Depressive Symptoms and the Subsequent Risk of Parkinson's Disease: A Nationwide Cohort Study.

OBJECTIVE: Only a few studies have focused on depressive symptoms and Parkinson's disease (PD) risk. As a time lag exists from the onset of depressive symptoms to the diagnosis of depression, elucidating the association between depressive symptoms and PD development might be helpful for the early prediction of PD. We investigate the association between depressive symptoms and subsequent PD risk using nationwide population-based cohort database. DESIGN AND SETTING: Cohort study using the Korean National Health Insurance Service data between 2007 and 2017, with longitudinal follow-up until 2019. PARTICIPANTS: A total of 98,296 elderly people responded to a self-reported questionnaire from the National Health Screening Program on depressive symptoms. MEASUREMENTS: The association between depressive symptoms such as 1) decreased activity or motivation, 2) worthlessness, and 3) hopelessness and PD risk was analyzed. RESULTS: During median 5.06-year follow-up, 839 PD cases occurred: 230 in individuals with depressive symptoms and 609 in those without symptoms. Results showed an increased risk of PD development in those with depressive symptoms (HR = 1.47, 95% CI, 1.26-1.71), with dose-response association between the number of depressive symptoms and PD risk. Even in those already diagnosed with depression, combined depressive symptoms were linked to a higher risk compared to those without symptoms (with symptoms, HR = 2.71, 95% CI, 2.00-3.68; without symptoms, HR = 1.84, 95% CI, 1.43-2.36). CONCLUSION: Individuals with depressive symptoms were at an increased risk of developing PD, and there was a dose-response association between the number of depressive symptoms and PD risk.

Comparison of Particulate Steroid Injection vs Nonparticulate Steroid Injection for Lumbar Radicular Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: The objective of this study was to identify the difference on pain intensity and disability between particulate and nonparticulate steroid injections in patients with lumbar radicular pain. Subgroup analysis by study design, type of particulate steroid, and follow-up duration were performed. DATA SOURCES: We performed the literature search in the PubMed, Embase, and Cochrane Library up March, 2023. STUDY SELECTION: Studies, including randomized controlled trials (RCTs) and nonrandomized studies, that compared particulate steroid injection and nonparticulate steroid injection in patients with lumbar radicular pain were independently reviewed by 2 reviewers for eligibility for inclusion. DATA EXTRACTION: Outcomes of interest were pain intensity and disability. Two reviewers independently assessed the quality of included studies using the revised Cochrane Risk of Bias (RoB2.0) tool for RCTs and the Risk of Bias in Nonrandomized Studies of Interventions Tool (ROBINS-I) for nonrandomized studies. Effect sizes were estimated using mean difference (MD) and standardized mean difference (SMD). DATA SYNTHESIS: A total of 10 studies were included in this meta-analysis. The results showed no significant difference in visual analog scale, disability score and the numbers of patients with 50% pain reduction between particulate and nonparticulate steroid injection groups (P>.05). Particulate steroid injections showed significant better effect in pain scale in RCTs (MD=0.62; 95% CI 0.08-1.16, P=.02). In subgroup analysis with steroid types, methylprednisolone showed better effect compared with dexamethasone, while dexamethasone showed better effect compared with betamethasone. CONCLUSIONS: This meta-analysis suggested no significant differences between the particulate and nonparticulate steroid groups in pain or disability score. Therefore, considering the safety profile of nonparticulate steroids, nonparticulate steroid injection may be helpful in patients with lumbar radicular pain.

Association between Low Blood Pressure and Subsequent Risk of Parkinson's Disease in Older Adults Aged ≥75 Years.

INTRODUCTION: The association between blood pressure (BP) and incidence of Parkinson's disease (PD) in older adults remains uncertain. Therefore, this study aimed to investigate the association between BP (high or low) and PD incidence in adults aged ≥75 years. METHODS: In this nationwide population-based cohort study, we enrolled participants aged ≥75 years without a prior PD diagnosis who had undergone health examination provided by the Korean National Health Insurance Service at least once from January 1, 2009, to December 31, 2012. The participants were followed up until December 31, 2019, or the date of their death. The Cox proportional hazards model was used to assess the risk of PD depending on systolic BP (SBP), diastolic BP (DBP), and pulse pressure. RESULTS: Overall, 963,525 participants were enrolled in the analysis and followed up until December 31, 2019, or the date of death (40.7% male, mean age 78.5 ± 3.6 years). The mean SBP and DBP were 131.4 ± 16.7 and 77.9 ± 10.3 mm Hg, respectively. During the 10-year follow-up period, 16,414 (1.7%) newly diagnosed cases of PD were reported. A significant inverse dose-response association was found between SBP and PD incidence. In the subgroup analysis, this association was maintained for most variables, including sex, use of antihypertensive medication, comorbidities, alcohol consumption, physical activity, and body mass index, except for smoking status. CONCLUSION: Lower SBP and DBP were associated with a higher PD incidence in older adults. These results may have substantial implications for determining the optimal BP control target in adults aged ≥75 years.

Korean vs. Western Exercise Capacity Nomograms for Korean Patients With Cardiovascular Disease.

BACKGROUND: Exercise capacity is known to be an independent predictor of cardiovascular events and mortality. However, most previous studies were based on Western populations. Further study is warranted for Asian patients according to ethnic or national standards. We aimed to compare prognostic values of Korean and Western nomograms for exercise capacity in Korean patients with cardiovascular disease (CVD). METHODS: In this retrospective cohort study, we enrolled 1,178 patients (62 ± 11 years; 78% male) between June 2015 and May 2020, who were referred for cardiopulmonary exercise testing in our cardiac rehabilitation program. The median follow-up period was 1.6 years. Exercise capacity was measured in metabolic equivalents by direct gas exchange method during the treadmill test. The nomogram for exercise capacity from healthy Korean individuals and a previous landmark Western study was used to determine the percentage of predicted exercise capacity. The primary endpoint was the composite of major adverse cardiovascular events (MACE; all-cause death, myocardial infarction, repeat revascularization, stroke and hospitalization for heart failure). RESULTS: A multivariate analysis showed that the risk of primary endpoint was more than double (hazard ratio [HR], 2.20; 95% confidence interval [CI], 1.10-4.40) in the patients with lower exercise capacity (< 85% of predicted) by Korean nomogram. The lower exercise capacity was one of the strong independent predictors along with left ventricular ejection fraction, age, and level of hemoglobin. However, the lower exercise capacity by Western nomogram could not predict the primary endpoint (HR, 1.33; 95% CI, 0.85-2.10). CONCLUSION: Korean patients with CVD with lower exercise capacity have higher risk of MACE. Considering inter-ethnic differences in cardiorespiratory fitness, the Korean nomogram provides more suitable reference values than the Western nomogram to determine lower exercise capacity and predict cardiovascular events in Korean patients with CVD.

The mortality rate of Parkinson's disease and related comorbidities: a nationwide population-based matched cohort study in Korea.

BACKGROUND: previous studies on mortality of Parkinson's disease (PD) enrolled a relatively small number of participants and were conducted in western countries. The objective of this study was to evaluate mortality rate of PD using a large nationwide cohort in Korea and to evaluate effects comorbidities have on mortality in PD. METHODS: the nationwide population-based cohort study was conducted using the Korean National Health Insurance Service-National Sample Cohort data. Patients with a primary diagnosis of PD were selected from the database. A matched cohort without PD was enrolled through randomly matching patients by sex, age, year of diagnosis, residential area and income level to the PD group with a ratio of 1:9. The Cox proportional hazard model was used to assess mortality risk between the two cohorts. A logistic regression analysis was used to identify mortality risk factors in PD cohort. RESULTS: in total, 25,620 patients were enrolled. The Cox proportional regression model had an adjusted hazard ratio of 2.479 [95% confidence interval (CI), 2.272-2.704] for mortality in PD cohort. Comorbidities, such as ischaemic stroke [odds ratios (OR) = 2.314, 95% CI, 1.895-2.824], haemorrhagic stroke (OR = 2.281, 95% CI, 1.466-3.550) and chronic obstructive pulmonary disease (OR = 1.307, 95% CI, 1.048-1.630) were associated with increased mortality, whereas dyslipidemia (OR = 0.285, 95% CI, 0.227-0.358) was negatively correlated with mortality. CONCLUSION: over the 10 year follow-up period, the PD cohort's mortality rate was 2.5 times higher than the comparison cohort. Understanding the effects that comorbidities have on morality in PD would be useful for predicting mortality in patients with PD.

Hip Fracture in Patients with Parkinson's Disease and Related Mortality: A Population-Based Study in Korea.

INTRODUCTION: Patients with Parkinson's disease (PD) are prone to falls, thereby increasing the risk of fractures and mortality. This population-based study investigated the risk of hip fractures and their effect on mortality in patients with PD in Korea. METHODS: National Health Insurance Service-National Sample Cohort data were used. Patients newly diagnosed with PD between 2006 and 2015 and age- and sex-matched individuals were classified into the PD group and the comparison group, respectively, with a 1:9 ratio. The Cox proportional hazards model was used to calculate hazard ratios (HRs), and the Kaplan-Meier method to identify survivorship. RESULTS: In total, 26,570 individuals were enrolled in the study: 2,657 in the PD cohort and 23,913 in the matched comparison cohort. The PD group had about a 2 times higher risk of hip fracture than the comparison group (3.95 vs. 1.94%, p < 0.001). According to sex, the difference between the PD and comparison groups for the risk of hip fracture was greater in males than in females. The highest difference in HR for hip fracture between the PD and comparison groups was found in individuals aged between 60 and 69 years. Regarding post-fracture mortality in patients with PD, the mortality risk was twice as high in the patients with hip fracture than in those without. The effect of hip fracture on mortality between these 2 groups was also the highest in individuals aged between 60 and 69 years. CONCLUSION: The PD group showed an approximately 2 times higher risk of hip fracture compared with the comparison group, and the post-fracture mortality rate was 2 times higher in the patients with PD with hip fracture than in those without. Those aged 60-69 years were associated with the highest risk of hip fracture and post-hip fracture mortality among patients with PD.

The Peripheral Role of CCL2 in the Anti-Nociceptive Effect of Sigma-1 Receptor Antagonist BD1047 on Inflammatory Hyperalgesia in Rats.

Our recent study demonstrated that the CC-chemokine ligand 2 (CCL2) present in primary afferent fibers (PAFs) plays an important role in the microglia-dependent neuronal activation associated with zymosan-induced inflammatory pain. The present study was aimed to evaluate whether BD1047 (a prototypical sigma-1 receptor (Sig-1R) antagonist) is capable of modifying elevated levels of inflammation-evoked CCL2 as a peripheral antinociceptive mechanism. In DRG primary culture, zymosan dose-dependently increased CCL2 release from isolectin B4 (IB4)-positive DRG neurons, a process that was inhibited by co-culture with BD1047. Single treatment of BD1047 before intraplantar injection of zymosan in rats significantly reduced thermal hyperalgesia and mechanical hyperalgesia, as well as CCL2 expression in DRG neurons and microglia activation in the spinal dorsal horn. In the Complete Freund's adjuvant (CFA)-induced inflammation model, repeated administration of BD1047 dramatically attenuated thermal hyperalgesia and mechanical hyperalgesia, and significantly diminished CCL2 immunoreactivity and microglia activation. Notably, CFA-induced inflammation significantly increased Sig-1R immunoreactivity in DRG neurons, which was co-localized with CCL2 and IB4, respectively. Taken together, our results suggest that BD1047's anti-nociceptive property was substantially mediated by the inhibition of CCL2 release in unmyelinated PAFs and that this may, in turn, have attenuated the spinal microglia activation that is associated with inflammatory pain.

Comparison Between M-Mode Ultrasonography and Fluoroscopy for Diaphragm Excursion Measurement in Patients With Acquired Brain Injury.

OBJECTIVES: Patients with acquired brain injury show decreased pulmonary function and diaphragm excursion (DE), which can affect functional outcomes. This study aimed to compare ultrasonography (US) and fluoroscopy for DE assessment and to determine how the relationship between pulmonary function test results and DE differs according to the paralytic condition. METHODS: From September 2017 to April 2018, we prospectively enrolled patients with acquired brain injury. The patients underwent a pulmonary function test, including the functional vital capacity, forced expiratory volume at 1 second, forced expiratory volume at 1 second-to-functional vital capacity ratio, peak cough flow, and respiratory muscle strength such as the maximal inspiratory pressure and maximal expiratory pressure. Diaphragm excursion was measured with M-mode US and fluoroscopy on admission. A partial correlation analysis was used to assess the correlation between US and fluoroscopy for DE assessment. RESULTS: During the study period, 50 patients with acquired brain injury were enrolled. After adjusting for age, sex, height, and weight, the correlation coefficients between US and fluoroscopy were 0.744 for the right side (P < .001) and 0.631 for the left side (P < .001). In a subgroup analysis for patients with hemiplegia, the correlation coefficients were 0.507 for the paretic side (P = .007) and 0.677 for the nonparetic side (P < .001). Diaphragm excursion in the nonparetic side was significantly correlated with the maximal inspiratory pressure, maximal expiratory pressure, and peak cough flow (P < .05). CONCLUSIONS: M-mode US can be an alternative method for DE measurement in patients with impaired locomotion function after acquired brain injury. Preserved function of the nonparetic side might affect pulmonary function after brain injury, which suggests the importance of prestroke respiratory function.

Does the Type of Extracorporeal Shock Therapy Influence Treatment Effectiveness in Lateral Epicondylitis? A Systematic Review and Meta-analysis.

BACKGROUND: Extracorporeal shock wave therapy (ESWT) has been used in various musculoskeletal disorders, including lateral epicondylitis. However, in 2005, a meta-analysis of randomized controlled trials showed that ESWT provides minimal or no benefit in terms of pain and function in patients with lateral epicondylitis. Since the review, several randomized controlled trials including different types of ESWT such as radial type for lateral epicondylitis have been published. Investigations of the effect modifiers such as symptom and follow-up duration on the effects of ESWT on lateral epicondylitis have not been performed. QUESTIONS/PURPOSES: (1) Does ESWT reduce pain and improve grip strength in patients with lateral epicondylitis? (2) Which type of ESWT, radial or focused, is more effective? (3) Is the duration of symptoms associated with the efficacy of ESWT for lateral epicondylitis? (4) Do improvements in pain scores remain in patients with longer follow-up? METHODS: The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to July 2019 for articles published in English or Korean. Studies were included if patient allocation was randomized, the sample was composed of patients with lateral epicondylitis, interventions were ESWT (focused or radial), comparison group only received sham stimulation or no additional treatment, and the study outcome was pain intensity or grip strength. The quality of the evidence was assessed using the Cochrane risk of bias tool. Twelve studies including 1104 participants fulfilled the inclusion criteria and were included in the meta-analysis. The mean difference for pain reduction and improvement in grip strength was calculated. RESULTS: The meta-analysis showed no clinically important difference in the VAS score (2.48 ± 7.55 versus 3.17 ± 9.78, mean difference -0.68 [95% confidence interval -1.17 to -0.19]; p = 0.006) and grip strength (38.02 ± 70.56 versus 34.85 ± 108.26, mean difference 3.33 [95% CI 0.93 to 5.73]; p = 0.007) after ESWT relative to the comparison group's score. Even though radial ESWT showed more improvement than focused, the mean difference for VAS did not exceed the minimal clinically important differences threshold. There were no clinically important effects on the VAS scores of patients with lateral epicondylitis (2.78 ± 5.57 versus 3.92 ± 6.29, mean difference -1.13 [95% CI -1.84 to -0.42]; p = 0.002) and focused ESWT did not improve pain in patients with lateral epicondylitis. In the subgroup analysis, ESWT was effective in patients with a symptom duration of more than 6 months (2.28 ± 8.48 versus 3.31 ± 11.81, mean difference -0.95 [95% CI -1.75 to -0.15]; p = 0.02) but not for those with shorter symptom duration. The effects did not last beyond 24 weeks (2.52 ± 9.19 versus 3.34 ± 5.93, mean difference -0.82 [95% CI -2.57 to 0.93]; p = 0.36). CONCLUSIONS: ESWT did not show clinically important improvement in pain reduction and grip strength. Radial ESWT, symptom duration of longer than 6 months, and short follow-up duration (less than 24 weeks) were related to better effects. Further studies are needed to determine the appropriate protocol and elucidate the effects according to the intervention type and specific disease condition. LEVEL OF EVIDENCE: Level I, therapeutic study.

Astrocyte D-serine modulates the activation of neuronal NOS leading to the development of mechanical allodynia in peripheral neuropathy.

Spinal D-serine plays an important role in nociception via an increase in phosphorylation of the N-Methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). However, the cellular mechanisms underlying this process have not been elucidated. Here, we investigate the possible role of neuronal nitric oxide synthase (nNOS) in the D-serine-induced potentiation of NMDA receptor function and the induction of neuropathic pain in a chronic constriction injury (CCI) model. Intrathecal administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt (LSOS) or the D-serine degrading enzyme, D-amino acid oxidase (DAAO) on post-operative days 0-3 significantly reduced the CCI-induced increase in nitric oxide (NO) levels and nicotinamide adenine dinucleotide phosphate-diaphorase staining in lumbar dorsal horn neurons, as well as the CCI-induced decrease in phosphorylation (Ser847) of nNOS (pnNOS) on day 3 post-CCI surgery. LSOS or DAAO administration suppressed the CCI-induced development of mechanical allodynia and protein kinase C (PKC)-dependent (Ser896) phosphorylation of GluN1 on day 3 post-surgery, which were reversed by the co-administration of the NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1). In naïve mice, exogenous D-serine increased NO levels via decreases in pnNOS. D-serine-induced increases in mechanical hypersensitivity, NO levels, PKC-dependent pGluN1, and NMDA-induced spontaneous nociception were reduced by pretreatment with the nNOS inhibitor, 7-nitroindazole or with the NMDA receptor antagonists, 7-chlorokynurenic acid and MK-801. Collectively, we show that spinal D-serine modulates nNOS activity and concomitant NO production leading to increases in PKC-dependent pGluN1 and ultimately contributing to the induction of mechanical allodynia following peripheral nerve injury.

Effect of Ultrasound-Guided Intercostal Nerve Block Versus Fluoroscopy-Guided Epidural Nerve Block in Patients With Thoracic Herpes Zoster: A Comparative Study.

OBJECTIVES: To compare the efficacy of a conventional fluoroscopy-guided epidural nerve block and an ultrasound (US)-guided intercostal nerve block in patients with thoracic herpes zoster (HZ). METHODS: This work was a comparative study of 38 patients with thoracic HZ pain and a chest wall herpetic eruption, aged 18 years or older, with pain intensity of 5 or greater on a numeric rating scale (NRS) for less than a 1-month duration. Patients were consecutively enrolled and assigned to 2 groups in which the intervention was either the US-guided intercostal nerve block or the fluoroscopy-guided epidural nerve block approach with the addition of a 5-mL mix of 2.5 mg of dexamethasone plus 0.5% lidocaine. The primary outcome measure was the NRS score reduction for the pain. Secondary outcomes included the duration of treatment, number of repeated injections until the final visit, and proportion of patients with pain relief after the first and final visits. RESULTS: All patients within both intervention groups showed significant pain relief on the NRS at the final follow-up point (P < .05). There was no significant difference in the mean value of NRS improvement based on the intervention type. There was also no statistically significant difference in the duration of treatment and the frequency of injection for pain relief. CONCLUSIONS: These findings showed that both the US-guided intercostal nerve block and the fluoroscopy-guided epidural nerve block were effective in patients with thoracic HZ. Compared data showed no significant differences in the pain reduction, duration of treatment, and frequency of injection. The US-guided intercostal nerve block, which is more accessible than the fluoroscopy-guided epidural nerve block, might be an alternative option for thoracic HZ.

Lesions Responsible for Impaired Visual Perception in Poststroke Patients Using Voxel-Based Lesion Symptom Mapping.

We aimed to clarify the clinical characteristics that affect visual perception (VP) and elucidate lesion locations correlated with impaired VP. We reviewed 61 patients with stroke. Clinical assessments of a motor-free VP test were used to evaluate VP after stroke. Regression analyses were performed to examine predictors of impaired VP. We generated statistical maps of lesions related to impaired VP using voxel-based lesion symptom mapping (VLSM). The group of patients who had right hemispheric lesions had significantly low VP function. In a regression model, impaired VP was predicted by cognitive function, age, lesion volume, and right hemispheric lesion. Using VLSM, we found lesion location associated with impaired VP after adjusting for age, lesion volume, and Korean version of mini mental status exam. The results showed a lesion pattern with predominant distribution in the right parietal lobe and deep white matter. Age, lesion volume, and cognitive impairment affected the results of VP tests. Even after adjustments, we found that lesions responsible for impaired VP were located in the right parietal lobe and deep white matter. This result confirmed right hemispheric dominance for VP using VLSM. Clin. Anat. 32:689-696, 2019. © 2019 Wiley Periodicals, Inc.

Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents.

Despite the relatively high prevalence of migraine or headache, the pathophysiological mechanisms triggering headache-associated peripheral hypersensitivities, are unknown. Since nitric oxide (NO) is well known as a causative factor in the pathogenesis of migraine or migraine-associated hypersensitivities, a mouse model has been established using systemic administration of the NO donor, nitroglycerin (NTG). Here we tried to investigate the time course development of facial or hindpaw hypersensitivity after repetitive NTG injection. NTG (10 mg/kg) was administrated to mice every other day for nine days. Two hours post-injection, NTG produced acute mechanical and heat hypersensitivity in the hind paws. By contrast, cold allodynia, but not mechanical hypersensitivity, occurred in the facial region. Moreover, this hindpaws mechanical hypersensitivity and the facial cold allodynia was progressive and long-lasting. We subsequently examined whether the depletion of capsaicin-sensitive primary afferents (CSPAs) with resiniferatoxin (RTX, 0.02 mg/kg) altered these peripheral hypersensitivities in NTG-treated mice. RTX pretreatment did not affect the NTG-induced mechanical allodynia in the hind paws nor the cold allodynia in the facial region, but it did inhibit the development of hind paw heat hyperalgesia. Similarly, NTG injection produced significant hindpaw mechanical allodynia or facial cold allodynia, but not heat hyperalgesia in transient receptor potential type V1 (TRPV1) knockout mice. These findings demonstrate that different peripheral hypersensitivities develop in the face versus hindpaw regions in a mouse model of repetitive NTG-induced migraine, and that these hindpaw mechanical hypersensitivity and facial cold allodynia are not mediated by the activation of CSPAs.

Lesions Responsible for Delayed Oral Transit Time in Post-stroke Dysphagia.

INTRODUCTION: Some stroke patients show oral phase dysphagia, characterized by a markedly prolonged oral transit time that hinders oral feeding. The aim of this study was to clarify the clinical characteristics and lesions responsible for delayed swallowing. METHODS: We reviewed 90 patients with stroke. The oral processing time plus the postfaucial aggregation time required to swallow semisolid food was assessed. The patients were divided into two groups according to oral transit time, and we analyzed the differences in characteristics such as demographic factors, lesion factors, and cognitive function. Logistic regression analyses were performed to examine the predictors of delayed oral transit time. Lesion location and volume were measured on brain magnetic resonance images. We generated statistic maps of lesions related to delayed oral phase in swallowing using voxel-based lesion symptom mapping (VLSM). RESULTS: The group of patients who showed delayed oral transit time had significantly low cognitive function. Also, in a regression model, delayed oral phase was predicted with low K-MMSE (Korean version of the Mini Mental Status Exam). Using VLSM, we found the lesion location to be associated with delayed oral phase after adjusting for K-MMSE score. Although these results did not reach statistical significance, they showed the lesion pattern with predominant distribution in the left frontal lobe. CONCLUSION: Delayed oral phase in post-stroke patients was not negligible clinically. Patients' cognitive impairments affect the oral transit time. When adjusting it, we found a trend that the lesion responsible for delayed oral phase was located in the left frontal lobe, though the association did not reach significance. The delay might be related to praxis function.

Association between cervical lordotic curvature and cervical muscle cross-sectional area in patients with loss of cervical lordosis.

Disruption of the cervical lordotic curve can cause undesirable symptoms such as neck pain, and cord compression. The purpose of this study was to investigate the biomechanics of loss of cervical lordosis by measuring the cross-sectional area (CSA) of the cervical muscles using magnetic resonance imaging (MRI), and to determine the relationship between cervical lordosis angle and cervical muscle status. The cervical lordosis angle was measured on standing lateral plain radiography using the posterior tangent technique in patients who complained of neck pain. The CSAs of the cervical flexor muscles including the longus cervicis and longus capitis, the cervical extensor muscles including the splenius capitis and semispinalis capitis, and the sternocleidomastoid muscle, were measured at the maximum levels by axial T1-weighted MRI. We compared neck muscle CSAs between the two groups, the correlation with cervical lordosis angle, and muscle status including CSA and imbalance. The CSA of the semispinalis capitis was significantly lower in the loss of cervical lordosis group, and the ratio of cervical flexor to extensor was significantly different between the two groups (P < 0.05). Partial correlation analysis revealed that the cervical lordotic angle was significantly positively correlated with the ratio of flexor to extensor muscle CSAs (P < 0.05). There is a significant relationship between cervical muscle imbalance, including extensor muscle weakness, and loss of cervical lordosis. An exercise program focusing on cervical extensor muscle strengthening and restoring the balance of flexor and extensor muscles is recommended for patients with loss of cervical lordosis. Clin. Anat. 31:710-715, 2018. © 2018 Wiley Periodicals, Inc.

Enhancing GABA Signaling during Middle Adulthood Prevents Age-Dependent GABAergic Interneuron Decline and Learning and Memory Deficits in ApoE4 Mice.

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAA receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic. SIGNIFICANCE STATEMENT: We previously reported that female apoE4-KI mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of cognitive deficits in aged mice. The current study demonstrates that enhancing GABA signaling by treating aged apoE4-KI mice with a GABAA receptor potentiator pentobarbital (PB) before and during behavioral tests rescued the cognitive deficits; but withdrawal of PB treatment for 2 weeks before the tests abolished the rescue, suggesting the importance of continuously enhancing GABA signaling. However, treating apoE4-KI mice during middle adulthood with PB for a short period of time prevented age-dependent hilar GABAergic interneuron decline and cognitive deficits late in life, suggesting early intervention by enhancing GABA signaling as a potential strategy to prevent AD related to apoE4.

A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity.

Background Self-injurious behaviors (SIBs) are devastating traits in autism spectrum disorder (ASD). Although deficits in pain sensation might be one of the contributing factors underlying the development of SIBs, the mechanisms have yet to be addressed. Recently, the Shank2 synaptic protein has been considered to be a key component in ASD, and mutations of SHANK2 gene induce the dysfunction of N-methyl-D-aspartate (NMDA) receptors, suggesting a link between Shank2 and NMDA receptors in ASD. Given that spinal NMDA receptors play a pivotal role in pain hypersensitivity, we investigated the possible role of Shank2 in nociceptive hypersensitivity by examining changes in spontaneous pain following intrathecal NMDA injection in S hank2-/- ( Shank2 knock-out, KO) mice. Results Intrathecal NMDA injection evoked spontaneous nociceptive behaviors. These NMDA-induced nociceptive responses were significantly reduced in Shank2 KO mice. We also observed a significant decrease of NMDA currents in the spinal dorsal horn of Shank2 KO mice. Subsequently, we examined whether mitogen-activated protein kinase or AKT signaling is involved in this reduced pain behavior in Shank2 KO mice because the NMDA receptor is closely related to these signaling molecules. Western blotting and immunohistochemistry revealed that spinally administered NMDA increased the expression of a phosphorylated form of extracellular signal-regulated kinase (p-ERK) which was significantly reduced in Shank2 KO mice. However, p38, JNK, or AKT were not changed by NMDA administration. The ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in a dose-dependent manner in wild-type mice. Moreover, it was found that the NMDA-induced increase in p-ERK was primarily colocalized with Shank2 proteins in the spinal cord dorsal horn. Conclusion Shank2 protein is involved in spinal NMDA receptor-mediated pain, and mutations of Shank2 may suppress NMDA-ERK signaling in spinal pain transmission. This study provides new clues into the mechanisms underlying pain deficits associated with SIB and deserves further study in patients with ASD.

Lesion location associated with balance recovery and gait velocity change after rehabilitation in stroke patients.

PURPOSE: Impaired gait function after stroke contributes strongly to overall patient disability. However, the response to rehabilitation varies between individuals. The aims of this study were to identify predictors of gait velocity change and to elucidate lesion location associated with change of balance and gait function. METHODS: We reviewed 102 stroke patients. The patients were divided into two groups according to gait ability post-rehabilitation, and we analyzed differences in their characteristics, such as demographic information, lesion factors, and initial balance function. Multivariate regression analyses were performed to examine the predictors of rehabilitation response. Lesion location and volume were measured on brain magnetic resonance images. We generated statistical maps of the lesions related to functional gains in gait and balance using voxel-based lesion symptom mapping (VLSM). RESULTS: The group of patients who regained independent ambulation function showed a smaller lesion size, a shorter duration from stroke onset, and higher initial balance function. In the regression model, gait velocity changes were predicted with the initial Berg balance scale (BBS) and duration post-onset. Absolute BBS changes were also correlated with the duration post-onset and initial BBS, and relative BBS changes were predicted by the baseline BBS. Using VLSM, lesion locations associated with gait velocity changes and balance adjusting for other factors were the insula, internal capsule, and adjacent white matter. CONCLUSION: Initial balance function as well as the interval between stroke onset and the initiation of therapy might influence balance recovery and gait velocity changes. Damage to the insula and internal capsule also affected gait velocity change after rehabilitation.

Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension.

Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg(-1), i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg(-1), i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatin-induced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg(-1), clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg(-1) clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg(-1) clonidine decreased allodynia similar to that of 0.10 mg kg(-1) clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects.

Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice.

Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.