水谷 泰彰

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a neurodegenerative disease with characteristic motor and autonomic symptoms. Impaired brain serotonergic innervation can be associated with various clinical indices of MSA; however, the relationship between clinical symptoms and cerebrospinal fluid (CSF) levels of 5-hydroxyindole acetic acid (5-HIAA), a main serotonin metabolite, has not been fully elucidated. METHODS: To compare CSF 5-HIAA levels between patients with MSA and healthy controls, we included 33 controls and 69 MSA patients with either predominant parkinsonian or cerebellar ataxia subtypes. CSF 5-HIAA levels were measured using high-performance liquid chromatography. Additionally, we investigated correlations between CSF 5-HIAA and various clinical indices in 34 MSA patients. RESULTS: CSF 5-HIAA levels were significantly lower in MSA patients than in controls (p < 0.0001). Probable MSA patients had lower CSF 5-HIAA levels than possible MSA patients (p < 0.001). In MSA patients, CSF 5-HIAA levels were inversely correlated with scores in Parts 1, 2, and 4 of the Unified Multiple System Atrophy Rating Scale, and with systolic and diastolic blood pressure in Part 3. Structural equation modeling revealed significant paths between serotonin and clinical symptoms, and significance was highest for activities of daily living, walking, and body sway. CONCLUSIONS: Serotonin dysfunction, as assessed by CSF 5-HIAA levels, may implicate greater MSA severity.

INTRODUCTION: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD. METHODS: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals. RESULTS: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0). CONCLUSIONS: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low.

BACKGROUND: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. METHODS: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. RESULTS: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days). CONCLUSIONS: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

OBJECTIVE: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. METHODS: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. RESULTS: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. INTERPRETATION: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.

BACKGROUND: Parkinson's disease (PD) is associated with cognitive decline through multiple mechanisms, including Alzheimer's disease (AD) pathology and cortical Lewy body involvement. However, its underlying mechanisms remain unclear. Recently, AD-related plasma biomarkers have emerged as potential tools for predicting abnormal pathological protein accumulation. We aimed to investigate the association between AD-related plasma biomarkers and cognitive decline in PD patients. METHODS: Plasma biomarkers were measured in 70 PD patients (49 with nondemented Parkinson's disease (PDND) and 21 with Parkinson's disease dementia (PDD)) and 38 healthy controls (HCs) using a single-molecule array. The study evaluated (1) the correlation between plasma biomarkers and clinical parameters, (2) receiver operating characteristic curves and areas under the curve to evaluate the discrimination capacity of plasma biomarkers among groups, and (3) a generalized linear model to analyze associations with Addenbrooke's Cognitive Examination-Revised and Montreal Cognitive Assessment-Japanese version scores. RESULTS: Plasma glial fibrillary acidic protein significantly correlated with cognitive function tests, including all subdomains, with a notable increase in the PDD group compared with the HC and PDND groups, while plasma neurofilament light chain captured both cognitive decline and disease severity in the PDND and PDD groups. Plasma beta-amyloid 42/40 and pholphorylated-tau181 indicated AD pathology in the PDD group, but plasma beta-amyloid 42/40 was increased in the PDND group compared with HCs and decreased in the PDD group compared with the PDND group. CONCLUSIONS: AD-related plasma biomarkers may predict cognitive decline in PD and uncover underlying mechanisms suggesting astrocytic pathologies related to cognitive decline in PD.

OBJECTIVE: In this study, we aimed to clarify the relationship between initial treatment response, prednisolone (PSL) dosage, clinical type, and recurrence in patients with hypertrophic pachymeningitis (HP). METHODS: The study cohort comprised eight patients with HP who had been admitted to our hospital from April 2015 to June 2020. Diagnostic criteria for HP included neurological abnormalities and dural thickening on magnetic resonance gadolinium-enhanced T1-weighted images. RESULTS: Relevant characteristics of the eight study patients are as follows. There were two men and six women. The average age at onset was 58.3 (range: 29-79) years. Three of them had myeloperoxidase-antineutrophil cytoplasmic antibody-related vasculitis, one immunoglobulin G4-related disease, and one ulcerative colitis. The remaining three patients had idiopathic HP. The average maximum dosage of PSL was 0.79 mg/kg/day, and the average daily maintenance dosage 0.18 mg/kg/day. Three patients needed additional immunosuppressive drugs. Both idiopathic and secondary HP initially responded well to PSL, with improvement in activities of daily living. Six patients had some sequelae related to cranial nerve involvement. No relapses occurred while the patients were taking moderate doses of PSL; however, all patients with idiopathic HP had recurrences when their PSL dosage was reduced. CONCLUSIONS: Patients with idiopathic HP and HP associated with immune disorders respond to steroids and immunosuppressive drugs and recover well. However, there is a high rate of relapse after reduction of PSL dosage, mainly in those with idiopathic HP.

This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder. We report a 59-year-old man who presented with progressive encephalomyelitis causing diplopia, bulbar palsy, severe dysautonomia, followed by stiffness and myoclonic cluster. Laboratory tests showed mild pleocytosis, with markedly elevated plasma levels of norepinephrine, epinephrine, and arginine vasopressin. Glycine-receptor antibodies were identified in both serum and CSF. Despite a poor response to methylprednisolone, immunoglobulins, and plasma exchange, α-blocker stabilized dysautonomia. Dysautonomia is presumed to be due to antibody-mediated disinhibited sympathetic hyperactivity; however, this case suggests that concomitant use of α-blocker with immunotherapy may ameliorate dysautonomia.

The pathophysiology of neuralgic amyotrophy (NA) remains to be elucidated. However, high-resolution magnetic resonance imaging and ultrasound sonography have provided new insights into the mechanism underlying the development of NA and its diagnosis. We report a case of idiopathic distal NA with hyperintensity and thickening in the inferior trunk extending to the posterior and medial fasciculus of the left brachial plexus, which was detected by magnetic resonance neurography (MRN) with diffusion-weighted whole-body imaging with background body signal suppression (DWIBS). The abnormal signal intensity diminished after the improvement of symptoms following corticosteroid treatment. MRN with DWI can help diagnose distal NA and evaluate the post-therapeutic response.

Clioquinol has been implicated as a causative agent for subacute myelo-optico-neuropathy (SMON) in humans, although the mechanism remains to be elucidated. In this study, we utilized astrocyte-derived cell line, KT-5 cells to explore its potential cytotoxicity on glial cells. KT-5 cells were exposed in vitro to a maximum of 50 μM clioquinol for up to 24 h. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte trazolium bromide (MTT) assay of the cells revealed that clioquinol induced significant cell damage and death. We also found that clioquinol caused accumulation of microtubule-associated protein light chain-3 (LC3)-II and sequestosome-1 (p62) in a dose- and time-dependent manner, suggesting the abnormality of autophagy-lysosome pathway. Consistent with these findings, an exposure of 20 μM clioquinol induced the accumulation of cellular autophagic vacuoles. Moreover, an exposure of 20 μM clioquinol provoked a statistically significant reduction of intracellular lysosomal acid hydrolases activities but no change in lysosomal pH. It also resulted in a significant decline of intracellular ATP levels, enhanced cellular levels of reactive oxygen species, and eventually cell death. This cell death at least did not appear to occur via apoptosis. 10 μM Chloroquine, lysosomal inhibitor, blocked the autophagic degradation and augmented clioquinol-cytotoxicity, whereas rapamycin, an inducer of autophagy, rescued clioquinol-induced cytotoxicity. Thus, our present results strongly suggest clioquinol acts as a potentially cytotoxic agent to glial cells. For future clinical application of clioquinol on the treatment of neurological and cancer disorders, we should take account of this type of cell death mechanism.

Cerebrospinal fluid (CSF) contains glycosphingolipids, including lactosylceramide (LacCer, Galβ(1,4)Glcβ-ceramide). LacCer and its structural isomer, galabiosylceramide (Gb2, Galα(1,4)Galβ-ceramide), are classified as ceramide dihexosides (CDH). Gb2 is degraded by α-galactosidase A (GLA) in lysosomes, and genetic GLA deficiency causes Fabry disease, an X-linked lysosomal storage disorder. In patients with Fabry disease, Gb2 accumulates in organs throughout the body. While Gb2 has been reported to be in the liver, kidney, and urine of healthy individuals, its presence in CSF has not been reported, either in patients with Fabry disease or healthy controls. Here, we isolated CDH fractions from CSF of patients with idiopathic normal pressure hydrocephalus. Purified CDH fractions showed positive reaction with Shiga toxin, which specifically binds to the Galα(1,4)Galβ structure. The isolated CDH fractions were analyzed by hydrophilic interaction chromatography (HILIC)-electrospray ionization tandem mass spectrometry (ESI-MS/MS). HILIC-ESI-MS/MS separated LacCer and Gb2 and revealed the presence of Gb2 and LacCer in the fractions. We also found Gb2 in CSF from neurologically normal control subjects. This is the first report to show Gb2 exists in human CSF.

To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer's disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

BACKGROUND: As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson's disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. OBJECTIVE: We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. METHODS: We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured. RESULTS: C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. CONCLUSION: Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.

Previous studies have shown that patients with Guillain-Barré syndrome express autoantibodies against ganglioside GM1 (GM1), although its pathogenic significance for the development of the disease remains to be elucidated. nSMase2 is the best characterized neutral sphingomyelinase (nSMase) found in neuronal cells. Activation of this enzyme leads to ceramide production, which is a known second messenger of the cell-death program in neuronal cells. We have explored the effects of anti-GM1 antibodies on sphingomyelin metabolism of PC12 cells stably transfected with human trk cDNA (PCtrk cells) by determining their effects on nSMase2 activity. The data we present here strongly suggest that anti-GM1 caused a significant change in sphingomyelin content of the membrane fraction in PCtrk cells. Both nSMase2 activity and the level of nSMase2 protein were significantly decreased by anti-GM1 treatment of PCtrk cells, while acidic SMase activities remained unchanged. Our results indicate, for the first time, that anti-GM1 may produce profound impacts on lipid metabolism in neuronal cell membranes.

Background: Although single-photon emission computerized tomography of the dopamine transporter (DATSPECT) is useful for diagnosing parkinsonian syndrome, its applicability toward the early phase of Parkinson's disease remains unknown. Methods: We enrolled 32 patients showing parkinsonism with normal cardiac I-123-metaiodobenzylguanidine (MIBG) uptake and abnormal DAT-SPECT findings among 84 consecutive patients with parkinsonism. We divided these patients into two groups (group 1: Parkinson's disease, group 2: corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy), and compared their clinical characteristics, specific binding ratios, and striatal asymmetry indexes on DAT-SPECT examinations. Results: The striatal asymmetry indexes were significantly lower in group 1 than in group 2 (p &lt; 0.05), but there were no differences in the specific binding ratios between the two groups. Conclusion: The combined use of striatal asymmetry index on DAT-SPEC' and cardiac MIBG scintigraphy might offer useful clues for the differential diagnosis of the early phase Parkinson's disease from other parkinsonian syndromes. (C) 2017 Elsevier B.V. All rights reserved.

Introduction: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. Methods: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole- body MR neurography based on diffusionweighted whole- body imaging with background body signal suppression ( DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. Results: The peripheral nervous system was visualized with 3-dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm(3)/m(2) in the brachial plexus and nerve roots and from 10.2 to 53.5 cm(3)/m(2) in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls ( P &lt; 0.05), and volume was positively correlated with disease duration. Conclusions: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP.

Objective: Acute multifocal embolic infarction (AMEI) is conventionally caused by etiologies such as cardioembolism due to atrial fibrillation (AO, but can also be caused by serious underlying diseases such as cancer. We characterized cancer-related AMEI and identified useful indicators for cancer-associated strokes. Methods: A retrospective analysis was performed on 35 patients with Af-related AMEI and 35 patients with cancer -related AMEI selected from 1235 consecutive patients with acute infarcts. All patients received diffusion weighted magnetic resonance (MR) imaging. Cerebral MR angiography, carotid and cardiac ultrasonography, electrocardiogram-monitoring and whole body computed tomography were also performed on these patients. D-dimer levels were evaluated on admission, and were measured during the sub-acute phase in 19 of the patients with Af and 27 of the patients with cancer. Results: Acute phase D-dimer levels were significantly higher in patients with cancer than in patients with Af alone. The cut-off D-dimer value to identify cancer-associated infarcts was 2.0 mu g/mL. D-dimer levels during the sub-acute phase remained elevated in the cancer patients. Conclusions: We may differentiate cancer-associated AMEI from Af using a D-dimer level &gt;= 2.0 mu g/mL, which does not decrease during the sub-acute phase. (C) 2016 Elsevier B.V. All rights reserved.

Background: Although most patients with Parkinson's disease (PD) show decreased cardiac I-123-metaiodobenzylguanidine (MIBG) uptake, some exhibit normal uptake. We evaluated the clinical characteristics of such patients. Methods: We enrolled 154 non-demented patients showing parkinsonism with normal cardiac MIBG uptake and had been clinically followed up during 29.9 +/- 27.6 months. We defined the patients who did not fit the exclusion criteria for PD and demonstrated &gt;= 30% reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score after anti-Parkinson agent administration as probable PD. We compared clinical characteristics and the cardiac MIBG heart-to-mediastinum (H/M) ratio between the probable PD group (N = 37) and other groups (N = 117). Results: The probable PD group showed significantly higher UPDRS motor scores and greater incidence of tremor/rigidity than those of other groups. In addition, they showed a significantly lower cardiac MIBG HIM ratio in the delayed phase (delayed, p &lt; 0.0001). Washout-rate (WR) was significantly higher in probable PD cases (p &lt; 0.0001). Among 16 probable PD patients undergoing serial cardiac MIBG scintigraphy, the delayed phase cardiac MIBG H/M ratio showed a significant decrease and WR significantly increased during follow-up periods. Conclusions: An increase in WR and lower delayed phase cardiac MIBG uptake were found to be characteristics of such patients. (C) 2015 Elsevier B.V. All rights reserved.

Background and purpose: Most patients with multiple system atrophy (MSA) develop autonomic dysfunction; however, orthostatic hypotension is not always present. Failure of the vasoconstrictor response is thought to be responsible for orthostatic hypotension, but the degree of impairment of this response in patients with MSA is unclear. We assessed autonomic function in patients with MSA by evaluating the vasoconstrictive response during a head-up tilt test and determining its relationship to orthostatic hypotension. As an additional examination, the efficacy of norepinephrine in treating orthostatic hypotension was also assessed. Methods: The study included 82 patients with MSA and 28 controls. Measures of total peripheral resistance were obtained during a head-up tilt test. Norepinephrine was administered to the patients lacking a vasoconstrictive response to evaluate its ability to treat orthostatic hypotension. Results: At a 60 tilt, orthostatic hypotension occurred in 47.6% of the patients and 0% of controls. Reduction in total peripheral resistance from baseline at a 60 degrees tilt was observed in 69.5% of the patients and 0% of controls. In patients with MSA, changes in systolic blood pressure from the baseline at a 60 tilt correlated positively with changes in the total peripheral resistance (r = 0.69, p &lt; 0.0001). Norepinephrine prevented the reduction of total peripheral resistance and development of orthostatic hypotension. Conclusions: A large number of patients with MSA with and without orthostatic hypotension have an impaired peripheral vasoconstrictive response, suggesting a high frequency of cardiovascular dysautonomia with an associated risk of developing orthostatic hypotension. A norepinephrine infusion was effective for treating orthostatic hypotension. (C) 2015 Elsevier Ltd. All rights reserved.

Objective: Olfactory dysfunction is considered to precede motor symptoms and early markers of Parkinson's disease (PD), while the relative time at which cardiovascular dysautonomia appears in PD is not well understood. To assess the appearance of cardiovascular dysautonomia in PD, we evaluated its relation to olfactory dysfunction in early-stage PD patients. Methods: Twenty-three non-demented PD patients within 2 years from the onset of motor symptoms were enrolled. We evaluated olfactory dysfunction by the Odor Stick Identification Test for Japanese (OSIT-J) and analyzed its relationship to the results of other cardiovascular autonomic tests and cardiac I-123-metaiodobenzylguanidine (MIBG) scintigraphy. Results: There was a correlation between olfactory scores and increased blood pressure in both the norepinephrine (r = 0.75, p &lt; 0.0001, n = 21) and dobutarnine (r = 0.57, p = 0.0087, n = 20) infusion tests and cardiac MIBG uptake (r = 0.42, p = 0.049, n = 23). The fall in orthostatic blood pressure during the head-up tilt test was not correlated with the olfactory scores, but the Valsalva maneuver revealed that OSIT-J scores correlated with the pressure recovery time from phase III to the return of blood pressure to baseline (r = 0.54, p = 0.037, n = 15) and with the magnitude of blood pressure overshoot during phase IV (r = 0.67, p = 0.0016, n = 20). Conclusion: Our results demonstrate that extensive components of the cardiovascular sympathetic system as well as the olfactory system are correlatively impaired in the early stage of PD, suggesting that degeneration of broad aspects of the cardiovascular sympathetic system occurs concurrently with olfactory system degeneration during the premotor phase of PD. (C) 2014 Elsevier Ltd. All rights reserved.

Purpose: Cardiac sympathetic denervation is associated with orthostatic hypotension (OH) in Parkinson's disease (PD); however, the physiological role of cardiac sympathetic nerves has yet to be elucidated. To clarify the role of the heart in orthostatic stress, we evaluated whether cardiac sympathetic nerves can alter cardiac activity and systolic blood pressure (BP) in association with elevations or depressions of total peripheral resistance during the head-up tilt test. Methods: Ninety-five PD patients and 17 normal controls were enrolled. Using impedance cardiography, we measured total peripheral resistance, stroke volume, heart rate, and systolic BP during the head-up tilt test. Cardiac denervation was defined as a heart-to-mediastinum ratio &lt;1.7 for cardiac I-123-metaiodobenzylguanidine uptake on delayed images. Results: At 60 degrees tilt, total peripheral resistance decreased from the initial value in 49 PD patients. Among these, 36 patients exhibited cardiac denervation with severe reductions in systolic BP but little change in stroke volume; among these patients 22 had OH. The remaining 13 patients without cardiac denervation exhibited significant increases in stroke volume and well-preserved systolic BP with no OH. On the other hand, 46 patients had elevations in total peripheral resistance and reduced stroke volume, but little change in systolic BP, regardless of the presence or absence of cardiac denervation. Only one of these patients experienced OH. Conclusion: Under orthostatic stress, cardiac sympathetic denervation with failure to increase total peripheral resistance leads to large reductions in systolic BP. However, patients without cardiac denervation exhibited a positive inotropic response against vasodilatation, which may prevent OH. (C) 2014 Elsevier Ltd. All rights reserved.

Background and purpose: Many non-motor symptoms are associated with Parkinson's disease (PD). Of these, pain and olfactory disturbance tend to be common premotor symptoms. PD has been shown to exhibit abnormal central pain processing, although underlying mechanisms are not yet fully understood. In order to investigate this further, we assessed PD patients by specific A delta stimulation with intra-epidermal needle electrode and determined olfactory function. Methods: Forty-two patients (18 males and 24 females) with PD and 17 healthy control subjects (8 males and 9 females) were studied. A thin needle electrode was used to stimulate epidermal A delta fibers, and somatosensory evoked potentials (SEPs) recorded at the vertex. Olfactory function was evaluated using the Odor Stick Identification Test for Japanese (OSIT-J) and its relationship with pain-related SEPs was investigated. Results: There were no significant differences in N1 latencies or P1 latencies although N1/P1 peak-to-peak amplitudes were significantly lower (p &lt; 0.01) in PD patients than in control subjects. In PD patients, there were significant correlations between N1/P1 amplitudes and disease duration (r = -0.35, p &lt; 0.05), Hoehn-Yahr stage (r = -0.38, p &lt; 0.05) and UPDRS part III (r = -0.42, p &lt; 0.01). Furthermore, the OSIT-J scores correlated with SEP amplitude (r = 0.41, p &lt; 0.01). Conclusion: Pain processing in PD patients was impaired under specific nociceptive stimulation of A delta fibers and significant correlation with smell dysfunction was detected. We suggest that this mechanism may involve the limbic system during PD pathology. (c) 2012 Elsevier Ltd. All rights reserved.

A 28-year-old man was admitted to our hospital because of severe headache and diplopia. Enhanced CT of the head revealed defects of contrast enhancement in the superior sagittal sinus and the right transverse sinus. Accordingly, he was diagnosed as suffering from cerebral venous thrombosis. The patient made a good recovery after receiving anticoagulant therapy. Investigations revealed a high plasma lipoprotein (a) [Lp (a)] level of 142 mg/dl. We thought that his high Lp (a) level was associated with a thrombotic tendency. His mother also had an elevated plasma Lp (a) level of 45 mg/dl. Cerebral venous thrombosis of unknown etiology is not rare. In such patients, we should investigate the plasma Lp (a) level.