Language：English   Publishing type：Research paper (scientific journal)  

The evidence that heart rate variability (HRV) decreases during early Parkinson's disease (PD) largely depends on electrocardiogram data. In this study, we examined HRV in PD using wearable sensors and assessed various evaluation methods for detecting disease-related alterations. We evaluated 27 patients with PD and 23 disease controls. The wearable sensors POLAR V800 HR and POLAR H10 were used for the HRV measurements. The participants wore the two sensors for approximately 24 h, and long-term HRV data were acquired. We analyzed the standard deviation of normal R-R intervals (SDNN) and coefficient of variation of R-R intervals (CVRR) for every 100 consecutive beats. Focusing on the fluctuation of SDNN and CVRR, we extracted the minimum, first decile, first quartile, and median values of SDNN and CVRR. The area under the receiver operating characteristic curve (AUC) for each HRV parameter was calculated to differentiate PD from the disease controls. The minimum values of SDNN and CVRR had the highest AUC (SDNN: AUC 0.90, 95% confidence interval [CI] 0.78-0.96; CVRR: AUC 0.90, CI 0.76-0.96) among the evaluation methods tested. The minimum values of SDNN and CVRR were significantly decreased in PD (SDNN: 9.5 ± 4.0 ms vs. 4.4 ± 2.0 ms, p < 0.0001; CVRR: 1.15 ± 0.33% vs. 0.65 ± 0.24%, p < 0.0001). We detected decreased HRV in PD using wearable sensors. Analyzing the minimum values of the HRV parameter in long-term recordings appears to be appropriate for detecting the decrease in HRV in PD.

DOI： 10.1007/s00702-022-02528-y

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Language：Japanese   Publisher：(一社)日本神経学会  

症例は71歳女性.63歳でパーキンソン病を発症し,66歳からウェアリングオフ,その後ジスキネジアも出現した.3日前からジスキネジアの増悪,前日から発熱あり,高クレアチンキナーゼ血症を認め入院.筋強剛を伴わず覚醒中に持続する重度ジスキネジアを認め,dyskinesia-hyperpyrexia syndrome(DHS)と診断した.全身管理と抗パーキンソン病薬の大幅な減量を行い,2週間で改善した.イストラデフィリンの過量服薬がDHSの誘因と考えられた.DHSは稀ではあるが致死的となり得る合併症であり,早期の診断が求められる.治療として,全身管理とともに抗パーキンソン病薬の減量が重要である.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J01550&link_issn=&doc_id=20220817430006&doc_link_id=10.5692%2Fclinicalneurol.cn-001740&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.cn-001740&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：npj Parkinson's Disease  

Non-motor symptoms (NMS) are common among patients with Parkinson’s disease and reduce patients’ quality of life (QOL). However, there remain considerable unmet needs for NMS management. Three monoamine oxidase B inhibitors (MAO-BIs), selegiline, rasagiline, and safinamide, have become commercially available in many countries. Although an increasing number of studies have reported potential beneficial effects of MAO-BIs on QOL and NMS, there has been no consensus. Thus, the primary objective of this study was to provide an up-to-date systematic review of the QOL and NMS outcomes from the available clinical studies of MAO-BIs. We conducted a literature search using the PubMed, Scopus, and Cochrane Library databases in November 2021. We identified 60 publications relevant to this topic. Overall, rasagiline and safinamide had more published evidence on QOL and NMS changes compared with selegiline. This was likely impacted by selegiline being introduced many years prior to the field embarking on the study of NMS. The impact of MAO-BIs on QOL was inconsistent across studies, and this was unlikely to be clinically meaningful. MAO-BIs may potentially improve depression, sleep disturbances, and pain. In contrast, cognitive and olfactory dysfunctions are likely unresponsive to MAO-BIs. Given the paucity of evidence and controlled, long-term studies, the effects of MAO-BIs on fatigue, autonomic dysfunctions, apathy, and ICD remain unclear. The effects of MAO-BIs on static and fluctuating NMS have never been investigated systematically. More high-quality studies will be needed and should enable clinicians to provide personalized medicine based on a non-motor symptom profile.

DOI： 10.1038/s41531-022-00339-2

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Language：English   Publisher：Journal of Neurosurgery  

OBJECTIVE Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy ameliorates symptoms in patients with essential tremor (ET). How this treatment affects canonical brain networks has not been elucidated. The purpose of this study was to clarify changes of brain networks after MRgFUS thalamotomy in ET patients by analyzing resting-state networks (RSNs). METHODS Fifteen patients with ET were included in this study. Left MRgFUS thalamotomy was performed in all cases, and MR images, including resting-state functional MRI (rsfMRI), were taken before and after surgery. MR images of 15 age- and sex-matched healthy controls (HCs) were also used for analysis. Using rsfMRI data, canonical RSNs were extracted by performing dual regression analysis, and the functional connectivity (FC) within respective networks was compared among pre-MRgFUS patients, post-MRgFUS patients, and HCs. The severity of tremor was evaluated using the Clinical Rating Scale for Tremor (CRST) score pre- and postoperatively, and its correlation with RSNs was examined. RESULTS Preoperatively, ET patients showed a significant decrease in FC in the sensorimotor network (SMN), primary visual network (VN), and visuospatial network (VSN) compared with HCs. The decrease in FC in the SMN correlated with the severity of tremor. After MRgFUS thalamotomy, ET patients still exhibited a significant decrease in FC in a small area of the SMN, but they exhibited an increase in the cerebellar network (CN). In comparison between pre- and post- MRgFUS patients, the FC in the SMN and the VSN significantly increased after treatment. Quantitative evaluation of the FCs in these three groups showed that the SMN and VSN increased postoperatively and demonstrated a trend toward those of HCs. CONCLUSIONS The SMN and CN, which are considered to be associated with the cerebello-thalamo-cortical loop, exhibited increased connectivity after MRgFUS thalamotomy. In addition, the FC of the visual network, which declined in ET patients compared with HCs, tended to normalize postoperatively. This could be related to the hypothesis that visual feedback is involved in tremor severity in ET patients. Overall, the analysis of the RSNs by rsfMRI reflected the patho-physiology with the intervention of MRgFUS thalamotomy in ET patients and demonstrated a possibility of a biomarker for successful treatment.

DOI： 10.3171/2022.5.JNS22411

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

<p>We present a 71-year-old woman with an eight-year history of Parkinson’s disease (PD). She began to experience wearing-off at the age of 66 and subsequently developed dyskinesia. She had worsened dyskinesias for three days, followed by a high fever, and she was subsequently hospitalized. On admission, severe dyskinesia, hyperpyrexia, and elevation of serum creatine kinase were observed. Severe dyskinesia without rigidity continued throughout the day and she was diagnosed with dyskinesia-hyperpyrexia syndrome (DHS). She was treated with standard medical care and anti-parkinsonian medications were reduced drastically. Dyskinesia started to wane three days after admission and almost disappeared on day twelve. Prior to admission, the patient reported she had been taking two to three times the dose prescribed of istradefylline, which was the suspected to be a trigger of DHS. Because DHS is a rare but potentially life-threatening complication, early recognition and diagnosis is vital. A proper treatment strategy for DHS may include standard medical care together with reduced anti-parkinsonian medications.</p>

DOI： 10.5692/clinicalneurol.cn-001740

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10072-020-05028-7

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Other Link： http://link.springer.com/article/10.1007/s10072-020-05028-7/fulltext.html

Language：English   Publisher：JOHN WILEY & SONS LTD  

Systemic sclerosis (SSc) is a multi-system autoimmune disease. Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against enzymes found within primary granules of neutrophils and lysosomes in monocytes. Although up to 12% of SSc patients have ANCA, only a minority of these patients develop an overlap syndrome with ANCA-associated vasculitis. We summarize previous reports on SSc patients with ANCA-associated neuropathy. In all the reported cases, the SSc diagnosis preceded the ANCA-associated neuropathy diagnosis. Seven of the eight patients with limited cutaneous SSc had interstitial lung disease (ILD). Thus, patients with ANCA-associated neuropathy in lSSc may be prone to complication with ILD.

DOI： 10.1002/cia2.12153

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.

DOI： 10.1016/j.neurobiolaging.2020.10.028

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER WIEN  

Although orthostatic hypotension is more prominent in multiple system atrophy (MSA) than in Parkinson's disease (PD), there is no study comparing the degree of decrease in total peripheral resistance and cardiac response during orthostatic stress between both diseases. In this study, we examined whether there is a difference in cardiovascular response between MSA and PD. We examined the results of the head-up tilt test in 68 patients with MSA, 28 patients with cardiac non-denervated PD, and 70 patients with cardiac denervated PD whose total peripheral resistance after 60 degrees tilting was lower than the value at 0 degrees. Differences in cardiac output and blood pressure changes were compared against the decrease in total peripheral resistance. There was no difference in the degree of decrease in total peripheral resistance among the three groups. However, the slope of the regression line revealed that the increase in cardiac output against the change in total peripheral resistance was significantly lower in the MSA group than in the cardiac non-denervated and denervated PD groups, and that the decrease in systolic blood pressure against the change in total peripheral resistance was significantly greater in the MSA group than in the cardiac non-denervated and denervated PD groups. In MSA, the cardiac response during orthostatic stress is lower than that in PD, possibly underlying the fact that orthostatic hypotension is more prominent in MSA than in PD.

DOI： 10.1007/s00702-020-02241-8

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Language：Japanese   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To clarify the relationship between nerve conduction study (NCS) and prognosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: We included 190 patients with sporadic ALS. We used onset age, sex, onset site (bulbar vs. spinal), revised El Escorial criteria category (definite vs. others), and the King's clinical systems, and the Milano-Torino (MiToS) functional staging systems, and decline rates of revised ALS functional rating scale (ALSFRS-R) as known prognostic factors. An NCS was performed on the median, ulnar, tibial, and sural nerves. The endpoint was death or the introduction of tracheostomy positive-pressure ventilation. Multivariate analysis for each NCS variable, known prognostic factors was performed using Cox stepwise proportional hazards analysis. Univariate analysis was performed for NCS variables that showed a significant association with prognosis in multivariate analysis. Survival was analyzed with a Kaplan-Meier curve and log-rank test. RESULTS: The Cox model identified the compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of the median nerve as prognostic factors. In the log-rank test, patients with higher median nerve CMAP amplitude had a significantly better prognosis than those with lower amplitude, regardless of age. And prognosis was better in the group with lower median nerve SNAP amplitude only in patients younger than the 25th percentile (~ 57 years). CONCLUSIONS: CMAP and SNAP amplitudes of the median nerve are considered to be independent prognostic factors of sporadic ALS.

DOI： 10.1007/s00415-020-09858-5

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Language：Japanese   Publishing type：Research paper (scientific journal)  

PURPOSE: Neurodegeneration of the nucleus ambiguus and the dorsal vagal motor nucleus has been implicated in cardiac parasympathetic dysfunction in multiple system atrophy (MSA). The nucleus ambiguus and the dorsal vagal motor nucleus, which are located in the medulla oblongata (MO), control the autonomic-specifically, the parasympathetic-functions of the body. The aim of our study was to investigate the relationship between cardiac parasympathetic dysfunction and the anteroposterior diameter of the MO in MSA by quantitatively analyzing magnetic resonance imaging (MRI) outcome measures. METHODS: We retrospectively assessed 40 consecutive patients with probable MSA and 25 age- and sex-matched controls. The anteroposterior diameter of the MO at two locations (MO diameter-A and -B) and the diameters of the midbrain and pons were measured by conventional MRI. A cardiac parasympathetic function score (CP-score) and cardiac sympathetic function score (CS-score) were generated by calculating the z-scores of multiple autonomic function tests. The relationship between the scores and the measured diameters of the brainstem was also investigated. RESULTS: The CP-score and CS-score were significantly lower in the patients with MSA than in the controls (CP-score: 0.61 ± 0.75 vs. - 0.38 ± 0.52, p < 0.001; CS-score: 0.91 ± 1.06 vs. - 0.57 ± 1.07, p < 0.001). Also, in the patients with MSA, the CP-score was significantly correlated with MO diameter-A (r = 0.40, p = 0.010), and the CS-score was significantly correlated with the diameter of the midbrain (r = 0.33, p = 0.038). CONCLUSION: The anteroposterior diameter of the MO is a potential imaging marker of parasympathetic dysfunction in MSA.

DOI： 10.1007/s10286-020-00675-4

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Language：Japanese   Publisher：Clinical Neurology and Neurosurgery  

DOI： 10.1016/j.clineuro.2020.105764

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The degree and frequency of orthostatic hypotension (OH) are high in patients with multiple system atrophy (MSA); however, the association of orthostatic blood pressure (BP) with the symptoms of OH and cognitive impairment in these patients remains unclear. The aim of this study was to clarify whether absolute BP and/or changes in BP during standing are related to OH symptoms and cognitive impairment in patients with MSA. Thirty-two patients with MSA were examined using the head-up tilt and cognitive function tests. OH symptoms were evaluated using a patient-reported scale. The results were compared with those for 15 age- and sex-matched healthy controls. Seventeen of the 32 (53.1%) patients had OH, with eight of them exhibiting OH symptoms, which were related to the absolute BP value at 60° tilt. However, OH symptoms were not related to the degree of decrease in BP during the tilt test, and they were frequently observed in patients with a mean BP of <80 mmHg at 60° tilt (sensitivity, 67%; specificity, 91%). Cognitive dysfunction assessed by the Mini-Mental State Examination (MMSE; ≤ 26) was also associated with a low mean BP at 60° tilt (odds ratio, 1.32; 95% confidence interval, 1.04-1.67; p = 0.02). The upright BP value is associated with OH symptoms and the MMSE score in patients with MSA. Thus, careful observation of OH symptoms can enable early management of BP and the detection of cognitive impairment in these patients.

DOI： 10.1016/j.jocn.2020.03.040

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER WIEN  

Wheelchair use is an important indicator of disease progression in Parkinson's disease (PD). Here, we investigated whether orthostatic hypotension (OH) affects the time to wheelchair use. We examined 33 PD patients with OH and 95 without OH. Median time to start using a wheelchair calculated from the time of disease onset was significantly shorter in patients with OH than in those without OH (12.0 vs 19.0 years; p < 0.001). Thus, appropriate management of OH and motor function is necessary.

DOI： 10.1007/s00702-019-02127-4

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in aceruloplasminemia patients with other gene mutations. </p>

DOI： 10.2169/internalmedicine.9855-17

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Cardiac parasympathetic function is strongly affected by aging. Although sympathetic dysfunction has been well documented in Parkinson's disease (PD), cardiac parasympathetic dysfunction has not been well studied. The objective of this study was to clarify the development of cardiac parasympathetic dysfunction in the early phase of PD and to explore the age-corrected correlation between cardiac parasympathetic dysfunction and cardiac sympathetic dysfunction. We reviewed 25 healthy controls and 56 patients with idiopathic PD of Hoehn and Yahr stages I-III. We evaluated cardiac parasympathetic function using the Valsalva ratio, the baroreflex sensitivity (BRS) and the coefficient of variation of RR intervals in the resting state (resting-CVRR) and during deep breathing (DB-CVRR). In addition, we measured cardiac I-123-metaiodobenzylguanidine (MIBG) uptake to investigate the relationship between cardiac sympathetic and parasympathetic dysfunction in PD. Compared with healthy controls, patients with PD showed significantly decreased cardiac parasympathetic parameters (resting-CVRR 2.8 +/- 1.3 vs. 1.7 +/- 0.6%, p &lt; 0.001; DB-CVRR 5.8 +/- 2.3 vs. 3.8 +/- 1.7%, p &lt; 0.001; Valsalva ratio 1.52 +/- 0.26 vs. 1.34 +/- 0.17, p &lt; 0.01; BRS 10.6 +/- 9.5 vs. 5.0 +/- 5.4 ms/ mmHg, p &lt; 0.01). In particular, resting-CVRR and DB-CVRR were significantly decreased in the early phase of PD. In age-corrected analyses, none of the parasympathetic indices correlated with the delayed cardiac I-123-MIBG uptake. These observations indicate that cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in parallel with cardiac sympathetic dysfunction.

DOI： 10.1007/s00415-016-8348-0

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Introduction Lower body mass index (BMI) is associated with orthostatic hypotension (OH) in the general population, especially in the elderly
however, no studies have addressed this issue in Parkinson's disease (PD). Methods We investigated the results of the head-up tilt test and BMI of patients with PD, and evaluated whether BMI is related to orthostatic systolic blood pressure (SBP) change during the head-up tilt test. PD patients were divided into male and female groups, and further divided into middle-aged (age &lt
65 years) and elderly (age ≥ 65 years) subgroups in each sex. Results OH was observed in 13 of 64 male and 12 of 75 female patients with PD. BMI was lower in patients with OH than in those without, in both men and women. In the elderly group, a significant correlation between BMI and orthostatic SBP change was found (men, r = 0.47, p = 0.006
women, r = 0.43, p = 0.005), and a BMI below mean − 0.5 standard deviation increased OH odds (men: BMI &lt
20.5
odds ratio, 6.79
95% CI, 1.06–43.36
women: BMI &lt
18.5
odds ratio, 5.11
95% CI, 1.05–24.96). Conclusion Lower BMI is a predisposing factor of OH in elderly patients with PD.

DOI： 10.1016/j.jns.2016.11.027

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

IntroductionLeptin is involved in the regulation of blood pressure; however, no studies have evaluated the role of leptin in blood pressure changes during orthostatic stress in PD patients. The aim of this study was to determine whether plasma leptin levels influence orthostatic blood pressure changes in PD patients.
MethodsWe enrolled 55 patients and 25 age-matched healthy controls in this study. Associations between head-up tilt test measurements and leptin levels were evaluated.
ResultsSystolic blood pressure changes during the head-up tilt tests were strongly correlated with leptin levels at baseline and at a 60-degree head-up tilt in PD patients, but not in control subjects. Multiple regression analysis also demonstrated that leptin levels were associated with orthostatic blood pressure changes.
ConclusionThese observations suggest that low leptin levels may be associated with orthostatic hypotension during the head-up tilt test in patients with PD. (c) 2016 International Parkinson and Movement Disorder Society

DOI： 10.1002/mds.26678

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>Pain and cognitive impairment are important clinical features in patients with Parkinson's disease (PD). Although pain processing is associated with the limbic system, which is also closely linked to the cognitive function, the association between pain and cognitive impairment in PD is still not well understood. The aim of the study was to investigate the association between pain processing and cognitive impairment in patients with PD. </p><p><b>Methods </b>Forty-three patients with PD and 22 healthy subjects were studied. Pain-related somatosensory evoked potentials (SEPs) were generated using a thin needle electrode to stimulate epidermal Aδ fibers. Cognitive impairment was evaluated using the Mini-Mental State Examination (MMSE), the Frontal Assessment Battery, and Japanese version of the Montreal Cognitive Assessment (MoCA-J), and their correlation with pain-related SEPs was investigated. </p><p><b>Results </b>The N1/P1 amplitude was significantly lower in PD patients than the controls. N1/P1 peak-to-peak amplitudes correlated with the MMSE (r=0.66, p<0.001) and MoCA-J scores (r=0.38, p<0.01) in patients with PD. These amplitudes also strongly correlated with the domains of attention and memory in the MMSE (attention, r=0.52, p<0.001; memory, r=0.40, p<0.01) and MoCA-J (attention, r=0.45, p<0.005; memory, r=0.48, p<0.001), but not in control subjects. </p><p><b>Conclusion </b>A good correlation was observed between the decreased amplitudes of pain-related SEPs and an impairment of attention and memory in patients with PD. Our results suggest that pathological abnormalities of the pain pathway are significantly linked to cognitive impairment in PD. </p>

DOI： 10.2169/internalmedicine.55.7067

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Event date： 2022.9

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Event date： 2022.7

Presentation type：Poster presentation  

Event date： 2022.5

Presentation type：Poster presentation  

Event date： 2021.7

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2021.5

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2020.8 - 2020.9

Language：Japanese   Presentation type：Oral presentation (general)