Masumi Ito

Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P

Objective: We evaluated comprehensive neuropsychological tests and regional brain blood flow to compare cognitive dysfunction between two types of multiple system atrophy: predominant cerebellar ataxia (MSA-C) and predominant parkinsonism (MSA-P). Methods: Twenty-one patients with MSA-C, 14 patients with MSA-P, and 21 age- and education-matched control subjects were subjected to neuropsychological tests and SPECT. The neuropsychological tests examined general cognition, verbal and visual memory, working memory, visuospatial and constructional ability, language, executive function, depression, and anxiety, while SPECT analysis examined brain perfusion. Results: Patients with MSA-P showed severe involvement of visuospatial and constructional function, verbal fluency, and executive function compared with control subjects. Patients with MSA-C showed involvement only in visuospatial and constructional function compared with control subjects and a milder degree of involvement compared with patients with MSA-P. Patients with MSA-P tended toward a wide and severe impairment in cognitive function compared with patients with MSA-C. In addition, neuropsychological impairment in patients with MSA-P was significantly correlated with a decrease in prefrontal perfusion. This significant relation was not correlated to other factors such as age, education, and severity of cerebellar ataxia and parkinsonism, which are relevant factors associated with cognitive performance. Conclusions: Patients with multiple system atrophy–parkinsonism show more severe and more widespread cognitive dysfunctions than patients with multiple system atrophy–cerebellar ataxia. Our results also indicate that cognitive dysfunction in patients with multiple system atrophy–parkinsonism may be associated with prefrontal involvement. GLOSSARY: MSA = multiple system atrophy; MSA-C = MSA-cerebellar; MSA-P = MSA-parkinsonism.

An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement

A Japanese male patient presented with gait disturbance at the age of 69 years. His principal symptom was cerebellar ataxia for several years. He was initially diagnosed as having olivopontocerebellar atrophy because dysarthria and ataxia gradually developed, and head CT scan showed apparent atrophy of the cerebellum and brainstem and dilatation of the fourth ventricle. Later, he showed vertical gaze palsy, dysphagia, retrocollis, parkinsonism, axial dominant rigidity and grasp reflex, and therefore, the diagnosis was modified to progressive supranuclear palsy (PSP). Progressive atrophy of the frontotemporal lobe, cerebellum and brainstem, and dilatation of the lateral, third and fourth ventricles were evident on MRI. Gastrostomy and tracheotomy were performed 9 and 10 years after onset, respectively, and the patient died after 11 years disease duration. At autopsy the brain weighed 1000 g and showed atrophy of the frontotemporal lobe, cerebellum and brainstem. Neurofibrillary tangles, mainly globose‐type revealed by Gallyas‐Braak silver staining, were extensively observed in the cerebral cortex and subcortical grey matter. Numerous glial fibrillary tangles, including tuft‐shaped astrocytes and coiled bodies, and extensive argyrophilic threads were also recognized, particularly in the frontal lobe, basal ganglia, cerebellar white matter, brainstem and spinal cord. The Purkinje cell layer showed severe neuron loss with Bergmanns gliosis, and the dentate nucleus showed severe neuron loss with grumose degeneration. Tau‐positive/Gallyas‐positive inclusions in the Purkinje cells and the glial cells of the Purkinje cell layer were observed. Pathological findings of the present patient were consistent with the diagnosis of PSP, but the olivopontocerebellar involvement, particularly in the cerebellum, was generally more severe, and the quantity of tau‐positive/Gallyas‐positive structures were more abundant than in typical PSP cases. The existence of a distinct, rare PSP subtype with severe olivopontocerebellar involvement, “PSP‐C“, which tends to be clinically misdiagnosed as spinocerebellar degeneration in the early disease stage, is noteworthy. The present case corresponded to this rare subtype of PSP.

An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type.

A 73‐year‐old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2‐weighted images in the initial stage, and a later high‐signal intensity region was observed in the cerebral cortex in diffusion‐weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp‐wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patients clinical symptoms and disease course were atypical for Creutzfeldt–Jakob disease (CJD), and a stable state with nasal tube‐feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic‐type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long‐term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic‐type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque‐like PrP deposition. Western blot analysis of protease‐resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.

Enhanced Aquaporin-4 immunoreactivity in sporadic Creutzfeldt-Jakob disease

Aquaporin‐4 (AQP‐4) is a water channel protein located on the plasma membrane of astrocytes and is regulated under various conditions. In the present study, a series of brains with sporadic Creutzfeldt‐Jakob disease (sCJD) were investigated to determine the possible contribution of AQP‐4 in the development of sCJD pathology. Six cases of subacute spongiform encephalopathy (SSE) and four cases of panencephalopathic (PE)‐type sCJD were included. Increased AQP‐4 immunoreactivity compared to that in controls was observed in all sCJD patients, particularly in the cerebral neocortex and cerebellar cortex. AQP‐4 immunoreactivity was present in the cell bodies and processes of protoplasmic astrocytes in SSE and around cell bodies and processes of hypertrophic astrocytes in PE‐type sCJD. Analysis of serial sections showed the development of sCJD pathology, particularly in neocortical lesions, as follows: PrP deposition; spongiform change and gliosis; enhanced staining for AQP‐4; hypertrophic astrocytosis; and neuronal loss and tissue rarefaction. Strong AQP‐4 immunoreactivity was present in burnt‐out lesions such as those of status spongiosus. These results indicate that increased AQP‐4 expression in sCJD is an early pathologic event and appears to remain until the late disease stage. We suggest that increased expression of AQP‐4 is a pathologic feature of sCJD.

An autopsied case of MM1 + MM2‐cortical with thalamic‐type sporadic Creutzfeldt‐Jakob disease presenting with hyperintensities on diffusion‐weighted MRI before clinical onset

A 78‐year‐old Japanese man presented with rapidly progressive dementia and gait disturbances. Eight months before the onset of clinical symptoms, diffusion‐weighted magnetic resonance imaging (DWI) demonstrated hyperintensities in the right temporal, right parietal and left medial occipital cortices. Two weeks after symptom onset, DWI showed extensive hyperintensity in the bilateral cerebral cortex, with regions of higher brightness that existed prior to symptom onset still present. Four weeks after clinical onset, periodic sharp wave complexes were identified on an electroencephalogram. Myoclonus was observed 8 weeks after clinical onset. The patient reached an akinetic mutism state and died 5 months after onset. Neuropathological examination showed widespread cerebral neocortical involvement of fine vacuole‐type spongiform changes with large confluent vacuole‐type spongiform changes. Spongiform degeneration with neuron loss and hypertrophic astrocytosis was also observed in the striatum and medial thalamus. The inferior olivary nucleus showed severe neuron loss with hypertrophic astrocytosis. Prion protein (PrP) immunostaining showed widespread synaptic‐type PrP deposition with perivacuolar‐type PrP deposition in the cerebral neocortex. Mild to moderate PrP deposition was also observed extensively in the basal ganglia, thalamus, cerebellum and brainstem, but it was not apparent in the inferior olivary nucleus. PrP gene analysis showed no mutations, and polymorphic codon 129 showed methionine homozygosity. Western blot analysis of protease‐resistant PrP showed both type 1 scrapie type PrP (PrPSc) and type 2 PrPSc. Based on the relationship between the neuroimaging and pathological findings, we speculated that cerebral cortical lesions with large confluent vacuoles and type 2 PrPSc would show higher brightness and continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrPSc. We believe the present patient had a combined form of MM1 + MM2‐cortical with thalamic‐type sporadic Creutzfeldt‐Jakob disease (sCJD), which suggests a broader spectrum of sCJD clinicopathological findings.

Gerstmann­Sträussler­Scheinker disease with P102L prion protein gene mutation presenting with rapidly progressive clinical course

We describe an autopsied case of a Japanese woman with Gerstmann-Straeussler-Scheinker disease (GSS) presenting with a rapidly progressive clinical course. Disease onset occurred at the age of 54 with dementia and gait disturbance. Her clinical course progressively deteriorated until she reached a bedridden state with myoclonus 9 months after onset. Two months later, she reached the akinetic mutism state. Nasal tube feeding was introduced at this point and continued for several years. Electroencephalograms showed diffuse slowing without periodic sharp-wave complexes. Diffusion-weighted magnetic resonance imaging (MRI) showed widespread cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed a Pro to Leu point mutation at codon 102 with methionine homozygosity at codon 129. The patient died of respiratory failure after a total disease duration of 62 months. Neuropathologic examination revealed widespread spongiform change with numerous eosinophilic amyloid plaques (Kuru plaques) in the cerebral and cerebellar cortices by H & E staining. Diffuse myelin pallor with axon loss of the cerebral white matter, suggestive of panencephalopathic-type pathology was observed. Numerous PrP immunopositive plaques and diffuse synaptic-type PrP deposition were extensively observed, particularly in the cerebral and cerebellar cortices. Western blot analysis of proteinase Kresistant PrP showed a characteristic band pattern with a small molecular band of 6 kDa. The reason for the similarity in clinicopathologic findings between the present case and Creutzfeldt-Jakob disease is uncertain; however, the existence of an unknown disease-modifying factor is suspected.

An autopsy case of diffuse neurofibrillary tangles with calcification : Early stage pathologic findings

A 66‐year‐old man with no medically remarkable past or family history gradually showed personality changes, memory disturbance, sleeplessness and abnormal behavior. Neurologic examination showed no focal signs and neither parkinsonism nor cerebellar ataxia was recognized. He died 4 years after the onset of dementia due to chronic renal failure. Neuropathologic examination revealed neuronal loss and gliosis in the temporal cortex, particularly in the subiculum, parahippocampal gyrus and entorhinal cortex, and insular cortex. NFTs were observed to be widespread in the cerebral cortex, especially the temporal cortex and brainstem, while senile plaques were not observed. Gallyas‐Braak silver staining revealed the presence of numerous NFTs, glial inclusions and neuropil threads throughout the cerebral neocortex, limbic system, hippocampus and brainstem. The subiculum showed the most severe involvement; severe atrophy, severe neuron loss, and numerous ghost tangles (extracellular NFTs) were apparent. Although NFTs contained both monoclonal anti‐3repeat‐tau antibody (RD3) and RD4 immunoreactivity, this differed between the intracellular NFTs and ghost tangles. RD3 immunoreactivity was mainly observed in ghost tangles and neuropil threads, whereas RD4 immunoreactivity was mainly observed in intracellular NFTs and glial inclusions. Calcification was also found to be widespread in the cerebral cortex and white matter, basal ganglia, thalamus, cerebellar cortex, white matter and dentate nucleus. These characteristic neuropathologic findings lead to the pathologic diagnosis of diffuse neurofibrillary tangles with calcification (DNTC). It is argued that this patient showed early stage pathologic signs of DNTC due to a short disease duration, which may provide clues regarding the progression of this rare disease.

An autopsy case of Creutzfeldt‐Jakob disease with a prion protein gene codon 180 mutation presenting with pathological laughing and an exaggerated startle reaction

A 78‐year‐old Japanese woman presented with slow progressive disorientation and memory disturbances. Pathological laughing was observed at an early disease stage and continued for several months. Around the same time, the patient began to exhibit an exaggerated startle reaction and mild myoclonus. The pathological laughing and startle reaction disappeared before the patient reached an akinetic mutism state approximately 16 months after symptom onset. MRI showed extensive hyperintensity of the cerebral cortex and striatum on diffusion‐weighted images, and swelling in the cerebral cortex on T2‐weighted and fluid attenuated inversion recovery images. A prion protein (PrP) gene analysis revealed a V180I mutation with methionine homozygosity at codon 129. Neuropathological examination showed extensive spongiform changes with characteristic various‐sized and non‐confluent (VaSNoC) vacuoles in the cerebral neocortex and striatum. Gliosis and hypertrophic astrocytosis were generally mild in character. Neurons were relatively preserved in number. We believe that pathological laughing and an exaggerated startle reaction are possible pathognomonic findings of V180I genetic Creutzfeldt‐Jakob disease. Based on the pathological findings of the present case, the presence of the VaSNoC‐type spongiform changes with relative preservation of the neurons in the cerebral cortex and a lack of apparent brainstem involvement are associated at least in part with the pathological laughing and startle reaction.

Central nervous system involvement in n-hexane polyneuropathy demonstrated by MRI and proton MR spectroscopy

The organic solvent n-hexane is awell-described causal agent in olyneuropathy. Althoughmost cases of n-hexane polyneuropathy esult from industrial exposure to glues containing the chemical, ome are caused by addictive inhalation. In abuse cases, neuroogical manifestations are generally severe because of the high ntensity of exposure. n-Hexane polyneuropathy has two characteristic electrophysilogical features: conduction block and conduction slowing. Nerve iopsy specimens show primarily axonal swelling as well as secndary paranodal myelin retraction and myelin thinning, which ay underlie the electrophysiological features [1]. In contrast to oluene toxicity, the damage caused by n-hexane has been conidered to be mostly restricted to peripheral nerves [2]. Although any cases of peripheral neuropathy due to n-hexane toxicity have een reported, central nervous system (CNS) involvement has not een fully described in humans, although it has been observed in nimalmodels [3]. A previous electrophysiological study suggested he presence of CNS lesions by evoked potential abnormalities [4].

B-type natriuretic peptide and cardiovalvulopathy in Parkinson disease with dopamine agonist

Objective: To elucidate the usefulness of plasma B-type natriuretic peptide (BNP) values for evaluating adverse effects of pergolide or cabergoline on cardiovalvulopathy in patients with Parkinson disease. Methods: Twenty-five patients treated with pergolide or cabergoline (ergot group) and 25 patients never treated with ergot derivatives (non-ergot group) were enrolled. Plasma BNP values and detailed echocardiography were evaluated. Thirty age- and gender-matched controls were similarly evaluated. Results: Patients with regurgitation more than grade 3 were more frequent in the ergot group than in the non-ergot group as well as control groups (24%, 0%, 3%, p = 0.001). Both composite regurgitation scores and plasma BNP values were significantly higher in the ergot group than in controls. In the ergot group, the cumulative dose correlated to both tenting area (r = 0.57, p = 0.004) and tenting distance (r = 0.62, p = 0.001). Furthermore, plasma BNP values were higher in patients with severe or multiple regurgitation groups (p < 0.001), and were correlated with composite regurgitation score (r = 0.70, p < 0.001). Multiple regression analyses revealed that BNP values were independently correlated with both composite regurgitation and left ventricular ejection fraction. Conclusion: The combination of comprehensive echocardiography and plasma B-type natriuretic peptide levels elucidates the presence of cardiac damage in patients with Parkinson disease using ergot derivative dopamine agonists.