity in patients with cerebrovascular occlusive disease by comparing results with an established method of measuring CBF. Ten patients with severe or complete occlusion of the internal carotid artery were compared with 17 healthy subjects to evaluate regional differences and identify variables that indicate a change in the BOLD signal. Dilation of cerebral vessels was induced by breath holding, and the R2* change was examined with gradient-echo, echo-planar imaging. Before measuring the regional change in the BOLD signal, actual timing of “activated” and “rest” periods was corrected by shifting the phase of a sine-wave template to obtain the largest correlation coefficient. Percent signal change was calculated on a pixel-by-pixel basis and was compared with CBF measured by single-photon emission computed tomography (SPECT) before and after acetazolamide challenge. The degree of impairment and the distribution of impaired areas detected by the BOLD study correlated with the results of SPECT. Overall sensitivity and specificity of the BOLD technique by visual inspection were 100% and 98.4%, respectively. A negative response (decreased CBF) frequently was observed in areas of exhausted reserve capacity, suggesting that a “steal” phenomenon exists. The percent change and the ΔCBF were well correlated (P < 0.01). The mean percent change in most areas of impaired reserve capacity was more than 2 SD below the mean values in healthy subjects. The present method of semiquantitative BOLD analysis can be used to create a map of the cerebral hemodynamic state. Furthermore, the development of reliable, generally accessible techniques for evaluating cerebral hemodynamics opens the door for clinical studies to monitor and treat patients with compromised reserve. This study is an attempt to develop such analysis.

Poor Recovery of Mitochondrial Redox State in CA1 After Transient Forebrain Ischemia in Gerbils

BACKGROUND AND PURPOSE Several investigations have detected evidence of apoptosis in delayed neuronal death, but controversy prevails regarding this point. Recent studies have implicated mitochondria in apoptotic events. To explore relationships between delayed neuronal death and dysfunction of the respiratory chain, we analyzed mitochondrial redox changes in the gerbil hippocampus. METHODS We assessed the mitochondrial redox state in gerbil hippocampus before, during, and at various time points after 5 minutes of forebrain ischemia. The redox state was examined with a low-temperature fluorometer. Fluorescence signals of flavoprotein and NADH were measured, and their fluorescence ratio was calculated as a mitochondrial redox ratio (MRR) equal to flavoprotein/(flavoprotein+NADH). RESULTS Ischemia increased NADH and decreased flavoprotein signals in all hippocampal areas, but reduction in MRR was greater in CA1 than in other areas of the hippocampus. Immediately after recirculation, MRR recovery was delayed in the CA1 and the dentate gyrus, and the reduction in MRR persisted in CA1. CONCLUSIONS These results suggest that during ischemia CA1 experiences more pronounced hypoxia (state V) than less vulnerable regions. Persistent MRR reduction in CA1 is attributed to dysfunction of the electron transport system, and this phenomenon may be importantly involved in apoptosis.

Different atrophic patterns in early- and late-onset Alzheimer's disease and evaluation of clinical utility of a method of regional z-score analysis using voxel-based morphometry.

Background/Aims: We evaluated the differential patterns of brain atrophy in early- and late-onset Alzheimer’s disease (AD) by measuring regional z-scores of voxel-based morphometry and assessed the availability of the method for clinical use. Methods: The first 50 patients with probable AD were compared to 83 age-matched control subjects to identify the brain atrophy. Regions of interest were set in the areas showing z-scores >4. To find substantial differences in the atrophy pattern, principal component analysis was performed. The second group of 56 patients with memory complaints entered the study for evaluation of the clinical use of the model. Results: The centers of the regions of interest were the amygdala, anterior hippocampi, posterior hippocampi, temporal cortices and subcallosal cortex, and left posterior cingulate cortex (PCC). Eigenvectors of the temporal cortices and left PCC showed counter-directions to those of patient age, suggesting that patients with younger onset age were preferentially associated with atrophy of those regions. Differential analyses of the second group showed high availability for the detection of abnormal brain atrophy in people with subjective memory complaints. Conclusion: AD with earlier onset is preferentially related to PCC and temporal lobe atrophy. Voxel-based morphometry can be statistically analyzed, and this method has the potential for bias-free assessment of brain atrophy.