A new therapeutic strategy with istradefylline for postural deformities in Parkinson’s disease

Aim of the study. Postural deformities are common in Parkinson’s disease (PD) patients. Several treatment options have been reported, but responses to these treatments appear unpredictable. Istradefylline is a novel drug for PD. Cases of PD patients whose postural deformities were improved after withdrawal of dopamine agonists and initiation of istradefylline are presented. Materials and Methods. Four consecutive patients with postural deformities including antecollis, Pisa syndrome, and camptocormia were recruited and treated with istradefylline in combination with withdrawal of dopamine agonists, which are possible causes of postural deformities. Results. The dopamine agonists were discontinued an average of 26 months after the development of the postural deformities, and istradefylline was initiated an average of 1.3 months after dopamine agonist withdrawal. Three patients with preserved paraspinal muscle volume showed good responses to the treatment regimen at least two months after dopamine agonist withdrawal. Conclusions and clinical Implications. Postural deformities caused by dopamine agonists generally improve less than two weeks after dopamine agonist withdrawal. Given the response time in the present study, the response was unlikely to be caused solely by dopamine agonist withdrawal. Istradefylline can be a potential therapeutic option; however, appropriate selection of patients for treatment with istradefylline is warranted

Impact of non-motor fluctuations on QOL in patients with Parkinson’s disease

IntroductionLong-term levodopa treatment in patients with Parkinson’s disease (PwPD) often causes motor fluctuations, which are known to affect their quality of life (QOL). These motor fluctuations may be accompanied by fluctuations in non-motor symptoms. There is no consensus on how non-motor fluctuations affect QOL.MethodsThis was a single-center, retrospective study and included 375 patients with Parkinson’s disease (PwPD) who visited the neurology outpatient department of Fukuoka University Hospital between July 2015 and June 2018. All patients were evaluated for age, sex, disease duration, body weight, and motor symptoms by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III, depression scale by the Zung self-rating depression scale, apathy scale, and cognitive function by the Japanese version of The Montreal Cognitive Assessment. A nine-item wearing-off questionnaire (WOQ-9) was used to assess the motor and non-motor fluctuations. QOL in PwPD was investigated using the eight-item Parkinson’s Disease Questionnaire (PDQ-8).ResultsIn total, 375 PwPD were enrolled and classified into three groups according to the presence or absence of motor and non-motor fluctuations. The first group included 98 (26.1%) patients with non-motor fluctuations (NFL group), the second group included 128 (34.1%) patients who presented with only motor fluctuations (MFL group), and the third group included 149 (39.7%) patients without fluctuations in motor or non-motor symptoms (NoFL group). Among them, the PDQ-8 SUM and SI were significantly higher in the NFL group than in the other groups (p < 0.005), implying that the NFL group had the poorest QOL among groups. Next, multivariable analysis showed that even one non-motor fluctuation was an independent factor that worsened QOL (p < 0.001).ConclusionThis study showed that PwPD with non-motor fluctuation had a lower QOL than those with no or only motor fluctuation. Moreover, the data showed that PDQ-8 scores were significantly reduced even with only one non-motor fluctuation

Eosinophilic Granulomatosis with Polyangiitis Presenting with Myocarditis as an Initial Symptom: A Case Report and Review of the Literature

A 66-year-old woman with a history of bronchial asthma had shortness of breath and fatigue upon mild exercise. She was diagnosed as congestive heart failure. A blood test showed eosinophilia without the presence of anti-neutrophil cytoplasmic antibody (ANCA), and a myocardial biopsy specimen revealed eosinophilic infiltration in the myocardium. Eosinophilia was improved when she was administered short-term methylprednisolone. After that, she had numbness and pain in her lower limbs with re-elevation of eosinophils. She had dysesthesia and hypalgesia in the distal part of the limbs. Sural nerve biopsy revealed axonal degeneration and thickness of the arterial wall, indicating a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA). Two courses of steroid pulse therapy were performed, resulting in marked improvement of her sensory symptoms. ANCA-negative EGPA might be associated with myocarditis and peripheral neuropathy. A sufficient immunotherapy should have been considered to prevent rapid progression

Effects of drug discontinuation after short-term daily alendronate administration on osteoblasts and osteocytes in mice

In order to determine whether osteoclastic bone resorption is restarted after withdrawn of bisphosphonates, we conducted histological examinations on murine osteoclasts, osteoblasts and osteocytes after discontinuation of a daily regimen of alendronate (ALN) with a dosage of 1 mg/kg/day for 10 days. After drug discontinuation, metaphyseal trabecular number and bone volume remained unaltered for the first 4 days. Osteoclast number did not increase, while the number of apoptotic osteoclasts was elevated. On the other hand, tissue non-specific alkaline phosphatase-immunoreactive area was markedly reduced after ALN discontinuation. In addition, osteocytes showed an atrophic profile with empty lacunar areas during and after ALN treatment. Interestingly, as early as 36 h after a single ALN injection, osteocytes show signs of atrophy despite the presence of active osteoblasts. Structured illumination microscopy system showed shortening of osteocytic cytoplasmic processes after drug cessation, suggesting a possible morphological and functional disconnection between osteocytes and osteoblasts. Taken together, it appears that osteoclastic bone resorption is not resumed after ALN discontinuation; also, osteoblasts and osteocytes hardly seem to recover once they are inactivated and atrophied by ALN. In summary, it seems that one must pay more attention to the responses of osteoblasts and osteocytes, rather focusing on the resuming of osteoclastic bone resorption after the ALN discontinuation

Isotope microscopic assessment for localization of 15N-minodeonate in bone

Minodronate has been highlighted for its sustained effects on osteoporotic treatment. To determine the cellular mechanism of its sustained effects, we have assessed the localization of minodronate in mouse bones through isotope microscopy, by labeling it with a stable and rare nitrogen isotope (15N-minodronate). Eight-weeks-old male mice intravenously received 15N-minodronate (1 mg/kg) were fixed after three hours, 24 hrs, one week and one month. Isotope microscopy localized 15N-minodronate predominantly beneath osteoblasts (bone forming surface) rather than nearby osteoclasts (bone-resorbing surface). Literally, alendronate, another nitrogen-containing bisphosphonate, has been reported to accumulate on the bone-resorbing surface, and suddenly inhibit the osteoclasts. In contrast, minodronate appears to coat the bone-forming surface, without immediate inhibition of osteoclasts. A single injection of minodronate chronologically increased metaphyseal trabeculae, whereas the numbers of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts and alkaline phosphatase (ALP)-reactive osteoblastic area were not reduced. Apoptotic osteoclasts were not apparent, but, finally being observed in the later stage of the experiments, while ALP-reactive osteoblasts were persisted on the trabeculae. Osteoclasts have developed ruffled borders at 3 hrs after minodronate administration; however, osteoclasts were roughly attached to the bone surfaces and did not form ruffled borders at 24 hrs after the administration. Von Kossa staining clearly demonstrated that osteoclasts did not incorporate the minodronate-treated bone matrix, while osteoclasts included abundant bone minerals inside in the control specimens. Taken together, minodronate accumulates in bone underneath osteoblasts rather than under bone-resorbing osteoclasts ; therefore, it is likely that the osteoclasts are not able to resorb and incorporate the minodronate-coated bone matrix, which may result in osteoclastic survival, avoiding osteoclastic apoptosis and consequently inducing cell coupling with osteoblasts. In conclusion, the resistance of miniodronate-coating bone from osteoclastic resorption, and the consequent cell coupling with osteoblasts appear to produce a long-lasting and bone-preserving effect

Table_1_Impact of weight loss for depressive symptom in mid-stage patients with Parkinson’s disease: a 4-year follow-up study.docx

IntroductionWeight loss is one of the non-motor symptoms frequently seen in patients with Parkinson’s disease (PwPD). Weight loss in PwPD is known to be negatively associated with motor and other non-motor symptoms and has been shown to influence the prognosis of PD. In this study, we followed weight change over a 4-year period in PwPD at a single institution and investigated the relationship between weight change and patients’ motor and non-motor symptoms.MethodsPwPD who visited our hospital from January 2018 to December 2022 were enrolled. Body weights were measured at two points in 2018 (at the start of observation, ‘baseline’) and 2022 (at the end of observation, ‘end date’). In addition, motor symptoms, disease severity, cognitive function, and psychiatric symptoms were evaluated during the same period, and the relationship with weight loss was examined.ResultsData of 96 PwPD were available for a 4-year follow-up. At baseline, the mean age was 65.7 ± 10.0 years, the mean disease duration was 6.8 ± 4.0 years, and the mean Hoehn and Yahr stage was 2.4 ± 0.7. Among them, 48 patients (50.0%) had a weight loss of ≥5% from baseline (weight loss group; mean loss was 6.6 ± 2.9 kg). The weight loss group was older (p = 0.031), had a lower Mini-Mental State Examination (MMSE) at baseline (p = 0.019), a significantly lower body mass index (p ConclusionWeight loss in PwPD in mid-stage was more likely with increasing age, and ≥ 5% weight loss was associated with worsening depression. Further research is needed regarding the significance of weight loss in PwPD.</p

Pituitary metastasis of breast cancer mimicking IgG4-related hypophysitis

IgG4-related hypophysitis, which is the pituitary gland inflammation caused by IgG4 positive lymphocytes, can affect cavernous sinus and orbital apex leading to developing cranial nerve related symptoms such as orbital apex syndrome (OAS). Here we report a case of hypopituitarism associated with OAS caused by pituitary metastasis of the breast cancer with elevated serum IgG4 level, who initially resembled to IgG4-related hypophysitis. Although this case had some features in common with igG4-related hypophysitis. The symptoms and pituitary enlargement were typical. However, steroid treatment did not improve her symptoms. Thus, we performed a tissue biopsy. Histopathologic examination of the hypophyseal tumor confirmed metastatic breast cancer in her pituitary. Pituitary metastatic tumor should be suspected if a case with OAS was once diagnosed as a cancer. Keywords: Orbital apex syndrome, Pituitary metastasis, IgG4-related hypophysiti

Localization of minodronate in bone

Minodronate is highlighted for its marked and sustained effects on osteoporotic bones. To determine the duration of minodronate’s effects, we have assessed the localization of the drug in mouse bones through isotope microscopy, after labeling it with a stable nitrogen isotope (15N-minodronate). In addition, minodronate-treated bones were assessed by histochemistry and TEM. Eight-weeks-old male ICR mice received 15N-minodronate (1mg/kg) intravenously and were sacrificed after three hours, 24 hrs, one week and one month. Isotope microscopy showed that 15N-minodronate was present mainly beneath osteoblasts rather than nearby osteoclasts. At 3 hrs after minodronate administration, histochemistry and TEM showed osteoclasts with well-developed ruffled borders. However, osteoclasts were roughly attached to the bone surfaces and did not feature ruffled borders at 24 hrs after minodronate administration. The numbers of TRAP-positive osteoclasts and ALP-reactive osteoblastic area were not reduced suddenly, and apoptotic osteoclasts appeared in 1 week and 1 month after the injections. Von Kossa staining demonstrated that osteoclasts treated with minodronate did not incorporate mineralized bone matrix. Taken together, minodronate accumulates in bone underneath osteoblasts rather than under bone-resorbing osteoclasts; therefore, it is likely that the minodronate-coated bone matrix is resistant to osteoclastic resorption, which results in a long-lasting and bone-preserving effect

Biological application of focus ion beam-scanning electron microscopy (FIB-SEM) to the imaging of cartilaginous fibrils and osteoblastic cytoplasmic processes

Objectives: The aim of this study is a biological application of focused ion beam-scanning electron microscopy (FIB-SEM) to demonstrate serial sectional images of skeletal tissues, here presenting the ultrastructure of 1) cartilaginous extracellular fibrils and 2) osteoblastic cytoplasmic processes. Methods: Seven weeks-old female wild-type mice were fixed with half-Karnovsky solution and subsequent OsO4, and the tibiae were extracted for block staining prior to observation under transmission electron microscope (TEM) and FIB-SEM. Results: TEM showed the fine fibrillar, but somewhat amorphous ultrastructure of the intercolumnar septa in the growth plate cartilage. Alternatively, FIB-SEM revealed bundles of stout fibrils at regular intervals paralleling the septa’s longitudinal axis, as well as vesicular structures embedded in the cartilaginous matrix of the proliferative zone. In the primary trabeculae, both TEM and FIB-SEM showed several osteoblastic cytoplasmic processes on the osteoid, with numbers higher than those seen in the bone matrix. FIB-SEM revealed the agglomeration of cytoplasmic processes beneath the osteoblasts, which formed a tubular continuum extending from those cells. Based on these findings, we postulated that osteoblasts not only extend their cytoplasmic processes through to the bone matrix, but also stack these cell processes on the osteoid of the primary trabeculae. Conclusion: Taken together, it is likely that FIB-SEM imaging strategy on serial sections may successfully deliver new insights on the ultrastructure of cartilage and bone tissues