Nobutsugu Hirono

Impact of white matter changes on clinical manifestation of Alzheimer's disease: A quantitative study

Background and Purpose There have been conflicting results involving the clinical significance of white matter changes in patients with Alzheimer’s disease (AD). We studied the association between the volume of white matter hyperintensities (WMHs) on T2-weighted images and cognitive, neurological, and neuropsychiatric symptoms. Methods The subjects were 76 AD patients who had WMHs but no obvious cerebrovascular diseases. We quantified the volume of WMHs by using fast-fluid–attenuated inversion recovery images and whole brain atrophy by using 3D spoiled gradient-echo images. Effects of WMHs and brain atrophy on dementia severity, cognitive function, neuropsychiatric disturbances, and neurological findings were examined. Results Whole brain atrophy was significantly associated with dementia severity and cognitive disturbances, as well as with grasp reflex and some kinds of neuropsychiatric disturbances. After we controlled for the effects of brain atrophy, duration of symptoms, and demographic factors, we found that WMH volume was not associated with global cognitive disturbances or dementia severity but was significantly associated with urinary incontinence, grasp reflex, and aberrant motor behaviors. Brain atrophy and WMH volume were not significantly correlated either before or after controlling for age, sex, education, and duration of symptoms. WMH volume was associated with hypertension, but brain atrophy was not positively correlated with any vascular risk factors. Conclusions Our results support the hypothesis that WMHs in AD patients are superimposed phenomena of vascular origin. WMHs contribute to specific neurological and neuropsychiatric manifestations but not to global cognitive impairment, which is more closely associated with brain atrophy.

Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community

Background: Despite many studies about the association between caregiver burden and behavioral and psychological symptoms of dementia (BPSD), there have been no population-based studies to evaluate caregiver burden associated with each BPSD. Objective: To evaluate caregiver burden associated with the individual BPSD in elderly people living in the community. Methods: The subjects were 67 participants with dementia living with their caregivers (diagnosed in the third Nakayama study): 51 Alzheimer’s disease, 5 vascular dementia and 11 other. The Neuropsychiatric Inventory (NPI) and NPI Caregiver Distress Scale (NPI-D) were used to assess subjects’ BPSD and related caregiver distress, respectively. Results: In the subjects exhibiting BPSD, aberrant motor behavior had the highest mean NPI score, and depression/dysphoria had the lowest. Agitation/aggression had the highest mean NPI-D score, and euphoria/elation had the lowest. Delusion, agitation/aggression, apathy/indifference, irritability/lability and aberrant motor behavior showed a correlation between the NPI and NPI-D scores. Conclusion: The burden associated with BPSD is different for each symptom and does not always depend on frequency and severity of BPSD. These findings suggest that some symptoms, such as agitation/aggression and irritability/lability, may affect the caregivers significantly, although their frequency and severity are low.

Medial temporal structures relate to memory impairment in Alzheimer’s disease: an MRI volumetric study

OBJECTIVES Memory impairment is not only the earliest clinical symptom but a central and prominent feature throughout the course of Alzheimer’s disease. Alzheimer related pathological alterations in the medial temporal structures may account for the memory impairments in patients with Alzheimer’s disease. The aim of this study was to elucidate the role of the medial temporal structures in memory impairment caused by Alzheimer’s disease. METHODS Using high resolution MRI and a semiautomated image analysis technique, volumes of the medial temporal structures (amygdaloid complex, hippocampal formation, subiculum, and parahippocampal gyrus) were measured, and correlations between atrophy of each structure and memory dysfunction in patients with Alzheimer’s disease were examined. RESULTS Patients with Alzheimer’s disease showed poor performance on verbal and non-verbal memory tests, and MRI volumetry showed a significant volume reduction of the medial temporal lobe structures. Volumes of the amygdaloid complex and of the subiculum correlated with memory performance. Stepwise regression analyses disclosed that the volume of the right amygdaloid complex specifically predicted visual memory function and to some extent verbal memory function, and that the volume of the left subiculum specifically predicted verbal memory function. Atrophy of the hippocampus did not predict severity of memory impairment. CONCLUSIONS The presence of perihippocampal damage involving the amygdala proper, its surrounding cortex, and the subiculum further increased the severity of memory impairment attributable to hippocampal damage in Alzheimer’s disease.

Differences in cerebral metabolic impairment between early and late onset types of Alzheimer's disease.

UNLABELLED The purpose of this study was to delineate the specific patterns of cerebral glucose metabolism with regard to the time of onset of Alzheimers disease (AD). METHODS Two groups of 20 AD patients with different ages of onset were examined. The early onset (EO) and late onset (LO) groups had mean ages of onset of 53.9 and 72.7 years. Groups of age-matched normal subjects were used as controls. A regional relative cerebral glucose metabolic image of each subject was obtained by 2-[18F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). NEUROSTAT program was used for spatial normalization and voxel-based statistical parametric mapping (SPM) 99 was used for statistical analyses. RESULTS Both AD groups had significant hypometabolic regions in the bilateral parieto-temporal regions compared with the age-matched groups. The EO group had more severe hypometabolism in the bilateral parietal and posterior cingulate cortices and precuneus region than the LO group. However, LO group showed no significant hypometabolic regions compared to the EO group. CONCLUSION The effects of time of AD onset were delineated as a double dissociation, that is, EO AD patients have a more severe reduction of glucose metabolism. Our finding suggests the existence of biological subtypes of AD.

Visual hallucinations and regional cerebral metabolism in dementia with lewy bodies (DLB)

To investigate the neurobiological bases of visual hallucinations in dementia with Lewy bodies (DLB), regional cerebral glucose metabolism was compared among three patient groups; DLB with visual hallucinations, DLB without visual hallucinations and Alzheimers disease (AD) without visual hallucinations. The regional metabolism was significantly lower in both DLB groups than in the AD group in the primary visual area and the posterior temporal, parietal and lateral occipital association areas. The hypometabolism in the right posterior temporal and parietal areas was significantly milder in DLB with visual hallucinations than in DLB without hallucinations. The hypometabolism in the primary visual cortex and the relatively preserved metabolism in the right temporoparietal association cortices may be associated with the occurrence of visual hallucinations in DLB patients.

Factors associated with psychotic symptoms in Alzheimer’s disease

OBJECTIVES Many clinical and biological factors have been reported to be associated with the presence of psychosis in patients with Alzheimer’s disease, although the associations were variable. The aim of this study was to clarify factors associated with the presence of psychosis in patients with Alzheimer’s disease. METHODS Psychiatric functioning was studied in 228 patients with Alzheimer’s disease based on the results of the behavioural pathology in Alzheimer’s disease rating scale or the neuropsychiatric inventory. The effects of sex, education level, age, duration of illness, cognitive function, and apolipoprotein E genotype were investigated for dichotomous psychotic status with a multiple logistic regression analysis. RESULTS Of the 228 patients with Alzheimer’s disease, 118 (51.8%) showed evidence of delusions or hallucinations. Of these, 94 had delusions only, three had hallucinations only, and 21 had both. Older age, female sex, longer duration of illness, and more severe cognitive impairment were the factors independently associated with the presence of psychosis. The presence of psychosis was not significantly related to either educational level or apolipoprotein E genotype. CONCLUSIONS Age, sex, and severity of illness were independent factors associated with the presence of psychosis in patients with Alzheimer’s disease. The reason why some patients with Alzheimer’s disease develop psychosis remains unclear. There may be distinctive subtypes of Alzheimer’s disease or the presence of individual factors which affect the development of psychosis.

Occipital Glucose Metabolism in Dementia with Lewy Bodies with and without Parkinsonism: A Study Using Positron Emission Tomography

Reduction of glucose metabolism in the occipital lobe is reported in dementia with Lewy bodies (DLB) and Parkinson’s disease. If dysfunction of the nigrostriatal system is responsible for occipital hypometabolism, (1) DLB patients with parkinsonism would show a lower occipital metabolism than do patients without parkinsonism, and (2) DLB patients without parkinsonism would show an occipital metabolism comparable to those of normal subjects and patients with Alzheimer’s disease (AD). To examine these hypotheses, we studied the regional cerebral metabolic rate of glucose (rCMRglc) in patients with a clinical diagnosis of DLB or AD, using 18F-fluorodeoxyglucose and positron emission tomography. The subjects consisted of 15 DLB patients with parkinsonism, 7 DLB patients without parkinsonism and 7 AD patients without parkinsonism. The medial and lateral occipital rCMRglc was significantly lower in the DLB patients without parkinsonism than in the AD patients. There were no significant differences in occipital metabolic rates between the DLB groups with and without parkinsonism. DLB patients without parkinsonism showed a significant reduction of occipital glucose metabolism which is comparable with that of DLB patients with parkinsonism. The neurobiological bases of occipital hypometabolism in DLB may be pathological processes in the brainstem or basal forebrain structures other than the nigrostriatal system.

Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E ε4 allele

Although apolipoprotein E ε4 is an established risk factor for Alzheimers disease, its effect on the rate of progression of Alzheimers disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty‐five patients with probable Alzheimers disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1‐year interval. On a two‐way analysis of variance, the effect of the apolipoprotein E ε4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one‐way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 ± 4.27%) and without the apolipoprotein E ε4 allele (6.99 ± 4.24%). Apolipoprotein E ε4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E ε4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimers disease and should be taken into consideration in longitudinal studies including clinical drug trials.

Neuronal substrates for semantic memory: A positron emission tomography study in Alzheimer's disease

We examined 57 patients with mild Alzheimer’s disease by using three kinds of verbal semantic memory tests (category fluency, confrontation naming and generation of verbal definition) and correlated each score with regional cerebral glucose metabolism determined by 18F-fluorodeoxyglucose and positron emission tomography. The scores of all three verbal semantic memory tests correlated significantly with regional cerebral glucose metabolism in the left inferior temporal gyrus, even after controlling for the effects of age, sex and educational attainment. In contrast, the scores of the word recall test did not correlate significantly with regional cerebral glucose metaboliosm in the left inferior temporal gyrus, neither before nor after controlling for these confounders. Our results suggested that the left inferior temporal lobe contributes to verbal semantic memory.

Everyday Memory Impairment of Patients with Mild Cognitive Impairment

We evaluated everyday memory impairment in 24 patients with mild cognitive impairment (MCI) with the Rivermead Behavioral Memory Test (RBMT) and compared the scores with those of 48 age-, sex- and education-matched normal controls (NC) and 48 age-, sex- and education-matched Alzheimer disease (AD) patients. Overall everyday memory was impaired in MCI patients but the severity was milder than that in AD patients. The MCI patients showed impairment of everyday memory tasks requiring delayed recall. But they could normally perform tasks immediately after memorizing, except for recalling and retracing a simple new route. The total Profile score correctly classified 100% of the MCI patients and 91.7% of NC, thus demonstrating the usefulness of the RBMT for diagnosing MCI patients. Prospective memory tasks were not useful for detecting the patients with MCI.