巴金森病与多系统萎缩患者的交感神经皮肤反应研究

目的：研究原发性巴金森病（IPD）与多系统萎缩（MSA）交感神经皮肤反应（SSR）,以探讨它们自主神经功能障碍的差异。方法：对31例IPD、17例MSA和83位正常人的SSR结果比较,分析PD组和MSA组SSR异常特征和与病程、自主神经症状的相关性。结果：MSA组SSR异常率（76％）显著高于IPD组（45％）,以双侧异常多见。3年内病程的SSR异常率为73％,并与自主神经症状相关。IPD组SSR异常与病程显著相关,与自主神经症状无完全对应关系,SSR异常更多见于震颤侧。结论：MSA广泛而严重的自主神经系统受累可能是SSR异常显著有别于IPD的基础。SSR异常出现早,呈双侧改变,且与自主神经症状有对应关系,则更多提示MSA的可能。     

alpha-synuclein from platelets is not phosphorylated at serine 129 in Parkinson's disease and multiple system atrophy

Parkinson's disease (PD) and multiple system atrophy (MSA) are characterized pathologically by inclusions in the brain containing alpha-synuclein, which is phosphorylated at serine 129. alpha-Synuclein is present not only in the brain but also in platelets; platelets have previously been used to study mitochondrial function in PD. We undertook to determine whether alpha-synuclein extracted from platelets of patients with PD and MSA is phosphorylated at serine 129 and could be used as a peripheral marker of these disorders. Immunoblots indicated that platelet alpha-synuclein is not phosphorylated at serine 129 in PD and MSA.     

Pervasive and diffuse muscle activity during REM sleep and non-REM sleep characterises multiple system atrophy in comparison with Parkinson's disease

Multiple system atrophy (MSA) and Parkinson's disease (PD) may share overlapping features particularly at early disease stage, including sleep alterations, but have profoundly different prognoses. Certain sleep phenomena and disorders of motor control are more prevalent in multiple system atrophy, such as REM sleep behaviour disorder (RBD). We quantitatively tested whether pervasive muscle activity during sleep occurs in subjects with multiple system atrophy versus Parkinson's disease. Laboratory polysomnographic studies were performed in 50 consecutive subjects with Parkinson's disease and 26 age- and gender-matched subjects with multiple system atrophy at <5 years from disease onset. The distributions of normalised electromyographic activity of submentalis, wrist extensor, and tibialis anterior muscles in different wake–sleep states during the night were analysed. Subjects with multiple system atrophy had significantly higher activity of submentalis, wrist extensor, and tibialis anterior muscles than subjects with Parkinson's disease during non-REM sleep, including separately in stages N1, N2, and N3, and during REM sleep, but not during nocturnal wakefulness. The activity of wrist extensor and tibialis anterior muscles during non-REM sleep and the activity of tibialis anterior muscles during REM sleep were also significantly higher in subjects with multiple system atrophy and RBD than in subjects with Parkinson's disease and RBD. In conclusion, with respect to Parkinson's disease, multiple system atrophy is characterised by a pervasive and diffuse muscle overactivity that involves axial and limb muscles and occurs not only during REM sleep, but also during non-REM sleep and between subjects with comorbid RBD.     

Pathological changes in the cerebellum of patients with multiple system atrophy and Parkinson's disease—a stereological study

Multiple system atrophy (MSA) and Parkinson's disease (PD) are synucleinopathies characterized by aggregation of α‐synuclein in brain cells. Recent studies have shown that morphological changes in terms of cerebral nerve cell loss and increase in glia cell numbers, the degree of brain atrophy and molecular and epidemiological findings are more severe in MSA than PD. In the present study, we performed a stereological comparison of cerebellar volumes, granule and Purkinje cells in 13 patients diagnosed with MSA [8 MSA‐P (striatonigral subtype) and 5 MSA‐C (olivopontocerebellar subtype)], 12 PD patients, and 15 age‐matched control subjects. Only brains from MSA‐C patients showed a reduction in the total number of Purkinje cells (anterior lobe) whereas both MSA‐P and MSA‐C patients had reduced Purkinje cell volumes (perikaryons and nuclei volume). The cerebellum of both diseases showed a reduction in the white matter volume compared to controls. The number of granule cells was unaffected in both diseases. Analyses of cell type‐specific mRNA expression supported our structural data. This study of the cerebellum is in line with previous findings in the cerebrum and demonstrates that the degree of morphological changes is more pronounced in MSA‐C than MSA‐P and PD. Further, our results support an explicit involvement of cerebellar Purkinje cells and white matter connectivity in MSA‐C > MSA‐P and points to the potential importance of white matter alterations in PD pathology.     

Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease

Background: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.     

Altered regional homogeneity in motor cortices in patients with multiple system atrophy

Typical histopathological findings of multiple system atrophy (MSA) have been observed in motor related cortices, in addition to the common areas of the striatum, substantia nigra, olivopontocerebellar pathways, the intermediolateral cell columns of the spinal cord, and the cerebellum. The purpose of this study is to test the hypothesis that functional impairment associated with the histopathological findings exists in the motor cortex of MSA patients using resting-state fMRI. Twenty clinically probable MSA patients (9 with MSA-P and 11 with MSA-C subtype) and 11 healthy controls (HCs) were studied. The regional homogeneity (ReHo) approach was used to analyze low frequency spontaneous fluctuation of blood oxygen level dependent signal. Compared with the HCs, the MSA patients showed significantly decreased ReHo in the left primary sensorimotor cortex, posterior cingulate cortex, left lateral prefrontal cortex (PFC) and right inferior parietal lobule (IPL), together with increased ReHo in the right primary sensorimotor cortex, bilateral premotor cortices, bilateral supplementary motor areas, medial PFC and left IPL. The results support the hypothesis that motor cortex areas can be functionally involved and likely play a role in motor circuit dysfunction in MSA patients.     

Depressive symptom patterns in patients with Parkinson's disease and other older adults.

Research on depression in Parkinson's disease (PD) has suggested that PD patients experience a qualitatively different depression from that of other older adults, endorsing fewer cognitive symptoms of depression (e.g., guilt, failure) and greater somatic (e.g., poor sleep) and mood symptoms (e.g., sadness, hopelessness); however, this has never been tested directly. In the present study, two PD groups, one with cognitive impairment (PD + CI; n = 26) and one without cognitive impairment (PD; n = 45), and three control groups of older adults were compared on measures of depressive symptomatology. The control groups included a physically disabled group (n = 46), a cognitively impaired group (CI; n = 21), and a healthy group (n = 50). Confirmatory factor analysis verified a four-factor model of depressive symptoms (Cognitive, Mood, Somatic, and Fatigue symptoms). Comparisons revealed that the PD group had a depressive-symptom pattern that was not significantly different from the disabled and healthy groups. The PD + CI group had a symptom pattern that was more similar to the CI group than to the PD group. Implications for the conceptualization of depression in older adults are discussed.     

Multijoint movement control in Parkinson's disease

Impairments in the performance of complex actions in Parkinson's disease (PD) patients are well documented. The aim of the present study was to investigate potential mechanisms that may be contributing to impaired movement performance in PD patients. PD patients and age-matched control subjects performed rapid pointing movements to a series of four tabletop targets. The height of the table was adjusted until the targets could be achieved with arm movements in the horizontal plane. The targets were arranged such that target 1 required elbow extension only and targets 2–4 required increasing amounts of horizontal shoulder flexion in addition to the elbow extension. While the control subjects accelerated and decelerated the elbow and shoulder joints simultaneously regardless of the target location, the PD patients decomposed motion during the acceleration phase by accelerating first the shoulder and then the elbow joint. For PD patients this decomposition of arm segments was associated with greater coactivation of the muscles about the elbow when elbow extension and shoulder flexion were simultaneously required (targets 2–4), in contrast to the single joint action. The control subjects decreased elbow joint coactivation while the patients increased it across the four targets. The resulting peak interaction torques at both the elbow and shoulder joints occurred relatively later for the PD patients. The coactivation patterns observed in PD patients may reduce the ability to take advantage of interaction torques and may also contribute to joint motion decomposition. Electronic Publication     

Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease,dementia with Lewy bodies,multiple system atrophy,and amyotrophic lateral sclerosis

In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.     

Event-related desynchronization of motor cortical oscillations in patients with multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism (MSA-P), cerebellar and autonomic deficits. In Parkinson’s disease (PD), an impaired modulation of motor cortical mu and beta range oscillations may be related to the pathophysiology of bradykinesia. Event-related desynchronization (ERD) of these oscillations occur for 1–2 s preceding a voluntary movement in normal subjects and patients with PD treated with levodopa while only lasting around 0.5 s in untreated patients. Motor cortical rhythms were recorded from subdural strip electrodes in three patients with MSA-P while taking their regular dopaminergic medications. Following a ready cue, patients performed an externally cued wrist extension movement to a go cue. In addition, recordings were obtained during imagined wrist extension movements to the same cues and during self-paced wrist extensions. ERD and event-related synchronization were examined in subject-specific frequency bands. All patients showed movement-related ERD in subject-specific frequency bands below ~40 Hz in both externally cued and self-paced conditions. Preparatory ERD latency preceding self-cued movement was 900 ms in one patient and at or after movement onset in the other two patients. In the externally cued task, a short lasting (<1.3 s) ready cue-related ERD that was not sustained to movement onset was observed in two patients. Imagined movements resulted in go cue-related ERD with a smaller magnitude in the same two patients. These results indicate that the modulation of motor cortical oscillations in patients with MSA that are treated with levodopa is similar to that occurring in untreated patients with PD. The findings suggest that cortical activation in patients with MSA is diminished, may be related to pathophysiological changes occurring in the basal ganglia and correlates with the poor clinical response that these patients typically obtain with dopaminergic therapy.     

Disorder in reciprocal innervation upon initiation of voluntary movement in patients with Parkinson's disease

Summary Reciprocal innervation of the soleus motoneurones upon initiation of voluntary ankle dorsiflexion was investigated in eight patients with Parkinson's disease. H-reflex and visually guided step tracking methods were used for testing moto-neurone excitability and for controlling the timing of movement initiation, respectively. While reciprocal inhibition appeared almost simultaneously with the agonist electromyographic (EMG) onset in normal subjects (Kagamihara and Tanaka 1985), facilitation appeared in the majority of patients under the same onset condition. It increased slowly, reaching a maximum at about 100 ms after the EMG onset. It then subsided slowly at around 200–300 ms, and was replaced thereafter by an inhibitory effect. No coactivation of the soleus muscle was detected electromyographically. The facilitation between the EMG onset and the onset of mechanical contraction was attributed to the direct effect of the descending command from the brain, suggesting a certain disorder in controlling the system for reciprocal innervation.     

Symptoms and medications change patterns for Parkinson's disease patients stratification

Quality of life of patients with Parkinson's disease degrades significantly with disease progression. This paper presents a step towards personalized management of Parkinson's disease patients, based on discovering groups of similar patients. Similarity is based on patients’ medical conditions and changes in the prescribed therapy when the medical conditions change. We present two novel approaches. The first algorithm discovers symptoms’ impact on Parkinson's disease progression. Experiments on the Parkinson Progression Markers Initiative (PPMI) data reveal a subset of symptoms influencing disease progression which are already established in Parkinson's disease literature, as well as symptoms that are considered only recently as possible indicators of disease progression by clinicians. The second novelty is a methodology for detecting patterns of medications dosage changes based on the patient status. The methodology combines multitask learning using predictive clustering trees and short time series analysis to better understand when a change in medications is required. The experiments on PPMI data demonstrate that, using the proposed methodology, we can identify some clinically confirmed patients’ symptoms suggesting medications change. In terms of predictive performance, our multitask predictive clustering tree approach is mostly comparable to the random forest multitask model, but has the advantage of model interpretability.     

Peripheral vasoconstriction in patients with sleep related periodic leg movements

Two patients complaining of insomnia had sleep-related periodic leg movements (nocturnal myoclonus) on polysomnographic evaluation. Both also complained of cold feet and had abnormal peripheral pulse examinations. Treatment with phenoxybenzamine, alpha-adrenergic blocker, normalized the peripheral pulse responses, reduced the complaint of insomnia, and reduced the sleep related leg movements but resulted in only mild sleep improvements. Peripheral pulse examinations of ten other patients with sleep-related periodic leg movements revealed abnormal responses in four. From these and other results, it is hypothesized that the sympathetic nervous system may mediate the periodicity of sleep related periodic leg movements.     

Investigating body motion patterns in patients with Parkinson's disease using matching pursuit algorithm

Several recent studies have quantified abnormalities in Parkinsonian gait. However, few studies have attempted to quantify the regularity of body motion during walking in patients with Parkinson's disease. The aim of the paper was to characterise body motion patterns in healthy, elderly subjects and patients with Parkinson's disease during walking. Body motion was recorded during walking for 16 patients with Parkinson's disease and ten healthy, elderly subjects using a tri-axial accelerometer device. To characterise the body motion patterns, time-frequency patterns of the body acceleration signal were estimated using a matching pursuit algorithm. Data from the study showed that the healthy, elderly subjects and patients with Parkinson's disease had different time-frequency patterns. The time-frequency patterns were classified into four distinct patterns based on their time durations: vertical (<0.15 s), circular (0.15–0.5 s), short horizontal (0.5–2.0 s) and long horizontal (>2.0 s). The data showed that the energy of the long horizontal patterns, representing long-term smooth and regular (rhythmic) activities, significantly decreased, but the energy of the circular patterns, representing irregular activities, increased in the patients with mild Parkinson's disease, compared with those of the healthy, elderly subjects (p<0.01). Futhermore, these features were seen more clearly in the body motions of severe case patients than is that of mild case patients. It was concluded that these differences are probably due to a lack of ability to control normal and smooth movement is Parkinson's disease.     

Emotional changes with multiple sclerosis and Parkinson's disease.

Multiple sclerosis (MS) and Parkinson's disease (PD) are relatively common neurological disorders. Both disorders are chronic and progressive, produce varying degrees of physical disability, and result in characteristic neuropathological changes to a variety of subcortical brain structures. Patients with MS or PD also exhibit a higher prevalence of emotional disorders relative to other patient groups with comparable degrees of physical disability. The present review (a) examines specific methodological issues associated with research in this area, (b) describes the range and severity of emotional disorders in MS and PD, and (c) examines both endogenous and reactive explanations to account for the increased prevalence of emotional dysfunction in these two disorders. Suggestions for future research are offered, as well as implications for treatment.     

帕金森患者的睡眠障碍

目的：探讨帕金森病患者睡眠结构紊乱与病程的长短、病情的严重程度以及用药种类的关系。方法：应用多项睡眠图描记分析技术（polysomnography），分析17例帕金森病患者的睡眠总时间、睡眠效率、睡眠潜伏期、睡眠醒觉的次数和时间。结果：睡眠效率低于80％的15例，睡眠潜伏期大于30min者9例．睡眠中醒觉的时间大于60min者15例。病程大于5年的患者的平均睡眠总时间（173min）与病程小于5年者（276min）相比显著减少，差异具有显著意义（P=0．02）。病程大于5年的患者睡眠潜伏期（72min）较病程小f5年者的睡眠潜伏期（35rain）明显延长，呈明显的正相关（r=0．44，P〈0．05）。H—Y分级与总睡眠时间呈负相关（r=0．49，P〈0．05），与睡眠潜伏期呈正相关（r=0．56，P〈0．05）。服用两种以I：药物哲的睡眠潜伏期较用一种药物者的明显延长（P=0．02）。结论：帕金森病患者的睡眠结构存在明显异常，主要表现为睡眠总时间减少、睡眠效率减低、睡眠觉醒的时间和次数增多及睡眠潜伏期延氐。帕金森病患者病程的长短与总睡眠时间成反比，病情的严重程度与睡眠时间及效率成反比，而与睡眠潜伏期及睡眠中醒觉的次数成正比，用药种类的多少与睡眠潜伏期成正比。     

Breathing and locomotion in patients with Parkinson's disease

The phase relationship between respiration and locomotion was examined in ten patients with Parkinson's disease (PD, mean age 65, range 51-79 years) and in six healthy subjects (mean age 63, range 58-68 years). Locomotion was measured by means of pressure sensors attached below the subjects' feet. Respiration was measured using respiratory inductive plethysmography. The data were recorded with a battery-driven portable device. We determined the coordination degree as the portion of steps which occurred within 12/50 bins of the respiratory cycle. The mean degree of coordination of PD patients was 45.0%+/-11.9%, for the healthy subjects 85.1%+/-10.8% (P<0.001). Three healthy subjects showed a 2:1 ratio between step and breathing rate, three a 3:2 ratio. Two PD patients showed a coordination of 4:1 and 3:1, respectively, with a larger scatter than in controls. In the other eight patients steps were almost equally distributed over the entire respiratory cycle. We conclude that in patients with PD the coordination between locomotion and breathing is reduced.