An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology.

We report an autopsy case of Creutzfeldt-Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77-year-old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post-mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic-type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid beta plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer-type pathology of this case are remarkable. We suppose that amyloid beta plaques might act as a facilitating factor for PrP deposition.

Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation.

Hydroxyl radical, ascorbate free radical, superoxide dismutase (SOD) activities, Cu,Zn-SOD protein, Mn-SOD protein, 8-hydroxy-2' -deoxyguanosine (8-OHdG) and metals were compared in red blood cells (RBC), plasma and/or cerebrospinal fluid (CSF) between patients with sporadic amyotrophic lateral sclerosis (SALS), familial ALS (FALS) showing the Leu126Ser mutation in the Cu, Zn-SOD gene and controls. In patients with FALS or SALS, concentrations of hydroxyl radical in blood and ascorbate free radical and 8-OHdG in CSF were higher than control group values, while SOD activities in RBC and CSF were lower. In contrast, Cu, Zn-SOD protein concentrations in RBC were low only in FALS patients. Concentrations of Cu in CSF of SALS patients were higher than in controls. Thus, the pathogenesis of increased oxidative stress differs between SALS patients and FALS patients with a mutant Leu126Ser SOD1 gene.

Influence of repetitive transcranial magnetic stimulation on disease severity and oxidative stress markers in the cerebrospinal fluid of patients with spinocerebellar degeneration.

Ataxia severity, cerebellar hemispheric blood flow (CHBF), ascorbate free radical (AFR), superoxide dismutase protein, superoxide scavenging activity, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in cerebrospinal fluid (CSF) were compared before and after an 8-week course of repetitive transcranial magnetic stimulation (rTMS) in 20 patients with spinocerebellar degenerations (SCD). SCD patients showed higher AFR, 8-OHdG, and superoxide scavenging activity than 19 controls. In SCD patients, AFR and ataxia severity declined, and CHBF increased after rTMS. As the SCD patients showed negative correlations between ataxia severity and CHBF or superoxide scavenging activity, the therapeutic mechanism of rTMS may involve decreased oxidative stress and increased CHBF.

Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia.

The pathophysiological basis of cognitive dysfunction, including frontotemporal dementia (FTD), in patients with amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALSD) remains unclear. On the other hand, increased expression of cyclooxygenase-2 (COX-2) in the spinal cord is thought to play a pivotal role in motor neuron degeneration in ALS. In this study, to assess the relationship between the neuronal COX-2 expression in the cerebrum, the formation of tau- and alpha-synuclein-negative but ubiquitin-positive neuronal inclusions (UPIs), and dementia in motor neuron disease (MND), we examined neuronal COX-2 immunoreactivity in the frontal cortex and hippocampus of patients with non-demented ALS without UPIs ( n=11), ALSD with UPIs ( n=6), and normal controls ( n=24) using a quantitative immunohistochemical technique. Neuronal COX-2 expression in all CA1-4 in the hippocampus was significantly up-regulated in the ALSD group, and, to lesser degree but significantly, in the ALS group. Neuronal COX-2 expression in the frontal cortex was also significantly up-regulated in the ALSD group but not in the ALS group. These findings suggest that (1) the frontal cortex and hippocampus of MND are involved in the same pathogenic process associated with COX-2 induction that has been observed in spinal anterior horn cells, (2) COX-2 induction in the cerebrum is a pathogenic process that can occur even in the absence of UPI formation in MND, and (3) COX-2 expression in the cerebrum may be associated with cognitive dysfunction in MND.

Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban.

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

An autopsied case of dementia with Lewy bodies with supranuclear gaze palsy.

A 66-year-old man had suffered from a slow and steady decline in both physical and cognitive function for four years. He showed bradykinesia and small step gait with supranuclear vertical gaze palsy, especially upward gaze palsy. He was started on levodopa therapy but without response. A diagnosis of progressive supranuclear palsy was clinically suspected. He died at age 69. Pathologically, many alpha-synuclein positive inclusions were detected both in the brain stem and cerebral cortices, and the diagnosis of dementia with Lewy bodies was made. Scattered alpha-synuclein-positive inclusions and threads, which may be a pathological substrate for supranuclear gaze palsy, were identified in the rostal midbrain. From a review of five cases of dementia with Lewy bodies with supranuclear gaze palsy including this case, the absence of falls in the early stage of the disease, fluctuation of cognition, hallucination and vertical gaze palsy with a more severe defect in the upward direction distinguished dementia with Lewy bodies with vertical gaze palsy from progressive supranuclear palsy. In the differential diagnosis of parkinsonism with gaze palsy, clinicians should consider dementia with Lewy bodies with gaze palsy as well as progressive supranuclear palsy.

Selective colocalization of transglutaminase-like activity in ubiquitinated intranuclear inclusions of hereditary dentatorubral-pallidoluysian atrophy.

To investigate the role of transglutaminase (TG) in the pathophysiology of dentatorubral-pallidoluysian atrophy (DRPLA), the distributions of ubiquitin-positive neuronal intranuclear inclusions (Ub-NII) and TG activity were studied in three patients with DRPLA and four disease controls. In the cerebellar granule cells of DRPLA, 2.5-4.9% of neurons had Ub-NII, and 7.5-9.8% of them were TG positive. In the frontal cortex; however, the ratio of neurons with Ub-NII was relatively low compared with those in the cerebellar cortex, and no Ub-NII was TG positive. There was no distinct difference in the ratio of neurons with Ub-NII and their TG positivity between the cases with homozygous or heterozygous DRPLA patients. The selective and good colocalization of Ub-NII and TG in the cerebellar granule cells may reveal a role of TG in the neurodegenerative process in DRPLA.