Sadayuki Matsumoto

Ubiquitin-immunoreactive filamentous inclusions in anterior horn cells of Guamanian and non-Guamanian amyotrophic lateral sclerosis.

SummaryImmunohistochemical studies with an antibody to ubiquitin revealed the presence of filamentous inclusions in spinal anterior horn cells in all of six patients with Guamanian amyotrophic lateral sclerosis (ALS) and one of six cases of parkinsonism-dementia complex (PD) on Guam. Similar ubiquitin-reactive filamentous inclusions were found in all of seven non-Guamanian sporadic ALS patients examined. No similar inclusions were seen in six normal controls or in non-ALS patients who had chromatolytic neurons. The filamentous inclusions differed from spinal neurofibrillary tangles, a characteristic feature of Guamanian ALS and PD, since they were restricted to anterior horn cells and did not react with anti-tau antibody. The chromatolytic neurons of non-ALS patients occasionally had weak diffuse immunoreactivity, but no focal inclusions were detected. These results suggest that ubiquitin-reactive focal filamentous inclusions may reflect a characteristic degenerative process of anterior horn cells of motor neuron disease.

Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS

BACKGROUNDnALS exclusively involves motor neurons, however, accumulating evidence suggests involvement of sympathetic neurons, as in other diseases including Parkinsons disease and multiple system atrophy. In these diseases increased risk of sudden cardiac arrest is established, while that in ALS remains uncertain.nnnMETHODSnThe authors retrospectively studied 12 pathologically confirmed sporadic ALS patients who received no assisted ventilation. Among them, two patients died of sudden cardiac arrest. Changes in QTc interval and dispersion, indices of sympathetic activities obtainable by routine electrocardiograms, were evaluated at the early stage and the terminal stage. Pathologically, intermediolateral nucleus (IML) sympathetic neurons in the upper thoracic cord were examined.nnnRESULTSnThe QTc intervals and dispersion were significantly increased at the terminal stage compared with that at the early stage (p<0.01). The numbers of IML neurons were significantly lower in ALS patients than in controls (p=0.017), and had linear inverse correlation with the rate of increases in maximum QTc interval and QTc dispersion (p=0.01, r=-0.915 and p=0.02, r=-0.884). Notably, two patients with sudden cardiac arrest showed longer QTc interval, larger QTc dispersion, and lower number of IML neurons than most of others.nnnCONCLUSIONSnPatients with ALS had reduced sympathetic activities at the terminal stage of disease, presumably due to neuronal loss in IML, which may increase risk of sudden cardiac arrest. Thus, prolonged QTc intervals and increased QTc dispersion may suggest an increased risk of sudden death in ALS, as in other neurodegenerative diseases.

Basophilic inclusions in sporadic juvenile amyotrophic lateral sclerosis : an immunocytochemical and ultrastructural study

SummaryThis report concerns immunocytochemical and ultrastructural studies on the basophilic inclusions in two cases of sporadic juvenile amyotrophic lateral sclerosis (ALS). The inclusion had a globular, irregularshaped, or sometimes fragmented appearance. Ultrastructurally, the inclusions consisted mainly of thick filamentous structures associated with granules. Focal neurofilamentous accumulations were occasionally observed among the granulofilamentous structures. The basophilic inclusions occasionally showed granular reaction product deposits with an antibody to ubiquitin. The inclusions did not react with antibodies to phosphorylated neurofilament and to tau protein.

Ubiquitin-positive inclusion in anterior horn cells in subgroups of motor neuron diseases: A comparative study of adult-onset amyotrophic lateral sclerosis, juvenile amyotrophic lateral sclerosis and werdnig-hoffmann disease

This report concerns the expression of ubiquitin in anterior horn cells of various subgroups of adult and infantile motor neuron disease (MNDs); immunohistochemical techniques were employed. Ubiquitin-positive skein-like inclusions (SLIs) were found in all cases of adult-onset amyotrophic lateral sclerosis (ALS), including 16 cases with sporadic ALS, two cases of familial ALS with posterior column degeneration and Lewy body-like hyaline inclusions (LBHIs), two sporadic ALS cases with LBHIs, and three cases of sporadic ALS with dementia. SLIs were not found in anterior horn cells of 5 cases with Werdnig-Hoffmann disease (WHD). However, granular ubiquitin-positive deposits were seen in ballooned neurons of WHD patients. No ubiquitinated materials were found in the perikarya of two sporadic juvenile ALS patients with basophilic inclusions (BIs), but granular ubiquitin-immunoreactive deposits were occasionally observed in the BIs. These results suggest that ubiquitin-positive SLIs are characteristic features of various forms of adult-onset ALS and that aggregated ubiquitinated granules are characteristic of ballooned neurons of WHD. Ubiquitinated structures and their distribution patterns may reflect degenerative processes of anterior horn cells, and may be useful for classifying subgroups of motor neuron diseases.

An adult-onset case of sporadic motor neuron disease with basophilic inclusions

SummaryA 36-year-old man developed motor neuron signs consisting of weakness and atrophy of the right upper limb, which progressed to involve the other limbs along with development of upper motor neuron signs including pseudobulbar palsy. He died 8.5 years after onset. Bilateral precentral gyri and putamina were grossly atrophic. In addition to severe degeneration of bilateral pyramidal tracts and marked neuronal cell loss of the precentral gyri and putamina, basophilic inclusions were widely distributed in the motor cortex, putamina, general somatic motor neurons such as the hypoglossal nucleus and spinal anterior horns, and other areas like the red nucleus and inferior olive. The inclusions were clearly shown with Nissl stain to be anilinophilic irregular masses with distinct rims. Ultrastructurally the inclusions appeared to consist of thick filamentous structures of 12–25 nm in diameter studded with electron-dense ribosomelike granules. Thick filamentous profiles were relatively short or occasionally fragmentary, haphazardly mingled with various amounts of granules and other organelles. No prominent accumulation of 10-nm neurofilaments or eosinophilic inclusions like Bunina bodies were found. The inclusions were indistinguishable from those reported in so-called “juvenile” amyotrophic lateral sclerosis.

Combination of cyclosporine A with corticosteroids is effective for the treatment of neuromyelitis optica.

Neuromyelitis optica (NMO) and associated NMO spectrum disorders (NMOSDs) are neuroinflammatory diseases that frequently result in severe neurological disabilities. The aim of this study was to explore additional treatment options for NMO/NMOSD patients who are seropositive for anti-aquaporin 4 (AQP4) antibodies. We retrospectively evaluated the efficacy of immunosuppressants for NMO/NMOSDs by reviewing the clinical records of 52 patients confirmed as seropositive for anti-AQP4 antibodies. Of the 52 patients, 26 (23 women, three men) had received at least one kind of immunosuppressant other than corticosteroids. After eliminating ineligible cases, we evaluated the following 24 treatments in 22 patients (20 women, two men) that used azathioprine (AZA) (nxa0=xa09), cyclophosphamide (nxa0=xa01), cyclosporine A (CyA) (nxa0=xa09), tacrolimus (nxa0=xa02), methotrexate (nxa0=xa01), and mizoribine (nxa0=xa02). Both AZA and CyA treatments allowed us to decrease the median dose of the coadministered prednisone without affecting the expanded disability severity scale scores. In patients with relapsing-remitting courses, the annual relapse rate decreased from 1.7 (1.2–2.7) to 0.47 (0.36–0.59) after AZA treatments (nxa0=xa06, Pxa0=xa00.028), and also showed a significant decrease from 2.7 (1.8–4.3) to 0.38 (0–0.97) after CyA treatment (nxa0=xa08, Pxa0=xa00.012). These results indicate that CyA as well as AZA may help stabilize the disease activity in NMO/NMOSD patients seropositive for anti-AQP4 antibodies. This is the first case series study demonstrating the efficacy of CyA for the treatment of NMO/NMOSDs.

Pael receptor is involved in dopamine metabolism in the nigrostriatal system

Pael receptor (Pael-R) has been identified as one of the substrates of Parkin, a ubiquitin ligase responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When Parkin is inactivated, unfolded Pael-R accumulates in the endoplasmic reticulum and results in neuronal death by unfolded protein stress, suggesting that Pael-R has an important role in the pathogenesis of AR-JP. Here we report the analyses on Pael-R-deficient (KO) and Pael-R-transgenic (Tg) mice. The striatal dopamine (DA) level of Pael-R KO mice was only 60% of that in normal mice, while in Pael-R Tg mice, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) as well as vesicular DA content increased. Moreover, the nigrostriatal dopaminergic neurons of Pael-R Tg mice are more vulnerable to Parkinsons disease-related neurotoxins while those of Pael-R KO mice are less. These results strongly suggest that the Pael-R signal regulates the amount of DA in the dopaminergic neurons and that excessive Pael-R expression renders dopaminergic neurons susceptible to chronic DA toxicity.

Altered T cell phenotypes associated with clinical relapse of multiple sclerosis patients receiving fingolimod therapy

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7+ central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56+ T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment. Each T cell subpopulation further increased during relapse. Interestingly, T cells from fingolimod-treated patients exhibited interferon-γ biased production, and more myelin basic protein-reactive cells was noted in CD56+ than in CD56− T cells. It is likely that the altered T cell phenotypes play a role in MS relapse in fingolimod-treated patients. Further clinical studies are necessary to investigate whether altered T cell phenotypes are a biomarker for relapse under fingolimod therapy.

Association of lipocalin-type prostaglandin D synthase with disproportionately enlarged subarachnoid-space in idiopathic normal pressure hydrocephalus

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Aβ) implicated in Alzheimer’s disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers.MethodsWe evaluated 22 patients (age: 76.4u2009±u20094.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Aβ42, Aβ40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score.ResultsL-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (pu2009=u20090.013 and pu2009=u20090.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman ru2009=u20090.753, pu2009<u20090.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman ru2009=u20090.602, pu2009=u20090.004), callosal angle (Spearman ru2009=u20090.592, pu2009=u20090.004), and ARWMC scores (Spearman ru2009=u20090.652, pu2009=u20090.001), but were negatively correlated with FAB scores (Spearman ru2009=u20090.641, pu2009=u20090.004).ConclusionsOur data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.

Clustering of multifocal cerebral infarctions in CADASIL: a case report

A 42-year-old Japanese man who suffered an accidental fall was admitted to our hospital and periventricular lucency was detected by head CT. Clinical manifestations were determined to include a 20-year history of alopecia and mood disorder without ischemic strokes or migraines. The patient reported having caught a cold 1 week before admission and subsequently decreased dietary intake in the preceding days. There was no history of consanguinity, but stroke and progressive dementia was documented in his mother with evidence of diffuse leukoencephalopathy on her MRI. His younger sister had a history of migraines and periventricular white matter lesions were recorded from her MRI. Upon examination, the patient’s core temperature was 37.1 C, blood pressure was 98/50 mmHg, and pulse was 83 beats/min. Neurological examination revealed mild abulia and cognitive impairment (Mini-Mental State Examination score, 20/30). Neither muscle weakness nor sensory disturbance could be detected. MRI-diffusion-weighted imaging (DWI) revealed multiple high intensities in the bilateral periventricular white matter and genu of the corpus callosum, accompanied by low apparent diffusion coefficient (ADC) values (Fig. 1a–d). Fluid-attenuated inversion recovery (FLAIR) images showed subcortical ischemic changes (Fig. 1e) N-isopropylp-[123 I]-iodoamphetamine single photon emission computed tomography (IMP-SPECT) showed global cerebral hypoperfusion (Fig. 1f). MR angiography, carotid ultrasonography, electrocardiography, echocardiography, and whole-body CT were all normal. Laboratory tests revealed elevated white blood cells (8,200/ll) and C-reactive protein (6.40 mg/dl). Hemostatic marker assays showed short prothrombin time (68.5%) and elevated fibrinogen level (522 mg/dl). Cardiovascular risk factors, collagen diseases, and metabolic abnormalities were not documented. These findings led us to perform a skin biopsy, which showed granular osmiophilic material (GOM) under ultrastructural examination (Fig. 1g, h). Direct sequencing analysis of whole blood sample revealed a Arg169Cys mutation caused by C?T transition at nucleotide position 583 within exon 4 of the NOTCH3 gene, establishing the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is a hereditary microangiopathy with recurrent transient ischemic attacks and strokes, migraines, mood disturbance, and progressive cognitive impairment [6]. Alopecia is known as a characteristic symptom of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) [5], while Yamada et al. has reported a CADASIL patient with alopecia [16]. A signal increase on MRI-DWI with low ADC values is highly accurate for the diagnosis of acute stroke [11]. Therefore, hyperintensity in DWI with low ADC values strongly indicate multiple ischemic lesions in the bilateral hemispheres. To our knowledge, these multifocal signal S. Saito A. Ozaki (&) M. Takahashi S. Matsumoto Department of Neurology, Kitano Hospital, The Tazuke Kofukai Medical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan e-mail: osk@kuhp.kyoto-u.ac.jp