Norio Murayama

Investigation of Lewy pathology in the visual pathway of brains of dementia with Lewy bodies

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 Brodmanns area 17), secondary visual pathway (pulvinar, Brodmanns 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.

Dementia with Lewy bodies: early diagnostic challenges.

Dementia with Lewy bodies (DLB) is defined pathologically as neurodegeneration associated with Lewy bodies (LB). LB‐related symptoms, including olfactory dysfunction, dysautonomia, and mood and sleep disorders, are increasingly recognized as clinical signs that enable the early detection of DLB, because these symptoms often antedate dementia by years or even decades. It remains unknown if the clinical history of LB‐related symptoms is sufficient for the prodromal state of DLB to be suspected in memory clinics. We retrospectively investigated the clinical courses, including olfactory dysfunction, dysautonomia, depression, and rapid eye movement sleep behaviour disorder, of 90 patients with probable DLB. The timing of LB‐related symptoms that preceded or followed relative to the onset of memory loss was calculated. LB‐related symptoms were present in 79 of 90 patients (87.8%) with probable DLB before or at the time of memory loss onset. These symptoms preceded the onset of memory loss between 1.2 and 9.3 years. We also report on four non‐demented patients with a clinical history of LB‐related symptoms in our memory clinic. All four patients showed reduced cardiac [123I]‐metaiodobenzylguanidine levels. Moreover, [18F]fluoro‐D‐glucose positron emission tomography scans revealed glucose hypometabolism in the occipital cortex in two patients. One patient converted to probable DLB with the development of parkinsonism 2 years after major depression was diagnosed. Based on a clinical history of LB‐related symptoms, we propose a conceptual framework to identify these symptomatic but non‐demented individuals that led us to suspect the underlying pathophysiology of Lewy body disease. Further prospective study is warranted to determine the clinical significance of LB‐related symptoms in non‐demented patients.

Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.

Parkinsons 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.

Construction of a 18F-FDG PET normative database of Japanese healthy elderly subjects and its application to demented and mild cognitive impairment patients

To construct a 18F‐FDG PET normative database of Japanese healthy elderly subjects and to apply it to demented and mild cognitive impairment (MCI) patients.

Diffuse occipital hypometabolism on [18F]‐FDG PET scans in patients with idiopathic REM sleep behavior disorder: Prodromal dementia with Lewy bodies?

Background:  Previous longitudinal studies have revealed that specific patterns on [18F]‐fluoro‐d‐glucose (FDG) positron emission tomography (PET) scans in patients with amnesic mild cognitive impairment can predict Alzheimers disease (AD). However, the significance of particular patterns on [18F]‐FDG PET scans in prodromal patients with dementia with Lewy bodies (DLB) remains unclear.

A follow up study of non-demented patients with primary visual cortical hypometabolism: Prodromal dementia with Lewy bodies

We previously reported non-demented patients with glucose hypometabolism in the primary visual cortex (PVC), which is the preferentially affected region in patients with dementia with Lewy bodies (DLB). It remains unknown, however, whether these patients represent a prodromal DLB state. Eleven non-demented patients who attended our memory clinic for more than three years (mean follow-up period: 44 ± 5 months) were examined. All the patients had glucose hypometabolism in the PVC on [(18)F]-fluoro-d-glucose (FDG) positron emission tomography (PET) scans at baseline. Four patients, including one with a clinical history of occipital bleeding, exhibited no core or suggestive features of DLB. Seven patients reported recurrent nocturnal dream-enactment behavior, which is consistent with probable rapid eye movement (REM) sleep behavior disorder (RBD). The condition of the patient with occipital bleeding was stable, which is consistent with an underlying non-neurodegenerative disorder. Of the remaining 10 patients, 5 had stable cognitive conditions (non-converters) and 5 exhibited progression to dementia (converters). The clinical diagnoses of 4 patients with probable RBD were changed to probable DLB. Despite no differences in psychological profiles at baseline between non-converters and converters, the initial pattern of cortical metabolism differed: converters had lower glucose hypometabolism in the parietal and the lateral occipital cortex compared to non-converters. The metabolic reduction in the PVC is present in patients with prodromal DLB. Moreover, the spatial profiles of reduced glucose metabolism at baseline could help to define the distinct prognostic subgroup that has a greater risk of conversion to DLB.

Immunohistochemical investigation of neurofibrillary tangles and their tau isoforms in brains of limbic neurofibrillary tangle dementia

Limbic neurofibrillary tangle dementia (LNTD) is a subset of senile dementia characterized by numerous neurofibrillary tangles (NFT) in the hippocampal area, although there is an absence or scarcity of amyloid deposits (AM) throughout the brain. In the present study, we immunohistochemically investigated regional numbers and tau isoforms of NFT in the hippocampal area of nine LNTD patients with anti-three-repeat (3R) tau-specific and anti-four-repeat (4R) tau-specific antibodies, differentiating NFT into three developmental stages of pretangles (PT), NFT and ghost tangles (GT). Consequently, most PT were 4R tau-positive, most GT were 3R tau-positive, and NFT were 3R tau-, 4R tau- or double-positive, suggesting that composition of tau isoforms may shift from a 4R tau-predominant pattern to a 3R tau-predominant pattern during the development of NFT. In addition, a large number of NFT showing different developmental stages and different rates of 3R tau- and 4R tau-positive neurons according to the region were found in the hippocampal area, suggesting that regions undergoing earlier NFT formation may show higher ratio of 3R tau-positive neurons to 4R tau-positive neurons, and that NFT formation may begin in the entorhinal and transentorhinal cortices, subsequently progress to the subiculum and CA1, and further to the CA2, amygdala and CA3-4, although progression to the neocortex is limited. Furthermore, 4R tau-positive astrocytes and grains were found in several patients, suggesting that LNTD is a form of tauopathy.

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan

Background:  Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimers disease.

Glucose hypometabolism in primary visual cortex is commonly associated with clinical features of dementia with Lewy bodies regardless of cognitive conditions

Although metabolic reduction in the primary visual cortex on [18F]‐fluoro‐d‐glucose (FDG) positron emission tomographic (PET) scans is the hallmark of dementia with Lewy bodies (DLB) for differential diagnosis from Alzheimers disease, the clinical significance of the metabolic pattern in patients without dementia remains unknown. The purpose of this study was to investigate the clinical profiles of patients without dementia with the metabolic pattern and its relevance to DLB.

Correlation in Lewy pathology between the claustrum and visual areas in brains of dementia with Lewy bodies

We investigated Lewy pathologies in the claustrum and the related cerebral cortices and subcortical nuclei of dementia with Lewy bodies (DLB) brains using alpha-synuclein-immunohistochemistry to clarify the relationship between Lewy pathology in the claustrum and visual misidentification of DLB patients. The claustrum is known to have strong reciprocal connections with the visual areas. Consequently, the claustrum demonstrated many Lewy bodies (LB) and LB-related neurites. The insular and inferior temporal cortices, amygdala, BA 18, 19, transentohrinal and cingulate cortices showed stronger or similar Lewy pathology as compared with the claustrum, while BA 17, precentral, postcentral and transverse temporal cortices showed weaker Lewy pathology. Comparing the correlation coefficient of Lewy pathology between the clausturm and other regions, BA 18 and 19 as well as the insular and transentorhinal cortices demonstrated a higher correlation coefficient. These findings suggest that Lewy pathology in the claustrum is more closely associated with that in visual areas than in auditory, somatosensory or motor areas, and that dysfunction of the visuo-claustral pathway participates in visual misidentification in addition to the visuo-amygdaloid pathway. The paralimbic cortices including the insular and transentorhinal cortices may connect visual areas with limbic areas by relay of the visuo-claustral or visuo-amygdaloid pathway.