Kazuhito Noda

Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: The Hisayama study

To explore the validity of the criteria for dementia with Lewy bodies (DLB) revised in 2005, we examined community based consecutive autopsy cases. 10.3% of the non‐demented subjects and 31.2% of the demented subjects showed the Lewy body pathology. Applying the revised pathological criteria to the 205 demented subjects, the types of LB pathology of 11 cases (5.4%) were brainstem‐predominant, 24 cases (11.7%) were limbic type and 24 cases (11.7%) were diffuse neocortical type, although there were many subjects not to fit the criteria exactly. The prevalence of Lewy bodies (LBs) was almost same regardless of gender; however, the extent of the LB pathology among females was more severe than that in males. The likelihood of DLB being modified by concomitant Alzheimers pathology was as follows: 27 cases (13.2%) showed low likelihood, 16 cases (7.8%) showed intermediate likelihood and 16 cases (7.8%) showed high likelihood. Since the numbers of clinical features of DLB were significantly higher in the pathological intermediate and high likelihood DLB groups than in the low likelihood DLB group or no LB group, both the intermediate and high likelihood groups of DLB should be considered as pathological DLB.

Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle-only dementia): The Hisayama study

Senile dementia of the neurofibrillary tangle type (SD‐NFT) is characterized by numerous neurofibrillary tangles (NFT) in the hippocampal region and the absence or minimal presence of senile plaques throughout the brain. We analyzed 207 demented subjects and 68 non‐demented subjects autopsied in the Hisayama study to investigate the clinicopathological aspects of SD‐NFT in the general Japanese population. The prevalence of SD‐NFT in the consecutive autopsy cases was 8/207 (3.9%), comprising three men and five women. The average age at onset and death was 83.8 ± 6.8 (mean ± SD; standard deviation) and 88.1 ± 7.6 years, respectively. A mild memory disturbance preceded a decrease in the ability to undertake the activities of daily living and the diagnosis of dementia. Focal cerebral symptoms, such as aphasia and paralysis, did not appear during the disease course of any subject. Gross examination of the brains showed moderate to severe diffuse cerebral atrophy with brain weight loss (mean ± SD; standard deviation: 1118.1 ± 124.0 g). Histologically, there were abundant NFT and neuropil threads predominantly in or limited to the limbic cortex. The density of NFT in the CA1/subiculum in SD‐NFT was much higher than the densities in the other hippocampal regions. The average density of NFT in CA1 in SD‐NFT subjects was 115.4 per 100× field (range 23–247), that in Alzheimer disease (AD) subjects was 80.1 (range 1–227), and that in non‐demented elderly subjects was 37.2 (range 0–203). Although many previous papers have reported that the densities of NFT in the limbic system in SD‐NFT were significantly higher than those in AD, there was considerable overlap of NFT densities in CA1 among the non‐demented elderly, AD subjects and SD‐NFT subjects.

Altered Expression of COX-2 in Subdivisions of the Hippocampus during Aging and in Alzheimer’s Disease: The Hisayama Study

Background: It has been reported that nonsteroidal anti-inflammatory drugs may delay the onset of Alzheimer’s disease (AD). Since nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX), COX-2, an inducible form of COX, may be involved in the pathology of AD in association with the arachidonic acid cascade. In addition, it has been suggested that alterations in the balance of polyunsaturated fatty acids are associated with brain dysfunctions such as neurodegerative pathologies of the aging brain. Method: To explore COX-2 expression in the hippocampus, we analyzed 45 consecutive autopsy subjects without dementia and 25 AD patients derived from the town of Hisayama, Japan. Results: The neuronal expression of COX-2 in the CA3 subdivision of the hippocampus, subiculum, entorhinal cortex and transentorhinal cortex were consistently observed in both nondemented and AD brains, and COX-2 immunoreactivity correlated with age in nondemented brains. In AD patients, neurons of CA1 exhibited increased COX-2 immunoreactivity which correlated with the severity of AD pathology. This correlation was not apparent in nondemented subjects. Conclusion: These results suggest that COX-2 expression may be differentially regulated among subdivisions of the hippocampus and that elevated COX-2 expression in the CA1 of AD brains may be associated with AD pathology and thus cognitive dysfunction.

Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of <-3 on both 3p12-q13 and 3p22-p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

Symmetrical brainstem encephalitis caused by herpes simplex virus

We describe a 53-year-old man with herpes simplex virus (HSV) brainstem encephalitis diagnosed based by positive HSV immunoglobulin M antibodies from cerebrospinal fluid. The MRI findings of this case had three unique features. First, the lesions were symmetrical. Second, the lesions may have been associated with reactivation of HSV infection in the region of the trigeminal nerve. Third, diffusion-weighted and apparent diffusion coefficient (ADC) imaging, conducted for the first time on an HSV brainstem encephalitis case, suggested that the lesions were associated with vasogenic edema.

Anhedonia in Japanese patients with Parkinson's disease: Analysis using the Snaith-Hamilton Pleasure Scale

BACKGROUND Anhedonia, a lowered ability to experience physical or social pleasure, has recently been recognized as a non-motor symptom of Parkinsons disease. OBJECTIVE To identify the frequency of anhedonia and the factors influencing hedonic tone in Japanese patients with Parkinsons disease. PATIENTS AND METHODS We recruited 86 consecutive outpatients with a clinical diagnosis of PD attending two Japanese hospitals (one university hospital and one community hospital) in February 2010. We used the self-rating Snaith-Hamilton Pleasure Scale (SHAPS) translated into Japanese language from the original English version to assess and quantify hedonic tone as a subjectively experienced phenomenon. We studied the association of anhedonia with the variables age, age at onset, gender, disease duration, disease severity and antiparkinsonian drugs. RESULTS Thirty-nine patients (45%) were male and 47 (55%) were female. Mean age was 72.01±9.07 (49-89) years, with mean age at onset of 64.93±11.42 (31-88) years. Mean disease duration was 7.20±5.54 (1-23) years. The mean Hoehn and Yahr scale was 2.76±0.78. The mean SHAPS score of the total sample was 1.19±1.86. The SHAPS score of 14 patients (16.3%) was 3 or more, indicating anhedonia. The mean SHAPS score was lower in patients taking pramipexole (0.58±0.97) than in patients not taking pramipexole (1.57±2.16). Multiple linear regression analysis identified pramipexole as a significant negative influencing factor on the SHAPS score, while disease severity and entacapone treatment were identified as positive influencing factors. The age, onset age, gender, disease duration, and use of pergolide, amantadine, zonisamide, selegiline, anticholinergic agents and droxidopa did not significantly affect the SHAPS score. CONCLUSION Anhedonia is not rare non-motor symptom in Japanese patients with Parkinsons disease. This study suggests an anti-anhedonic property of pramipexole.

Bell-shaped sensory impairments of all modalities in a neurosarcoidosis patient

We describe a 45-year-old man with neurosarcoidosis complaining of bell-shaped tightening and pain with sensory disturbance of superficial and deep sensations. The patient showed subacute progressive sensory impairment in bilateral C7-Th12 dermatomes. Triceps and patellar tendon reflexes were decreased. Chest X-ray revealed bilateral hilar lymphadenopathy without pleural effusion. There was abnormal accumulation of gallium in the bilateral hilar lymph nodes, parotid glands, and lacrimal glands on scintigraphy. Examination of bronchoalveolar lavage fluid showed an elevated CD4/CD8 ratio. Transbronchial lung biopsy showed non-caseating granulomas with many epitheloid cells and occasional Langhans giant cells without any necrotic lesion. The tuberculin reaction was negative, and elevation of serum lysozyme and IgG level were seen. These findings fulfilled the clinical criteria for sarcoidosis. Spine MRI demonstrated no abnormality. Studies of short-latency somatosensory evoked potentials showed delayed N13 latency and absent N19 and N28 potentials bilaterally. A nerve conduction study revealed no abnormality. The patients muscle strength was normal through the entire clinical course. Therefore, we consider that his sensory impairment was caused by peripheral neuropathy, especially in the dorsal root region. Neurosarcoidosis is important for differentiating bell-shaped sensory impairments of all modalities.

Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.