Research Landscapes and Gaps in Neuropsychiatric Assessment for Neurodegenerative Diseases: A Bibliometric Study on Huntington’s Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy

Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases.

Editorial: A Trends guide to Neurodegenerative Disease and Repair

Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral–pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.

No current therapies target the underlying cellular pathologies of age-related neurodegenerative diseases. Model organisms provide a platform for discovering compounds that protect against the toxic, misfolded proteins that initiate these diseases. One such protein, TDP-43, is implicated in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In yeast, TDP-43 expression is toxic, and genetic modifiers first discovered in yeast have proven to modulate TDP-43 toxicity in both neurons and humans. Here, we describe a phenotypic screen for small molecules that reverse TDP-43 toxicity in yeast. One group of hit compounds was 8-hydroxyquinolines (8-OHQ), a class of clinically relevant bioactive metal chelators related to clioquinol. Surprisingly, in otherwise wild-type yeast cells, different 8-OHQs had selectivity for rescuing the distinct toxicities caused by the expression of TDP-43, α-synuclein, or polyglutamine proteins. In fact, each 8-OHQ synergized with the other, clearly establishing that they function in different ways. Comparative growth and molecular analyses also revealed that 8-OHQs have distinct metal chelation and ionophore activities. The diverse bioactivity of 8-OHQs indicates that altering different aspects of metal homeostasis and/or metalloprotein activity elicits distinct protective mechanisms against several neurotoxic proteins. Indeed, phase II clinical trials of an 8-OHQ has produced encouraging results in modifying Alzheimer disease. Our unbiased identification of 8-OHQs in a yeast TDP-43 toxicity model suggests that tailoring 8-OHQ activity to a particular neurodegenerative disease may be a viable therapeutic strategy.

Clawson LL, Cudkowicz M, Krivickas L, Brooks BR, Sanjak M, Allred P, Atassi N, Swartz A, Steinhorn G, Uchil A, Riley KM, Yu H, Shoenfeld DA, Maragakis NJ. A randomized controlled trial of resistance and endurance exercise in amyotrophic lateral sclerosis. Amyotrophic Lateral Scler Frontotemporal Degene. 2018;19(3–4):250–8.Amyotrophic lateral sclerosis (ALS) is classified as a neurodegenerative disease that results in destruction of motor neurons in the brain and spinal cord (1). The cause of this disease is unknown, with 90% of all cases being nonfamilial (1). As ALS progresses, it results in cachexia, loss of muscle mass and movement coordination, paralysis, and eventual death (1). It is estimated that 30,000 people in the US (1) and 1,400 people in Australia (2) are living with ALS.According to the American Academy of Neurology the current standard of care for persons with ALS includes static stretching and passive range of motion to offset muscle and joint stiffness caused by neurologic decline (3). Low powered studies and conflicting research results of the effect of resistance (weights lifting) and/or aerobic exercise on ALS have led to difficulty determining recommendations for these modes of exercise (3). Some researchers indicate that vigorous aerobic or intense resistance training may increase the risk of (4) or exacerbate the progression (3) of ALS. Because of this, some clinicians instruct patients to avoid these forms of exercise. On the contrary, authors of several studies in mice (5) and humans (6) suggest resistance and aerobic exercise have multiple benefits for ALS, including delayed onset of symptoms, slowed progression, and improved quality of life, without being a major risk factor (7). The aim of this study was to determine the tolerance and compliance of exercise when comparing resistance, aerobic, and stretching or passive range of motion exercises in persons with ALS.This 24-week, randomized controlled trial included persons with ALS who met these inclusion criteria: (a) classified as having lab-supported probable or definite ALS, confirmed by a neurologist and (b) willingness to participate in this study. Exclusion criteria were not mentioned. Due to difficulty with the recruitment of persons with ALS who were willing to perform exercises, this study began in April 2012, with the last participant enrolled in September 2015.Fifty-nine participants were randomly assigned to resistance training (n = 21), aerobic exercise (n = 18), or static stretching or passive range of motion [S-ROM] (n = 20). Tolerability was defined as each participant completing ≥50% of total repetitions assigned for resistance training and S-ROM and ≥50% of aerobic exercise duration programmed at a specific heart rate and perceived exertions scale (Borg 6–20) rating. Compliance was defined as each participant attempting ≥50% of all exercise sessions for the 24-week period. Broad compliance measures were implemented with anticipation of rapid progression of ALS and inability to perform higher intensity or longer duration exercise. As a result, broad compliance measures afforded participants greater consistency with exercise completion at each session. To improve retention and avoid travel to treatment center, home-based exercise was programmed for all participants. The participants' “home exercise partner” was initially trained by a physical therapist, and appropriate exercise form was evaluated at follow-up visits throughout the course of the intervention. Outcome measures included exercise compliance and tolerance with secondary measures, including ALS Functional Rating Scale-Revised, ALS Scale for Quality of Life-Revised (3), Fatigue Severity Scale, Ash-worth Spasticity Scale (6), and Visual Analog Scale. Follow-up measures were taken at weeks 12 and 24. Training logs and teleconferences were used to track at-home exercise compliance and tolerance.All groups performed 3 exercise sessions per week. Resistance training included 2 sets of 8 repetitions with use of ankle or wrist weights. Initial intensity was 40% 1 repetition maximum (1RM) and was increased to 50% 1RM at week 4 and 70% 1RM at week 6. 1RM testing was conducted at baseline. Aerobic exercise included the use of a minicycle with 10 min of upper and lower body cycling, respectively, at 50%–70% heart rate reserve and 13–15 on the Borg scale. S-ROM exercise included 4 sets of 30-second static stretches for each exercise. For a list of exercises, see the Supplemental Material (https://www.tandfonline.com/doi/suppl/10.1080/21678421.2017.1404108).Analysis of all primary and secondary outcomes was conducted at 12 and 24 weeks. Over the course of the study, there were 4 serious adverse events resulting in withdrawal from the study, none of which were deemed a direct result of the exercise intervention or resulted in death. In addition, another 11 participants were lost to follow up (n = 4), co-enrollment in another study (n = 1), difficulty with travel (n = 1), or complication associated with disease progression (n = 2). Minor adverse events that are frequently seen in persons with ALS included musculoskeletal injury, fatigue, and falling, which did not differ between the groups.When assessing the proportion of participants that were able to tolerate exercise, the S-ROM, resistance, and aerobic groups were 77%, 65%, and 51% compliant. These results indicated all 3 modes of exercise are well tolerated by persons with ALS and safe to perform, with greatest compliance occurring in the S-ROM and resistance groups. There were no differences at 12 or 24 weeks regarding any of the secondary measures, which suggests that resistance and aerobic training did not exacerbate or cause accelerated progression of disease, reduce quality of life, or increase fatigue in this sample of participants.This is one of the first studies to demonstrate that resistance and aerobic exercise is safe and well tolerated for persons with ALS, and compliance with resistance training is comparable with standard care (S-ROM). The findings of this study are supported by previous researchers (6,8) that demonstrate short-term improvement in disability associated with supervised resistance and aerobic training. It is possible that differences in exercise adherence can be attributed to the intensity parameters being too low for resistance training or too high for aerobic training, resulting in lower compliance rates associated with the S-ROM, respectively. Future researchers will need to focus on specific frequency, intensity, type, and volume of exercise programming for the management of ALS. Although the clinical exercise physiologist should interpret the results of this study with caution, the use of resistance and aerobic training should be considered as a management technique for patients diagnosed with ALS.Quinn L, Hamana K, Kelson M, Dawes H, Collett J, Townsen J, Raymund R, van der Plas AA, Reilmann R, Frich JC, Rickards H, Rosser A, Busse M. A randomized, controlled trial of a multi-modal exercise intervention in Huntington's disease. Parkinsonism Relat Disord. 2016;31:4–52.Huntington's disease (HD) is a genetically linked neurodegenerative disease that is progressive and results in neuronal damage to the substantia nigra and cerebral cortex of the brain (1). HD is associated with nonmotor symptoms such as cognitive impairment, dementia, memory loss, and disorientation, as well as motor symptoms including chorea (irregular or rapid) and athetosis (slow or writhing involuntary) movements of the hands, feet, face, and trunk (1). Currently, there are approximately 30,000 people in the US (1) and 1,500 people in Australia (2) who are living with HD.The effectiveness of exercise as a management technique for HD is a relatively new research focus with limited studies. It is suggested that multimodal rehabilitation programs can improve physical function, quality of life (3), and possibly cognition (4) in persons with HD. Many challenges exist with determining the effectiveness of exercise-based interventions on HD, including level of supervision, appropriately programmed intensity, variability of cognitive impairment, exercise preference or tolerance, and comfort with exercise settings (5,6). These factors can lead to reduced initiation and adherence to exercise for persons with HD. Therefore, the aim of this study is to determine the effectiveness of a multimodal exercise program on persons with mild to moderate HD to determine safety, feasibility regarding retention and adherence, and improvement of physical fitness, motor control, physical function, and cognition.This was a randomized, controlled, multicenter trial, that assigned 32 of 312 screened participants to an exercise (n = 17) or control (n = 15) group for a 12-week intervention and 26-week follow up. Inclusion criteria were (a) genetically confirmed cases of HD, (b) ≥18 years of age, and (c) stable medication regime of antichoreic drugs for 4 weeks. Participants were excluded if they were (a) unable to use an exercise bike, (b) had psychological or physical limitation precluding exercise testing, and (c) currently in an exercise program. All participants who met inclusion criteria were screened for cardiovascular risk factors and underwent electrocardiogram testing to ensure safety with initiation of exercise.The control (CT) group was instructed to carry on with normal activity for the full duration of the intervention. Participants in the exercise (EX) group participated in three 50-min exercise sessions per week for a total of 12 weeks. Follow-up assessment occurred at week 13 and was compared with the baseline. Exercise included 25 min of cycling at 55%–85% age-predicted maximum heart rate (APMHR), 10–15 min of resistance training (2 sets of 15 repetitions), and 5 min of static stretching. For full details on the exercise program, see the Supplemental Material (https://www.prd-journal.com/article/S1353-8020(16)30243-7/fulltext#supplementaryMaterial). Participants could choose between their home or a medical fitness center to perform the exercise. An exercise professional provided gym-based supervision and at-home exercise for all 3 sessions during weeks 1–2, which was then tapered to 2 sessions for weeks 3–6, and 1 session for the final 6 weeks.Primary outcome measures included retention (completion of intervention) and adherence (completion of sessions), which was predetermined as >75% of supervised and unsupervised sessions and maintaining APMHR intensities for >75% (19/25 min) of the cycling duration. A series of secondary measures were also collected at baseline and follow-up assessment to determine improvement in motor control, quality of life, and physical and cognitive function (7–10).Three participants from the EX group dropped out before the 13-week assessment due to concomitant conditions, and 10 (n = 5 EX and n = 5 CT) were unable to be contacted at the 26-week period. Two serious adverse events occurred in the CT group, both attempted suicides, with 1 possibly being related to the week 13 assessment. A total of 97% of the EX group completed the intervention. Ninety-three percent of the EX group were able to complete the required sessions of the intervention, with only 75% achieving APMHR at each exercise session. Blunted heart rate response can be attributed to autonomic dysfunction commonly associated with HD, resulting in the inability to reach a predetermined percentage for APMHR (1). The EX and CT groups showed no differences in fall occurrence, suggesting that supervised exercise does not incur a greater fall risk in this population.The EX group improved aerobic fitness (VO2 MAX), motor function, and reduced body weight compared with the CT group. A reduced body weight may not be considered a positive finding because HD can lead to rapid weight loss in some people, resulting in cachexia and negative health outcomes (11). Follow-up assessment at 26 weeks indicated that all EX participants returned to low levels of physical activity after the intervention was terminated, and there were no differences in measured health outcome between groups.This is the first study to demonstrate that a multimodal exercise program is safe and that persons with mild to moderate HD can adhere to exercise with and without supervision and in different settings. The authors of this study showed improvement in aerobic fitness and motor control, but no improvement in strength, physical function, or cognition, which can all reduce quality of life in persons with HD (3). The exclusion of those with cognitive deficit and mental health disease, which is commonly associate with HD, may have resulted in reduced applicability of this study. The resistance training protocol may have used an intensity and/ or volume that was too low for improvement in strength. Future researchers might investigate the effects of resistance versus aerobic training and allow for a more robust sample of participants with and without HD-related cognitive impairment. The clinical exercise physiologist should encourage persons with HD to remain physically active using a multimodal program when safe and appropriate for an individual.The current Research Highlights editor would like to thank the JCEP Editorial Board for the opportunity to contribute this journal by authoring the Research Highlights for the past several years. We welcome Dr. Elizabeth O'Neill, DPE (Springfield College, Springfield, MA) as the new Research Highlights editor.

A definite diagnosis of neurodegenerative diseases is required for neuropathological examination during an autopsy. Each neurodegenerative disease has specific vulnerable regions and affected systems (system degeneration), and is typified by an accumulation of abnormal protein with the formation of characteristic morphological aggregates in the nerve and glial cells, called proteinopathy. The most common neurodegenerative diseases are tauopathy, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-synucleinopathy, including multiple system atrophy (MSA); and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). PSP and CBD show characteristic tau-positive astrocytic inclusions known as tufted astrocytes and astrocytic plaques, respectively. PiD shows tau-positive neuronal inclusions termed Pick bodies. MSA is characterized by α-synuclein-positive oligodendroglial inclusions, called glial cytoplasmic inclusions. ALS- and FTLD-TDP show TDP-43-positive neuronal inclusions, such as skein-like and round inclusions. Huntington's disease shows polyglutamine-positive neuronal inclusions, and Creutzfeldt-Jakob disease shows diffuse deposition of granular prions in the neuropil. The atypical proteins in these diseases have abnormal conformational properties. A comprehensive comparison of the clinical findings and neuropathological observations, including neuroanatomy and images acquired during life, is important to improve the sensitivity of clinical diagnosis.

Background:Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.Objective:We examined the potential association between long-term exposure to particulate matter in aerodynamic diameter [fine particulate matter ()] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.Methods:We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000–2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual concentrations estimated by a prediction model at a resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y exposure. We allowed for nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders.Results:We found a positive nonlinear association that plateaued above (, 95% CI: 1.04, 1.14 for a increase from 8.1 to ). We also found a linear positive association (, 95% CI: 1.01, 1.09 per increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.Conclusion:Our findings suggest that annual increase in county-level concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual concentration in our study was , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425

Objective: To examine whether there are clinical features in Japanese patients with both neurodegenerative diseases and cancers. Methods: We analyzed the clinical characteristics of consecutive Japanese patients with neurodegenerative diseases during the past 5 years, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), dementia with Lewy bodies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Results: Out of 292 patients, 39 patients had cancers, including a past history, as follows: ALS, n = 16; PD, n = 8; PSP, n = 7; CBD, n = 1, and MSA, n = 7. About 10% of patients with neurodegenerative diseases developed cancer after onset of the disease; about 30% of patients with ALS, PD, or PSP occurring with cancers died of cancer. Gastric cancer was most common before the onset of ALS (62.5%) but did not develop after the onset of ALS. Conversely, PD patients frequently developed gastric cancers after the onset of neurological signs (60.0%) in spite of no cancer before the onset of PD. The proportion of breast cancer in MSA (45.5%) was significantly higher than in other neurodegenerative diseases. Conclusion: ALS, PD, or MSA patients with cancer showed clinical characteristics unique to each neurodegenerative disease in Japan compared to other countries.

Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy.

Therapeutic Translation of iPSCs for Treating Neurological Disease

To diagnose neurodegenerative diseases (NDDs), physicians have been clinically evaluating symptoms. However, these symptoms are not very dependable—particularly in the early stages of the diseases. This study has therefore proposed a novel classification algorithm that uses a deep learning approach to classify NDDs based on the recurrence plot of gait vertical ground reaction force (vGRF) data. The irregular gait patterns of NDDs exhibited by vGRF data can indicate different variations of force patterns compared with healthy controls (HC). The classification algorithm in this study comprises three processes: a preprocessing, feature transformation and classification. In the preprocessing process, the 5-min vGRF data divided into 10-s successive time windows. In the feature transformation process, the time-domain vGRF data are modified into an image using a recurrence plot. The total recurrence plots are 1312 plots for HC (16 subjects), 1066 plots for ALS (13 patients), 1230 plots for PD (15 patients) and 1640 plots for HD (20 subjects). The principal component analysis (PCA) is used in this stage for feature enhancement. Lastly, the convolutional neural network (CNN), as a deep learning classifier, is employed in the classification process and evaluated using the leave-one-out cross-validation (LOOCV). Gait data from HC subjects and patients with amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) obtained from the PhysioNet Gait Dynamics in Neurodegenerative disease were used to validate the proposed algorithm. The experimental results included two-class and multiclass classifications. In the two-class classification, the results included classification of the NDD and the HC groups and classification among the NDDs. The classification accuracy for (HC vs. ALS), (HC vs. HD), (HC vs. PD), (ALS vs. PD), (ALS vs. HD), (PD vs. HD) and (NDDs vs. HC) were 100%, 98.41%, 100%, 95.95%, 100%, 97.25% and 98.91%, respectively. In the multiclass classification, a four-class gait classification among HC, ALS, PD and HD was conducted and the classification accuracy of HC, ALS, PD and HD were 98.99%, 98.32%, 97.41% and 96.74%, respectively. The proposed method can achieve high accuracy compare to the existing results, but with shorter length of input signal (Input of existing literature using the same database is 5-min gait signal, but the proposed method only needs 10-s gait signal).

Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1647 autopsied individuals, we report the incidence of 10 pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer's disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease or probable tauopathies. Up to seven pathologies were observed concurrently resulting in a heterogeneous mix of 161 pathological combinations. The presence of multiple additive pathologies associated with older age, increasing disease duration, APOE e4 allele and presence of dementia across the clinical groups. Fifteen to 67 combinations occurred in each group, with the unimpaired group defined by 35 combinations. Most combinations occurred at a <5% prevalence including 86 that were present in only one or two individuals. To better understand this heterogeneity, we organized the pathological combinations into five broad categories based on their age-related frequency: (i) 'Ageing only' for the unimpaired group combinations; (ii) 'ND only' if only the expected pathology for that individual's clinical phenotype was present; (iii) 'Other ND' if the expected pathology was not present; (iv) 'ND + ageing' if the expected pathology was present together with ageing-related pathologies at a similar prevalence as the unimpaired group; and (v) 'ND + associated' if the expected pathology was present together with other pathologies either not observed in the unimpaired group or observed at a greater frequency. ND only cases comprised a minority of cases (19-45%) except in the amyotrophic lateral sclerosis (56%) and multiple system atrophy (65%) groups. The ND + ageing category represented 9-28% of each group, but was rare in Alzheimer's disease (1%). ND + associated combinations were common in Alzheimer's disease (58%) and Lewy body disease (37%) and were observed in all groups. The Ageing only and Other ND categories accounted for a minority of individuals in each group. This observed heterogeneity indicates that the total pathological burden in ND is frequently more than a primary expected clinicopathological correlation with a high frequency of additional disease- or age-associated pathologies.

In this study, we used the Mendelian randomization (MR) method to systematically examine whether there is a bidirectional causal relationship between amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). We analyzed data from 6,44,924 participants using MR to evaluate causality. We employed inverse variance weighted and MR-Egger regression tests for MR analysis. Additionally, we performed sensitivity analyses using the MR-Egger test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. The inverse variance weighted analysis found no evidence of a risk effect between ALS and the neurodegenerative diseases AD, PD, FTD, MSA, and DLB. However, the MR-Egger analysis showed that both AD (odds ratio: 1.079, 95% confidence interval: 1.017-1.145, P = .029) and PD (odds ratio: 1.210, 95% confidence interval: 1.046-1.401, P = .020) have a risk effect on ALS, indicating that AD and PD increase the risk of ALS. Our MR analysis suggests that AD and PD may have a potential causal relationship with ALS. Conversely, ALS does not appear to have a causal relationship with the other neurodegenerative diseases examined (FTD, MSA, DLB).

Sleep disorders are common in neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), hereditary ataxias, and Alzheimer's disease (AD). Type, frequency, and severity of sleep disturbances vary depending on each of these diseases. Cell loss of the brainstem nuclei that modulates respiration, and dysfunction of bulbar and diaphragmatic muscles increase the risk for sleep-disordered breathing (SDB) in MSA and ALS. The most relevant SDB in MSA is stridor, whereas in ALS nocturnal hypoventilation due to diaphragmatic weakness is the most common sleep breathing abnormality. Stridor and nocturnal hypoventilation are associated with reduced survival in MSA and ALS. In contrast, sleep apnea seems not to be more prevalent in PD than in the general population. In some PD patients, however, coincidental obstructive sleep apnea (OSA) can be the cause of excessive daytime sleepiness (EDS). SDB can also occur in some hereditary ataxias, such as stridor in spinocerebellar ataxia type 3 (Machado-Joseph disease). The presence of concomitant OSA in patients with AD can have deleterious effects on nocturnal sleep, may result in EDS, and might aggravate the cognitive deficits inherent to the disease. However, whether OSA is more frequent in patients with AD than in the general population is uncertain. Recognition of SDB in neurodegenerative disease is important because they are associated with significant morbidity and potential effective treatments are available.

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.