Ichiro Akiguchi

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.

Characteristics of intracranial branch atheromatous disease and its association with progressive motor deficits

BACKGROUND Small deep brain infarcts are often caused by two different vascular pathologies: 1. atheromatous occlusion at the orifice of large caliber penetrating arteries termed branch atheromatous disease (BAD) and 2. lipohyalinotic degenerative changes termed lipohyalinotic degeneration (LD). We herein analyze and describe the characteristics of these 2 different pathologies. METHODS We studied 394 patients with penetrating artery territory infarcts in the territories of the lenticulostriate arteries and anterior pontine arteries. Radiologically defined BAD of the lenticulostriate arteries was defined as infarcts with size more than 10mm in diameter on axial slice and visible for 3 or more axial slices, and that of the anterior pontine arteries was defined as unilateral infarcts extending to the basal surface of the pons. Within each of the 2 territory groups, differences between BAD and LD were compared. RESULTS Ninety five patients in the lenticulostriate arteries group (36.1%) and 78 patients in anterior pontine arteries group (59.5%) were classified as BAD. Initial NIHSS, incidence of progressive motor deficits and poor functional outcome were significantly higher and incidence of concomitant silent lacunar infarcts tended to be lower in BAD than LD. In logistic regression analysis, BAD compared with LD was independently associated with PMD, in lenticulostriate arteries group (OR: 4.21, p=0.0001) and in anterior pontine arteries group (OR: 5.32, p=0.0018). CONCLUSIONS Radiologically defined BAD and LD had different characteristics. BAD was significantly associated with progressive motor deficits and considered as a major vascular mechanism of progressive motor deficits in penetrating artery infarcts.

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.

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.

The profile of hippocampal metabolites differs between Alzheimer's disease and subcortical ischemic vascular dementia, as measured by proton magnetic resonance spectroscopy

Alzheimers disease (AD) and subcortical ischemic vascular dementia (SIVD) have overlapping pathologies and risk factors, but their underlying neurodegenerative mechanisms are basically different. We performed magnetic resonance spectroscopy (MRS) to study metabolite differences between the two diseases in vivo. The subjects were 31 patients with SIVD and 99 with AD. Additionally, 45 elderly subjects were recruited as controls. We measured N-acetylaspartate (NAA), glutamine and glutamate (Glx), and myoinositol (mIns) concentration quantitatively using a 1.5-T MR scanner. N-acetylaspartate and Glx concentrations decreased in the hippocampus and cingulate/precuneal cortices (PCC) in both AD and SIVD patients, and the NAA decrease in the hippocampus was more prominent in AD than in SIVD. Interestingly, the pattern of mIns concentration changes differed between the two disorders; mIns was increased in AD but not increased in SIVD. If one differentiates between AD and SIVD by the mIns concentration in the hippocampus, the area under the receiver operating characteristic curve was 0.95, suggesting a high potential for discrimination. Our results suggest that proton MRS can provide useful information to differentiate between AD and SIVD. The difference of mIns concentrations in the hippocampus and PCC seems to reflect the different neurodegenerative mechanisms of the two disorders.

Hippocampal metabolites and memory performances in patients with amnestic mild cognitive impairment and Alzheimer’s disease

In patients with amnestic mild cognitive impairment (aMCI) and Alzheimers disease (AD), previous studies have reported the decrease of N-acetylaspartate (NAA) concentration and the increase of myo-inositol (MI) concentration using proton magnetic resonance spectroscopy (1H-MRS). However, it remains to be investigated what aspects of cognition these metabolite changes reflect. In this study we evaluated the correlations between the subtests of Wechsler Memory Scale-Revised (WMS-R) and the concentrations of NAA and MI. The study group was composed of 42 patients with aMCI and 67 patients with AD. 1H-MR spectra with a single voxel-point resolved spectroscopy (PRESS) at a short echo time were acquired from the bilateral hippocampi and posterior cingulate gyrus. Positive correlations were shown between the NAA concentration in the left hippocampus and verbal memory, visual memory, general memory, attention and delayed recall; and furthermore, between the NAA concentration in the right hippocampus and verbal memory and general memory. Negative correlations were shown between the MI concentration in the left hippocampus and verbal memory, general memory, and delayed recall, and between the MI concentration in the right hippocampus and verbal memory. There was no significant correlation between any subtest of WMS-R and these two metabolite concentrations in the posterior cingulate gyrus. These findings suggest that bilateral, especially left hippocampal NAA and MI concentrations are associated with memory dysfunction observed in patients with aMCI and AD. In contrast, NAA and MI concentrations in the posterior cingulate gyrus may be less related to memory function than those in the hippocampus.

14-3-3 proteins in Lewy body-like hyaline inclusions in patients with sporadic amyotrophic lateral sclerosis

Abstract14-3-3 proteins are highly conserved eukaryotic proteins that regulate various types of signal transduction pathways through phosphorylation-dependent protein-protein interactions. 14-3-3 mRNAs have been shown to be up-regulated in the injured rat motor neurons and in the spinal cords of patients with amyotrophic lateral sclerosis (ALS). To investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical studies on 14-3-3 using autopsied spinal cords from patients with sporadic ALS (sALS) and non-ALS subjects without spinal cord involvement. In the anterior horn of both groups, strong 14-3-3 immunoreactivity was observed in the somata and proximal processes of motor neurons. Many spheroids from all of the sALS cases were also immunopositive for 14-3-3. In addition, Lewy body-like hyaline inclusions (LBHIs), which were present in some sALS cases, were intensely immunostained. Our findings suggest that even in the severely affected anterior horn of patients with sALS, remaining motor neurons may contain abundant 14-3-3 proteins, and that 14-3-3 proteins may be partly associated with the pathogenesis of sALS, in particular with the formation of LBHIs.

Topographical and cytopathological lesion analysis of the white matter in Binswanger’s disease brains

The purpose of the present study was to document the topographical and cytopathological lesions in the white matter (WM) of Binswanger’s disease (BD) brains. Subcortical WM lesions in each lobe and fiber bundle lesions related to the medial thalamic and hippocampal structures in clinicopathologically proven BD brains were evaluated by Klüver-Barrera staining using a grading score. Lesions in the frontal subcortical WM of BD brains, brains from non-neurological patients, and brains with cerebral hemorrhage or large cortical infarcts were also examined immunohistochemically using molecular markers for axonal flow damage: amyloid precursor protein (APP); and for demyelinating axonopathy: encephalitogenic peptide (EP). Our results indicated that the WM lesions in BD were significantly more prominent in the frontal periventricular and subcortical regions as compared with other subcortical WM lesions, in the order of the parietal, occipital and temporal lobes. Fiber bundle lesions in the capsular genu, including the anterior thalamic peduncle, were also significantly more prominent in BD brains as compared with the other bundle lesions. Furthermore, the frequency of damaged nerve fibers labeled by the EP antiserum and APP immunoreactive fibers was significantly higher in BD brains as compared with the control brains. The grading scores for the WM damage correlated significantly with those for the APP and EP immunoreactive fibers in all brains, including the control brains. The axonal damage in the frontal WM lesions of the BD brains was clearly revealed in our study using immunohistochemistry for APP and EP.

Upregulated Expression of 14-3-3 Proteins in Astrocytes From Human Cerebrovascular Ischemic Lesions

Background and Purpose— Several types of chaperone proteins, such as heat shock proteins, have been reported to be associated with brain ischemia. The purpose of this study was to investigate whether an abnormal expression of 14-3-3 proteins, a novel type of molecular chaperones, occurs in human gray and white matter ischemic lesions. Methods— We prepared formalin-fixed, paraffin-embedded sections from 33 autopsied brains, consisting of 7 normal controls, 4 cases with cerebral thrombosis, 5 cases with cerebral embolism, 8 cases with multiple lacunar infarctions, and 9 cases with Binswanger disease. Deparaffinized sections from all cases were immunostained with anti-14-3-3 antibodies using the avidin-biotin-peroxidase complex method, and some sections were also double-immunostained for 14-3-3 and glial markers. Results— In the normal control brains, 14-3-3 immunoreactivity was mainly localized to the neuronal somata and processes. Strongly 14-3-3–immunopositive astrocytes were distributed in the infarct lesions and were particularly abundant in infarcts at the chronic stage. Intensely 14-3-3–immunolabeled astrocytes were also observed in the ischemic white matter lesions, and in the severely affected white matter lesions from patients with Binswanger disease, dense 14-3-3 immunoreactivity was found in clasmatodendritic astroglia as well as in reactive astrocytes. Conclusions— Our results suggest that 14-3-3 proteins may be induced mainly in astrocytes from human cerebrovascular ischemic lesions, and that the upregulated expression of 14-3-3 proteins in astrocytes may be involved in the formation of astrogliosis.