Ocular Motor Findings Aid in Differentiation of Spinocerebellar Ataxia Type 17 from Huntington's Disease.

Differentiation of spinocerebellar ataxia type 17 (SCA17) from Huntington's disease (HD) is often challenging since they share the clinical features of chorea, parkinsonism, and dystonia. The ocular motor findings remain to be elucidated in SCA17, and may help differentiating SCA17 from HD. We retrospectively compared the ocular motor findings of 11 patients with SCA17 with those of 10 patients with HD. In SCA17, abnormal ocular motor findings included impaired smooth pursuit (9/11, 82%), dysmetric saccades (9/11, 82%), central positional nystagmus (CPN, 7/11, 64%), abnormal head-impulse tests (4/11, 36%), and horizontal gaze-evoked nystagmus (GEN, 3/11, 27%). Among these, CPN was more frequently observed in SCA17 than in HD (7/11 (64%) vs. 0/10 (0%), p = 0.004) while saccadic slowing was more frequently observed in HD than in SCA17 (8/10 (80%) vs. 2/11 (18%), p = 0.009). Of six patients with follow-up evaluation, five later developed bilateral saccadic hypermetria (n = 4), GEN (n = 1), CPN (n = 1), bilaterally abnormal smooth pursuit (n = 1), and hyperactive head-impulse responses (n = 1) along with a clinical decline. Ocular motor abnormalities can be utilized as a diagnostic marker for differentiation of SCA17 from HD as well as a surrogate marker for clinical decline in SCA17.

Bilateral subthalamic nucleus deep brain stimulation is an effective treatment for diphasic dyskinesia.

BACKGROUND AND PURPOSE: The purpose was to assess the effect of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on diphasic dyskinesia in patients with Parkinson disease (PD) and to assess the factors associated with the remission of diphasic dyskinesia. METHODS: Medical records for PD patients who underwent bilateral STN DBS at the Movement Disorder Center of Seoul National University Hospital from March 2005 to November 2016 were reviewed. Patients were evaluated preoperatively and at 3, 6 and 12 months after surgery, and annually thereafter. The presence of peak-dose dyskinesia and diphasic dyskinesia is based on the interview and examination of patients at baseline and at each follow-up. RESULTS: Amongst 202 patients who underwent STN DBS, 66 patients who had diphasic dyskinesia preoperatively were included in the analysis. Diphasic dyskinesia disappeared in 49 (74%) after surgery. In 27 (55.1%) patients whose diphasic dyskinesia disappeared after DBS, peak-dose and diphasic dyskinesia disappeared persistently from as early as 3 months postoperatively. Age at onset was younger and disease duration at surgery was longer in patients whose diphasic dyskinesia persisted compared with patients whose diphasic dyskinesia disappeared. Multivariate Cox regression analysis demonstrated that patients with greater postoperative decrease of dopaminergic medications were more likely to have remission of diphasic dyskinesia. CONCLUSION: This study showed that bilateral STN DBS is effective in controlling diphasic dyskinesia and should be considered in PD patients with diphasic dyskinesia.

Clinical Association between Gout and Parkinson's Disease: A Nationwide Population-Based Cohort Study in Korea.

Background and Objectives: This retrospective cohort study aimed to investigate the association between gout and Parkinson's disease (PD) in Korea. Materials and Methods: Overall, 327,160 patients with gout and 327,160 age- and sex-matched controls were selected from the Korean National Health Insurance Service (NHIS) database. PD incidence was evaluated by reviewing NHIS records during the period from 2002 to 2019. Patients with a diagnosis of gout (International Classification of Diseases-10 (ICD-10), M10) who were prescribed medications for gout, including colchicine, allopurinol, febuxostat, and benzbromarone for at least 90 days were selected. Patients with PD who were assigned a diagnosis code (ICD-G20) and were registered in the rare incurable diseases (RID) system were extracted. Results: During follow-up, 912 patients with gout and 929 control participants developed PD. The incidence rate (IR) of overall PD (per 1000 person-years) was not significantly different between both groups (0.35 vs. 0.36 in gout and control groups, respectively). The incidence rate ratio (IRR) was 0.98 (95% CI: 0.89-1.07). The cumulative incidence of PD was not significantly different between the groups. No association between gout and PD was identified in univariate analysis (HR = 1.00, 95% CI: 0.91-1.10, p = 0.935). HR increased significantly with old age (HR = 92.08, 198, and 235.2 for 60-69 years, 70-79 years, and over 80 years, respectively), female sex (HR = 1.21, 95% CI: 1.07-1.37, p = 0.002), stroke (HR = 1.95, 95% CI: 1.76-2.16, p < 0.001), and hypertension (HR = 1.16, 95% CI: 1.01-1.34, p = 0.04). Dyslipidemia exhibited an inverse result for PD (HR = 0.6, 95% CI: 0.52-0.68, p < 0.001). Conclusions: This population-based study did not identify an association between gout and PD. Age, female sex, stroke, and hypertension were identified as independent risk factors for PD, and dyslipidemia demonstrated an inverse result for PD.

Urinary Symptoms and Urodynamic Findings in Patients with Spinocerebellar Ataxia.

Urinary dysfunctions are not considered symptoms of spinocerebellar ataxias (SCAs). However, given that a patient with SCAs without a family history might be misdiagnosed as MSA-C when having urinary dysfunctions, characterization of urinary dysfunctions in SCAs is needed not only to understand SCAs but also to correctly diagnosis patients with ataxia. We retrospectively reviewed medical records of 143 patients with genetically confirmed SCA1, 2, 3, 6, 7, 17, and DRPLA. Twenty-two patients (men n = 9; age 62.1 ± 10.9; disease duration 8.2 ± 2.9 years) who had lower urinary track symptoms (LUTS) were included in this study. Six patients underwent urodynamic study (UDS), and 2 underwent uroflowmetry. LUTS was present in 1 of 11 patients with SCA1, in 4 of 51 with SCA2, in 2 of 26 with SCA3, in 3 of 20 with SCA6, in 2 of 4 with SCA7, in 8 of 26 with SCA17, and in 2 of 5 with DRPLA. Overall, urinary frequency was the most common symptom (16 patients, 72.7%) followed by voiding difficulty. In three of the 6 patients with UDS, post-micturition residuals were > 100 ml. Detrusor overactivity was noted in three patients. Detrusor areflexia was observed in one. Four patients were diagnosed with a neurogenic bladder, 3 with a storage problem, and 1 with both storage and voiding problems. Fifteen percent of the patients with SCAs had LUTS, and LUTS occurred in various types of SCAs. Our results indicate that SCAs should be considered in patients with progressive cerebellar ataxia and urinary dysfunctions.

Progression of Oropharyngeal Dysphagia in Patients with Multiple System Atrophy.

We investigated the progression of oropharyngeal dysphagia in patients with multiple system atrophy (MSA), with particular emphasis on MSA subtype variation. Fifty-nine MSA patients (31 MSA-P, 21 MSA-C, and 7 MSA-PC) who had undergone at least one videofluoroscopic swallowing study (VFSS) to evaluate dysphagia symptoms were included. Clinical data and VFSS findings were retrospectively evaluated using the videofluoroscopic dysphagia scale (VDS), and the results of each MSA subtype group were compared. The median latency to onset of diet modification from onset of MSA symptoms was 5.995 (95% CI 4.890-7.099) years in all MSA patients, 5.036 (95% CI 3.605-6.467) years in MSA-P, and 6.800 (95% CI 6.078-7.522) years in MSA-C (P = 0.035). The latency to onset of diet modification from onset of dysphagia symptoms was 2.715 (95% CI 2.132-3.298) years in all MSA patients, 2.299 (95% CI 1.194-3.403) years in MSA-P, and 5.074 (95% CI 2.565-7.583) years in MSA-C (P = 0.039). The latencies to onset of tube feeding from onset of MSA symptoms and dysphagia symptoms were 7.003 (95% CI 6.738-7.268) years and 3.515 (95% CI 2.123-4.907) years, respectively, in all MSA patients, without significant difference between subtypes. In the patients who underwent VFSS follow-up for ≥ 1 year, 6 oral VDS items significantly worsened; only two pharyngeal items exhibited significant changes. Patients with MSA-P commenced diet modification earlier than patients with MSA-C, despite no significant difference in the latency to onset of tube feeding. Deterioration of dysphagia may be more pronounced in the oral function of MSA patients.

Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies.

Plazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1 to 3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration-time profiles. The base structural model included creatinine clearance (CLCR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The ranges of the α-, ß-, and γ-phase half-lives for the analysis population were 0.328 to 1.58, 2.77 to 5.38, and 25.8 to 36.5 h, respectively. Total and renal clearances in a typical cUTI or HABP/VABP patient were 4.57 and 4.08 liters/h, respectively. Starting dose adjustments for CLCR are sufficient for minimizing the variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a milligram-per-kilogram basis with adjustments for CLCR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renally impaired.

Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing.

Inherited disorders of spasticity or ataxia exist on a spectrum with overlapping causative genes and phenotypes. We investigated the use of whole-genome sequencing (WGS) to detect a genetic cause when considering this spectrum of disorders as a single group. We recruited 18 Korean individuals with spastic paraplegia with or without cerebellar ataxia in whom common causes of hereditary cerebellar ataxia and hereditary spastic paraplegia had been excluded. We performed WGS with analysis for single nucleotide variants, small insertions and deletions, copy number variants (CNVs), structural variants (SVs) and intronic variants. Disease-relevant variants were identified in ABCD1 (n = 3), CAPN1 (n = 2), NIPA1 (n = 1) and PLA2G6 (n = 1) for 7/18 patients (38.9%). A 'reverse phenotyping' approach was used to clarify the diagnosis in individuals with PLA2G6 and ABCD1 variants. One of the ABCD1 disease-relevant variants was detected on analysis for intronic variants. No CNV or SV causes were found. The two males with ABCD1 variants were initiated on monitoring for adrenal dysfunction. This is one of only a few studies to analyse spastic-ataxias as a continuous spectrum using a single approach. The outcome was improved diagnosis of unresolved cases for which common genetic causes had been excluded. This includes the detection of ABCD1 variants which had management implications. Therefore, WGS may be particularly relevant to diagnosing spastic ataxias given the large number of genes associated with this condition and the relatively high diagnostic yield.

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model.

Plazomicin is a novel aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model. ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem, and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem, or tigecycline human-equivalent doses alone or in combinations of plazomicin-meropenem and plazomicin-tigecycline. Treatments were initiated at 1 h postinfection and continued for 24 h. Efficacy was assessed by determination of mouse survival through 96 h. Compared with the survival of the controls, plazomicin monotherapy produced a significant improvement in survival for all mice infected with the isolates (P < 0.05) and resulted in overall survival rates of 86% (n = 50) and 53.3% (n = 30) for mice infected with isolates with plazomicin MICs of ≤4 and ≥8 mg/liter, respectively (P < 0.05). The survival of the meropenem and tigecycline groups correlated well with susceptibilities of their respective isolates, with incremental increases in survival being observed at lower MIC values. For mice infected with isolate Klebsiella pneumoniae 561 (plazomicin, meropenem, and tigecycline MICs, 8, >32, and 2 mg/liter, respectively), combination therapies showed a significant reduction in mortality compared with that achieved with any monotherapy (P < 0.05). Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably, for mice infected with isolates with plazomicin MICs of ≤4 mg/liter. As evidenced by our current data, coadministration of meropenem or tigecycline could potentially lead to a further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MICs of ≤4 mg/liter, including carbapenem-resistant isolates.

Characteristics of Early Oropharyngeal Dysphagia in Patients with Multiple System Atrophy.

BACKGROUND/AIMS: Dysphagia, a symptom of multiple system atrophy (MSA), is a major clinical concern. In this study, we investigate the characteristics of early oropharyngeal dysphagia (OD) in patients with MSA, and the differences between MSA subtypes. METHODS: Patients enrolled in the study had previously been diagnosed with MSA at the clinic of the Department of Neurology, and had been referred for a videofluoroscopic swallowing study (VFSS), between 2005 and 2014, to check for dysphagia. The clinical characteristics and VFSS findings were analyzed and compared between the MSA subtypes. RESULTS: This study enrolled 59 patients with MSA (24 men; 31 with MSA-P, 21 with MSA-C, and 7 with MSA-PC). Dysphagia symptoms were mostly limited to aspiration symptoms (90.48%) in patients with MSA-C, while difficulty in swallowing, increased mealtime, and drooling were frequent in those with MSA-P. The most common VFSS finding amongst patients was vallecular residue (n = 53, 89.8%), followed by penetration/aspiration (n = 40, 67.8%), and coating of the pharyngeal wall (n = 39, 66.1%). Comparison analysis between subtypes showed that apraxia and vallecular residue were more frequent and severe in MSA-P than in MSA-C (p = 0.033 and p = 0.010, respectively). CONCLUSION: Understanding early OD characteristics in patients with MSA and the differences between MSA subtypes could be helpful in managing dysphagia in patients with MSA. Several dysphagia symptoms similar to those of Parkinson disease were frequently observed in MSA-P, but not in MSA-C. A follow-up study is needed to elucidate the natural course of OD in MSA patients and the difference between MSA subtypes.

A case report of thoracolumbar paraspinal myopathy as the cause of camptocormia in a patient with atypical parkinsonism.

BACKGROUND: Camptocormia is severe flexion of the thoracolumbar spine, exaggerated during standing and walking but minimized in supine position. Even though camptocormia is a relatively common condition during the course of Parkinson's disease, there is ongoing controversy concerning its mechanisms. The most widely accepted and yet still disputed one is dystonia. However, based on myopathic changes observed in the paraspinal muscle biopsies of some PD patients with camptocormia, the attempt to attribute camptocormia to myopathy has continued. This case presents evidence for paraspinal myopathy as the cause of camptocormia in a patient with atypical parkinsonism. CASE PRESENTATION: A patient presented with a relatively acute onset of camptocormia and new-onset back pain. Upon examination, she had asymmetric parkinsonism. Magnetic resonance imaging of the lumbar spine revealed alterations in muscle signal intensity in the right paraspinal muscles at the L1-2 level. In the presence of persistent back pain, repeat imaging done two months later showed diffuse enlargement and patchy enhancement of the paraspinal muscles on T1-weighted imaging from T4 through sacrum bilaterally. About fifteen months after the onset of camptocormia, she underwent ultrasound-guided gun biopsy of the paraspinal muscles for evaluation of focal atrophy of the back muscles on the right. The biopsy revealed unmistakable myopathic changes, marked endomysial and perimysial fibrosis of the muscles, and merely mild infiltration of inflammatory cells but no clues regarding the cause of myopathy. On account of persistent back pain and MRI results indicative of ongoing inflammation, she was prescribed glucocorticoid, which she refused to take. Now merely two and a half years after the onset of camptocormia, she is in Hoehn and Yahr stage 4. CONCLUSIONS: The coincidence of back pain with the appearance of camptocormia and the imaging and pathology findings supportive of myopathy give strong evidence for paraspinal myopathy as the cause of the deformity in this patient. When a patient presents with a relatively acute onset of camptocormia accompanied by back pain, the clinician should not overlook the possibility of myopathy of paraspinal muscles, which may be one of the few treatable causes of camptocormia.

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy.

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R(2) = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated ß-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.

Pharmacokinetics/pharmacodynamics of a ß-lactam and ß-lactamase inhibitor combination: a novel approach for aztreonam/avibactam.

OBJECTIVES: The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-ß-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for aztreonam/avibactam across multiple clinical Enterobacteriaceae strains. METHODS: Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollow-fibre infection model (HFIM) using various dosing regimens simulating human-like PK for aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains. RESULTS: MIC values of aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the aztreonam PK/PD index was observed as % fT >MIC. Studies performed in the presence of a fixed dose of aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2-2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target. CONCLUSIONS: PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for ß-lactam/ß-lactamase inhibitor combinations.

Brain structure comparison among Parkinson disease, essential tremor, and healthy controls using 7T MRI.

Both Parkinson disease (PD) and Essential tremor (ET) are movement disorders causing tremors in elderly individuals. Although PD and ET are different disease, they often present with similar initial symptoms, making their differentiation challenging with magnetic resonance imaging (MRI) techniques. This study aimed to identify structural brain differences among PD, ET, and health controls (HCs) using 7-Tesla (T) MRI. We assessed the whole-brain parcellation in gray matter volume, thickness, subcortical volume, and small regions of basal ganglia in PD (n = 18), ET (n = 15), and HCs (n = 18), who were matched for age and sex. Brain structure analysis was performed automatic segmentation through Freesurfer software. Small regions of basal ganglia were manually segmented by ITK-SNAP. Additionally, we examined the associations between clinical indicators (symptom duration, unified Parkinson diseases rating scale (UPDRS), and clinical rating scale for tremor (CRST)) and brain structure. PD showed a significant reduction in gray matter volume in the postcentral region compared to ET. ET showed a significant reduction in cerebellum volume compared to HCs. There was a negative correlation between CRST scores (B and C) and gray matter thickness in right superior frontal in ET. This study demonstrated potential of 7T MRI in differentiating brain structure differences among PD, ET, and HCs. Specific findings, such as parietal lobe atrophy in PD compared to ET and cerebellum atrophy in ET compared to HCs, the importance of advanced imaging techniques in accurately diagnosing and distinguishing between movement disorders that present with similar initial symptoms.

Late-Onset Ataxia-Telangiectasia Presenting With Dystonia and Tremor: The Use of Nanopore Long-Read Sequencing Solving the Variant Phase.

Objectives: This study investigates atypical late-onset ataxia-telangiectasia (AT) cases in a Korean family, diagnosed via Nanopore long-read sequencing, diverging from the typical early childhood onset caused by biallelic pathogenic ATM variants. Methods: A 52-year-old Korean woman exhibiting dystonia and tremor, with a family history of similar symptoms in her older sister, underwent comprehensive tests including routine laboratory tests, neuropsychological assessments, and neuroimaging. Genetic analysis was conducted through targeted sequencing of 29 dystonia-associated genes and Nanopore long-read sequencing to assess the configuration of 2 ATM gene variants. Results: Routine blood tests and brain imaging studies returned normal results, except for elevated α-fetoprotein levels. Neurologic examination revealed dystonia in the face, hand, and trunk, along with cervical dystonia in the proband. Her sister exhibited similar symptoms without evident telangiectasia. Genetic testing revealed 2 heterozygous pathogenic ATM gene variants (p.Glu2014Ter and p.Glu2052Lys). Nanopore long-read sequencing confirmed these variants were in trans configuration, establishing a definite molecular diagnosis in the proband. Discussion: This report expands the known clinical spectrum of AT, highlighting a familial case of atypical AT. Moreover, it underscores the clinical utility of Nanopore long-read sequencing in phasing variant haplotypes, essential for diagnosing autosomal recessive disorders, especially beneficial for cases without parental samples.

A Survey of Perspectives on Telemedicine for Patients With Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) patients often find it difficult to visit hospitals because of motor symptoms, distance to the hospital, or the absence of caregivers. Telemedicine is one way to solve this problem. METHODS: We surveyed 554 PD patients from eight university hospitals in Korea. The questionnaire consisted of the clinical characteristics of the participants, possible teleconferencing. METHODS: , and preferences for telemedicine. RESULTS: A total of 385 patients (70%) expressed interest in receiving telemedicine. Among them, 174 preferred telemedicine whereas 211 preferred in-person visits. The longer the duration of disease, and the longer the time required to visit the hospital, the more patients were interested in receiving telemedicine. CONCLUSION: This is the first study on PD patients' preferences regarding telemedicine in Korea. Although the majority of patients with PD have a positive view of telemedicine, their interest in receiving telemedicine depends on their different circumstances.

Effects of Atomoxetine for the Treatment of Neurogenic Orthostatic Hypotension in Patients With Alpha-synucleinopathies: A Systematic Review of Randomized Controlled Trials and a Focus-Group Discussion.

BACKGROUND AND PURPOSE: Neurogenic orthostatic hypotension (nOH) is one of the most important nonmotor symptoms in patients with α-synucleinopathies. Atomoxetine is a selective norepinephrine transporter blocker that is a treatment option for nOH. This systematic review and expert focus-group study was designed to obtain evidence from published data and clinical experiences of Korean movement-disorder specialists about the efficacy and safety of atomoxetine for the pharmacological treatment of nOH in patients with α-synucleinopathies. METHODS: The study comprised a systematic review and a focus-group discussion with clinicians. For the systematic review, multiple comprehensive databases including MEDLINE, Embase, Cochrane Library, CINAHL, PsycInfo, and KoreaMed were searched to retrieve articles that assessed the outcomes of atomoxetine therapy. A focus-group discussion was additionally performed to solicit opinions from experts with experience in managing nOH. RESULTS: The literature review process yielded only four randomized controlled trials on atomoxetine matching the inclusion criteria. Atomoxetine effectively increased systolic blood pressure and improved OH-related symptoms as monotherapy or in combination with other drugs. Its effects were pronounced in cases with central autonomic failure, including multiple-system atrophy (MSA). Atomoxetine might be a safe monotherapy regarding the risk of supine hypertension. CONCLUSIONS: Atomoxetine is an effective and safe option for short-term nOH management, which could be more evident in patients with central autonomic dysfunction such as MSA. However, there is a paucity of evidence in the literature, and data from the focus-group discussion were inadequate, and so further investigation is warranted.

The effects of low-dose radiation therapy in patients with mild-to-moderate Alzheimer's dementia: an interim analysis of a pilot study.

PURPOSE: We aimed to determine whether low-dose radiotherapy (LDRT) is effective in patients with Alzheimer disease (AD). MATERIALS AND METHODS: We included patients according to the following criteria: probable Alzheimer's dementia according to the New Diagnostic Criteria for Alzheimer's Disease; confirmation of amyloid plaque deposits on baseline amyloid positron emission tomography (PET); a Korean Mini-Mental State Examination 2nd edition (K-MMSE-2) score of 13-26; and a Global Clinical Dementia Rating (CDR) score of 0.5-2 points. LDRT was performed six times at 0.5 Gy each. Post-treatment cognitive function tests and PET-CT examinations were performed to evaluate efficacy. The medication for AD treatment was maintained throughout the study period. RESULTS: At 6 months after LDRT, neurological improvement was seen in 20% of patients. Patient #2 showed improvement in all domains of the Seoul Neuropsychological Screening Battery II (SNSB-II). Moreover, the K-MMSE-2 and Geriatric Depression Score-Short Form scores improved from 20 to 23 and from 8 to 2, respectively. For patient #3, the CDR score (sum of box score) improved from 1 (4.0) to 1 (3.5) at 3 months follow-up. Moreover, the Z scores for language and related functions, memory, and frontal executive function improved to -2.56, -1.86, and -1.32, respectively at the 6-month follow-up. Two patients complained of mild nausea and mild hair loss during LDRT, which improved after treatment. CONCLUSION: One of the five patients with AD treated with LDRT experienced a temporary improvement in SNSB-II. LDRT is tolerable in patients with AD. We are currently under follow-up and will conduct cognitive function tests after 12 months after LDRT. A large-scale randomized controlled trial with a longer follow-up period is warranted to determine the effect of LDRT on patients with AD.

Evaluation of Efficacy and Safety Using Low Dose Radiation Therapy with Alzheimer's Disease: A Protocol for Multicenter Phase II Clinical Trial.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-ß (Aß) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. OBJECTIVE: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. METHODS: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aß42/Aß40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer's Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. CONCLUSIONS: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD.

The Derivatives of Cromolyn Ameliorate the Abnormal Misfolding of Amyloid Proteins and Neuroinflammation in the Neural Cells.

BACKGROUND: The representative symptom of Alzheimer's Disease (AD) has mainly been mentioned to be misfolding of amyloid proteins, such as amyloid-beta (Aß) and tau protein. In addition, the neurological pathology related to neuroinflammatory signaling has recently been raised as an important feature in AD. Currently, numerous drug candidates continue to be investigated to reduce symptoms of AD, including amyloid proteins misfolding and neuroinflammation. OBJECTIVE: Our research aimed to identify the anti-AD effects of two chemical derivatives modified from cromoglicic acid, CNU 010 and CNU 011. METHODS: CNU 010 and CNU 011 derived from cromoglicic acid were synthesized. The inhibitory effects of Aß and tau were identified by thioflavin T assay. Moreover, western blots were conducted with derivates CNU 010 and CNU 011 to confirm the effects on inflammation. RESULTS: CNU 010 and CNU 011 significantly inhibited the aggregation of Aß and tau proteins. Moreover, they reduced the expression levels of mitogen-activated protein (MAP) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) signaling proteins, which are representative early inflammatory signaling markers. Also, the inhibitory effects on the lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression referring to late inflammation were confirmed. CONCLUSION: Our results showing multiple beneficial effects of cromolyn derivatives against abnormal aggregation of amyloid proteins and neuroinflammatory signaling provide evidence that CNU 010 and CNU 011 could be further developed as potential drug candidates for AD treatment.