Multiple system atrophy variant with severe hippocampal pathology.

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann-Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann-Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.

Longitudinal Change of DAT SPECT in Parkinson's Disease and Multiple System Atrophy.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. OBJECTIVE: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). METHODS: We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from 7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. RESULTS: The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. CONCLUSIONS: Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD.

Prognosis of Cancer Patients with Aortic Stenosis Under Optimal Cancer Therapies and Conservative Cardiac Treatments.

Aortic stenosis (AS) is a life-threatening comorbidity of cancer patients. Aortic valve replacement (AVR) should be considered for some cancer patients, but neither the characteristics nor prognosis under conservative therapy is well known.We searched our echocardiography log (years 2005-2014) for cancer patients with AS, and 92 patients (54% female) were included in the study. To compare the survival curves, 470 control patients without AS were selected from our cancer registry.Mean age (± SD) was 77.6 ± 6.7 years for males and 81.6 ± 6.3 years for females. Mean aortic valve area (AVA) was 1.0 ± 0.3 cm2. Stomach, blood, and urinary bladder cancers were the major sites of current cancer. During the 5-year follow-up period, 44 patients with AS (48%) died; 26 (59%) due to cancer progression, 10 (23%) heart failure, and 4 (9%) stroke. Heart-failure death was significantly higher for patients with AS than for control patients (P < 0.001). Kaplan-Meier survival estimates were worse for stage I or II patients with AVA < 0.75 cm2 than for control patients (P = 0.016). Older age, advanced stages, absence of dyslipidemia, recent syncope, and chronic heart failure or AVA < 0.75 cm2 were significantly and independently associated with poor survival.Although the majority of cancer patients with AS died of cancer, a quarter died of heart failure. Careful follow-up is needed because cancer patients at earlier stages with symptomatic AS or AVA < 0.75 cm2 should be considered for AVR.

[Case of rapidly progressive syringomyelia due to a spinal hemangioblastoma].

A 35-year-old man came to the hospital showing signs of worsening dysesthesia on his right hand. The dysesthesia started on his right hand and then spread to his forearm in two months. It also appeared on his left hand transiently. Initial MR imaging revealed a high signal intensity lesion at Th1-Th10 with an irregular margin (presyrinx state) below C3 on T2WI. The legion extended up to the medulla oblongata rapidly. Corticosteroid therapy lead to a slight improvement in dysesthesia symptoms but did not last. Immunosuppressant was also ineffective. Further examination using Gd enhanced MR imaging in a neurosurgery clinic in a university hospital revealed a spinal tumor at the Th10 level. A tumor resection was performed and dysesthesia improved. Pathological analysis showed hemangioblastoma. Presyrinx and syrinx above Th1 disappeared after the operation. It is necessary to search the whole spine carefully for the possibility of a tumor in the case of steroid resistant progressive spinal lesions with an unknown origin. And we stress the importance of timely surgical intervention regardless of idiopathic or secondary syringomyelia. We would like to report this clinical course presenting MR imaging and discuss the mechanism of forming syringomyelia based on the hypothesis of the alteration of CSF flow.

[Clinical features and MRI findings in spinocerebellar ataxia type 31 (SCA31) comparing with spinocerebellar ataxia type 6 (SCA6)].

Since the discovery of spinocerebellar ataxia type 31 (SCA31) gene, we identified 6 patients whose SCA type had been unkown for a long period of time as having SCA31 in our hospital and realized that SCA31 is not a rare type of autosomal dominant spinocerebellar ataxia in this region. We examined and compared the clinical details of these six SCA31 patients and the same number of SCA6 patients, finding that some SCA31 patients had hearing loss in common while there are more wide range and complicated signs of extra cerebellum in SCA6 such as pyramidal signs, extrapyramidal signs, dizzy sensations or psychotic, mental problems. There is a significant difference in the number of extracerebellar symptoms between SCA31 and SCA6. There are differences also in MRI findings. Cerebellar atrophy starts from the upper vermis in SCA31, as well as some SCA types, whereas the 4th ventricule becomes enlarged in SCA6 even in the early stage of disease. We suggest that these differences in clinical and MRI findings can be clues for accurate diagnosis before gene analysis.

Calcium dependence of the priming, activation and inactivation of ryanodine receptors in frog motor nerve terminals.

We studied the effects of varying extracellular Ca(2+) ([Ca(2+) ](o) ) and Ca(2+) channel density and intracellular loading of Ca(2+) chelators on stimulation-induced rises in intracellular Ca(2+) ([Ca(2+) ](i) ) in frog motor nerve terminals with Ca(2+) imaging. The slowly waxing and waning components of rises in [Ca(2+) ](i) induced by repetitive tetani were suppressed by blockers of Ca(2+) pumps of the endoplasmic reticulum (thapsigargin and cyclopiazonic acid) and a blocker of ryanodine receptors [8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride] without affecting the initial quickly-rising component, thus reflecting the priming (and then subsequent rapid activation) and inactivation phases of Ca(2+) -induced Ca(2+) release (CICR) from the endoplasmic reticulum. A short tetanus-induced rise in [Ca(2+) ](i) was proportional to [Ca(2+) ](o) , whereas the component of CICR was non-linearly related to [Ca(2+) ](o) with saturation at 0.9 mm. The progressive blockade of Ca(2+) channels by ω-conotoxin GVIA caused proportional decreases in CICR and short tetanus-induced [Ca(2+) ](i) rises. Intracellular loading of BAPTA and EGTA reduced the magnitude of CICR as well as short tetanus-induced rises in [Ca(2+) ](i) with a greater effect of BAPTA than EGTA on CICR. The time to peak and the half decay time of CICR were prolonged by a low [Ca(2+) ](o) or Ca(2+) channel blocker or [Ca(2+) ](i) chelators. These results suggest that ryanodine receptors sense the high [Ca(2+) ](i) transient following single action potentials for triggering CICR, whereas the priming and inactivation processes of CICR sense a slower, persisting rise in [Ca(2+) ](i) during and after action potential trains. A model is presented that includes CICR activation in elementary units.