123I-FP-CIT SPECT findings and its clinical relevance in prodromal dementia with Lewy bodies.

PURPOSE: Evidence for the prodromal stage of dementia with Lewy bodies (DLB) is very limited. To address this issue, we investigate the 123I-FP-CIT SPECT measure of dopamine transporter binding finding and its clinical relevance. METHODS: We enrolled subjects into a prodromal DLB group (PRD-DLB) (n = 20) and clinical DLB group (CLIN-DLB) (n = 18) and compared these groups with an Alzheimer's disease control group (AD) (n = 10). PRD-DLB was defined as patients having the non-motor symptoms associated with Lewy body disease (LBD) [i.e. REM sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysfunction, and depression] and showing characteristic diffuse occipital hypometabolism in 18F-FDG PET. CLIN-DLB was defined as patients fulfilling the established criteria of probable DLB. Striatal specific binding ratio (SBR) of 123I-FP-CIT SPECT was used for objective group comparisons. The correlations between SBR and cognitive function (MMSE), motor symptoms (UPDRS3), and duration of LBD-associated non-motor symptoms were compared between the two DLB groups. RESULTS: Mean SBR scores of both PRD-DLB and CLIN-DLB were significantly lower than those of AD. No correlation was found between SBR and MMSE scores. Both in the CLIN-DLB and total DLB groups, SBR scores were negatively correlated with UPDRS3 scores, whereas no correlation was found in PRD-DLB. Among the LBD-related non-motor symptoms, duration of olfactory dysfunction, and RBD demonstrated negative correlation with SBR scores in PRD-DLB. CONCLUSION: 123I-FP-CIT SPECT may play a role for detecting DLB among the subjects in prodromal stage. During this stage, long-term olfactory dysfunction and/or RBD may indicate more severe degeneration of the nigro-striatal dopaminergic pathway.

Characteristics of mild cognitive impairment tending to convert into Alzheimer's disease or dementia with Lewy bodies: A follow-up study in a memory clinic.

AIM: To determine characteristics of MCI that can predict whether patients will go on to develop AD or DLB. METHODS: Ninety-three patients diagnosed with MCI underwent neuropsychological and neuroimaging examinations, and were followed-up for a mean of 44.9±19.3months. They were divided into four MCI subtypes (amnestic/non-amnestic MCI, single/multiple domain) according to neuropsychological findings, and into three other MCI categories (AD-type PET, DLB-type PET, and unknown-type PET) based on (18)F-fluorodeoxyglucose PET findings. Patients who were eventually diagnosed with AD, DLB, other dementia, or remained MCI were analyzed in relation to the groups to which they had initially been allocated at the MCI stage. RESULTS: Clinical diagnosis after follow-up determined AD in 21 patients (22.6%), DLB in 12 patients (12.9%), other dementia in 2 patients (2.2%), and non-converter in 58 patients (62.3%). Amnestic single-domain MCI and AD-type PET tended to convert into AD. Amnestic multiple-domain MCI and DLB-type PET tended to convert into DLB. A few patients with AD-type PET later developed DLB, and some with DLB-type PET later developed AD. CONCLUSIONS: Predicting which type of dementia a person with MCI will later develop might be possible based on early assessment with clinical symptoms in conjunction with neuropsychological and (18)F-fluorodeoxyglucose PET findings.

Prediction of later clinical course by a specific glucose metabolic pattern in non-demented patients with probable REM sleep behavior disorder admitted to a memory clinic: A case study.

The present study is a follow-up study of 11 non-demented patients with probable rapid eye movement (REM) sleep behavior disorder (RBD) at our memory clinic. During the follow-up period (mean±SD of 46.7±6.4 months), all 11 patients exhibited cognitive decline: four (Group A) exhibited core clinical features of dementia with Lewy bodies (DLB), along with severe cognitive decline, and were subsequently diagnosed as having probable DLB; four (Group B) did not exhibit core clinical features of DLB; and the remaining three (Group C) were diagnosed as having Parkinson's disease with dementia (PDD). Positron emission tomography with fluorodeoxyglucose-F18 at baseline revealed that Groups A and B exhibited glucose hypometabolism in the occipital lobe, especially in the primary visual cortex, and Group A tended to present hypometabolism in the parieto-temporal area as well. Group C tended to present hypometabolism in the medial prefrontal area and anterior cingulate gyrus. Neuropsychological examinations indicated poor performance in verbal memory and visuoperception in all groups. This case study suggests that patterns of hypometabolism and neuropsychological examinations at baseline may be indicators of the later clinical course of probable RBD patients.

Cognitive dysfunction in patients with very mild Alzheimer's disease and amnestic mild cognitive impairment showing hemispheric asymmetries of hypometabolism on ¹8F-FDG PET.

OBJECTIVE: We investigated cognitive dysfunction in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) who present hemispheric asymmetries of cerebral metabolic rate of glucose (CMRglc) decrease on (18) F-fluorodeoxyglucose positron emission tomography. METHODS: Based on the hemispheric asymmetries of CMRglc decrease in the posterior cingulate cortex, precuneus, and parietotemporal cortex, the patients were divided into three groups (a left-dominant hypometabolism group, a right-dominant hypometabolism group, and a non-dominant hypometabolism group). CMRglc decrease in the whole brain was controlled among the three groups. All the patients underwent mini-mental state examination (MMSE), Wechsler Memory Scale-Revised (WMS-R), and Wechsler Adult Intelligent Scale-Third (WAIS-III). RESULTS: There were no significant differences in MMSE and WAIS-III scores among the three groups. In WMS-R, the results indicated that the left-dominant group demonstrated significantly lower scores in verbal memory than the other two groups. Furthermore, the left-dominant group had a greater tendency to be diagnosed with AD rather than aMCI. CONCLUSIONS: Patients with AD and aMCI showing left-dominant hypometabolism tend to show severer impairment in verbal memory function and to be diagnosed with AD dementia.

Visuoperceptual assessments for differentiating dementia with Lewy bodies and Alzheimer's disease: illusory contours and other neuropsychological examinations.

We examined the utility of illusory contours (ICs) for the differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Thirty-five probable DLB patients, 35 probable AD patients controlled by age, years of education, and Mini-Mental State Examination (MMSE) score, and 30 cognitively normal subjects controlled by age and years of education underwent visuoperceptual examinations including ICs, pentagon copying in MMSE, overlapping figures, clock drawing test, cube copying, and line orientation. Four items in ICs (ICs-4) were found to be significantly impaired in DLB compared with AD, and a sensitivity and a specificity of total score of ICs-4 were 88.6% and 37.1%, respectively. When a score of ICs-4 is combined with a 10-point scaled score of pentagon copying in MMSE, a sensitivity and a specificity were 77.1% and 82.9%, respectively. The present study suggests that ICs-4 can be included in neuropsychological examinations to assess visuoperceptual impairment in DLB.

An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years.

The patient was a 72-year-old Japanese woman. At the age of 57, she started having difficulty performing daily work and developed agraphia. She also exhibited restlessness and loss of interest, and began to speak less. Thereafter, stereotypical behavior, gait disturbance and dysphagia were noted. CT scan demonstrated left-dominant frontal and temporal lobe atrophy. She died at the age of 72, about 16 years after the onset of symptoms. Neuropathologically, the brain weighed 867 g, and showed remarkable cerebral atrophy with degeneration of the white matter, predominantly in the left dorsal frontal lobe and anterior temporal lobe. Microscopically, severe neuronal loss and gliosis with rarefaction were found in the cerebral cortex, and severe destruction of myelin and axons was observed in the cerebral white matter. Moderate neuronal loss with gliosis was also found in the pallidum and substantia nigra. Gallyas-Braak staining and tau immunostaining revealed pretangle neurons, NFTs, ballooned neurons and astrocytic plaques in the cerebral cortex, subcortical nuclei and brainstem, and argyrophilic threads and coiled bodies in the subcortical white matter. Tau isoform-specific immunostaining revealed that most tau-immunoreactive structures were positive for 4-repeat (4R) tau, but some of the NFTs were positive for 3-repeat (3R) tau in the cerebral neocortex. Immunoblotting demonstrated an accumulation of 4R tau in the cerebral cortex and subcortical white matter. The patient was pathologically diagnosed as having corticobasal degeneration. Her long survival course likely accounts for the severe white matter degeneration and accumulation of 3R tau in NFTs.

Neuropathological investigation of hypocretin expression in brains of dementia with Lewy bodies.

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.

Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1.

We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine-adenine-guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post-mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post-mortem examination.

Peripheral lung adenocarcinomas: 10 mm or less in diameter.

BACKGROUND: Few reports have been published regarding peripheral lung adenocarcinomas that are 10 mm or less in diameter. This is considered to be the smallest tumor size detectable by present diagnostic modalities. METHODS: Clinicopathologic studies were performed in 57 patients with peripheral lung adenocarcinomas of 10 mm or less in diameter. Outcomes were compared with two other groups that consisted of 32 patients with adenocarcinomas between 11 and 15 mm in diameter and 35 patients with adenocarcinomas between 16 and 20 mm in diameter. Tumors were curatively resected between 1992 and 2002. RESULTS: The mean age was 61.7 years. The following three features were more frequent: female sex (78.9%), nonsmokers (77.2%), and cases with carcinoma detected by computed tomography despite negative chest radiography (96.5%). Negative lymphatic invasion (94.7%) was significantly higher. Three cases showed lymphatic invasion that was classified as types E or F, according to Noguchi's classification. There were no cases of lymph node metastasis, pleural involvement, or intrapulmonary metastasis. Well-differentiated type was in 93.0%. Types A and B, which are noninvasive alveolar replacement-type adenocarcinomas, were significantly dominant (86.0%). The 5-year postoperative survival rate was 97.3%, which was significantly better than in the other two groups (75.5%, 78.1%). CONCLUSIONS: Histopathologic features of most peripheral lung adenocarcinomas of 10 mm or less in diameter were types A and B. Types A and B were considered fundamentally indicated for thoracoscopic wedge resections. However, the other types required the standard operation.