Cerebrospinal fluid levels of neurofilament light chain in multiple system atrophy relative to Parkinson’s disease: a meta-analysis

As a biomarker of axonal injury, neurofilament light chain (NFL) in multiple system atrophy (MSA) patients and Parkinson’s disease (PD) patients has been investigated by numerous studies. However, cerebrospinal fluid (CSF) NFL changes are conflicting in MSA patients relative to PD patients to date. Therefore, the current study was carried out to find out possible heterogeneity sources. Furthermore, “Neurofilament”, “Neurofilament light chain” and “Multiple system atrophy” were employed to search “PubMed”, “Springer” and “Medline” databases until August 2016 with standard mean difference (Std.MD) being calculated. In addition, subgroup analysis and meta-regression were performed to assess possible heterogeneity sources. Nine studies were pooled, in which 212 MSA patients and 373 PD patients were involved. Moreover, CSF NFL in MSA patients was higher than that in PD patients [pooled Std.MD = 1.56, 95% CI (1.12, 2.00), p < 0.00001] with significant heterogeneity (I ² = 76%). Besides, population variations, sample size, the difference in CSF phosphorylated tau (p-tau) levels between MSA patients and PD patients, and Hoehn–Yahr staging of PD patients were the main heterogeneity sources. As shown by meta-regression, Hedges’s g of CSF NFL was correlated with CSF Std.MD of α-synuclein between MSA patients and healthy controls (r = ?1.34824, p = 0.00025). Therefore, CSF NFL increased in MSA patients relative to PD patients. Meta-regression showed that NFL was associated with α-synuclein in CSF of MSA patients relative to healthy controls. Due to the influence of heterogeneity sources, more prospective large sample studies are still needed to assess CSF NFL changes in MSA patients relative to PD patients.     

The role of α-synuclein in the pathogenesis of multiple system atrophy

The discovery of glial cytoplasmic inclusions (GCIs) in 1989 helped to define multiple system atrophy (MSA) as a clinicopathological entity, and drew attention to the prominent role played by these inclusions in the pathogenesis of the disorder. Subsequently, GCIs were shown to be highly positive for -synuclein, a neuronal protein that is normally absent in oligodendroglia except during embryonic development. The source of oligodendroglial -synuclein aggregation in MSA is unknown. Since genetic overexpression has been excluded, active uptake from dying neurons remains a possibility. The similar topography of oligodendroglial and neuronal pathology in MSA suggests a fundamental disturbance of the functional unit between oligodendroglia, axon, and neuron. Transgenic MSA mouse models are now available to determine these aspects of cellular disturbance experimentally.     

The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy

Summary. α-Synuclein, a synaptic protein of unknown function, is a major component of Lewy bodies and may play a role in the pathophysiological process of Parkinson’s disease (PD). In this study, we measured the plasma α-synuclein levels in 105 patients with PD, 38 patients with multiple system atrophy (MSA), and 51 age-matched controls. The α-synuclein level was significantly elevated in patients with PD (79.9 ± 4.0 pg/ml, p < 0.001) and in those with MSA (78.1 ± 3.5 pg/ml, p = 0.019) compared with the level in controls (76.1 ± 3.9 pg/ml). The α-synuclein level was higher in patients with PD than in those with MSA (79.9 ± 4.0 vs 78.1 ± 3.5, p = 0.016). Our study demonstrated that the α-synuclein level in plasma is elevated in patients with PD and MSA.     

Characterization of gait variability in multiple system atrophy and Parkinson’s disease

Journal of Neurology - Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls. We compared...     

Supine hypertension in Parkinson’s disease and multiple system atrophy

Objective

Supine hypertension (SH) is a feature of cardiovascular autonomic failure that often accompanies orthostatic hypotension and may represent a negative prognostic factor in parkinsonian syndromes. Here we investigated the frequency rate as well as the clinical and tilt test correlates of SH in Parkinson’s disease (PD) and multiple system atrophy (MSA).

Methods

197 PD (33 demented) and 78 MSA (24 MSA-Cerebellar, 54 MSA-Parkinsonian) patients who had undergone a tilt test examination were retrospectively included. Clinical-demographic characteristics were collected from clinical records at the time of the tilt test examination.

Results

SH (>140 mmHg systolic, >90 mmHg diastolic) occurred in 34 % of PD patients (n = 66, mild in 71 % of patients, moderate in 27 %, severe in 2 %) and 37 % of MSA ones (n = 29, mild in 55 % of patients, moderate in 17 %, severe in 28 %). No difference was observed in SH frequency between demented versus gender-, age- and disease duration-matched non-demented PD patients, or between patients with the parkinsonian (MSA-P) versus the cerebellar (MSA-C) variant of MSA. In PD, SH was associated with presence of cardiovascular comorbidities (p = 0.002) and greater systolic (p = 0.007) and diastolic (p = 0.002) orthostatic blood pressure fall. Orthostatic hypotension (p = 0.002), and to a lesser degree, lower daily dopaminergic intake (p = 0.01) and use of anti-hypertensive medications (p = 0.04) were associated with SH in MSA.

Interpretation

One-third of PD and MSA patients suffer from mild to severe SH, independently of age, disease duration or stage. In PD, cardiovascular comorbidities significantly contribute to the development of SH, while in MSA, SH appears to reflect cardiovascular autonomic failure.

     

Post mortem cerebrospinal fluid α-synuclein levels are raised in multiple system atrophy and distinguish this from the other α-synucleinopathies, Parkinson's disease and Dementia with Lewy bodies

Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p < 0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p < 0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.     

α-synuclein, LRRK2 and their interplay in Parkinson's disease

Of the various genetic factors contributing to the pathogenesis of Parkinson's disease (PD), only mutations in α-synuclein (α-syn) and LRRK2 genes cause clinical and neuropathological phenotypes closely resembling the sporadic cases. Therefore, studying the pathophysiological functions of these two PD-related genes is particularly informative in understanding the underlying molecular pathogenic mechanism of the disease. PD-related missense and multiplication mutations in α-syn may cause both early- and late-onset PD, whereas various PD-related LRRK2 missense mutations may contribute to the more common late-onset PD. While intensive studies have been carried out to elucidate the pathogenic properties of PD-related mutant α-syn and LRRK2, our knowledge of their normal functions and their potential genetic interplay remains rudimental. In this review, we summarize the progress made regarding the pathophysiological functions of α-syn, LRRK2 and their interaction in PD, based on the available literature and our unpublished observations.     

Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated -synuclein (anti-PSer129). Phosphorylated -synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated -synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.     

Involvement of α-synuclein in Parkinson's disease and other neurodegenerative disorders

Summary. A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the α-synuclein gene in autosomal dominant Parkinson's disease (PD). α-Synuclein is the main component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a fragment of α-synuclein (NAC) is the second major component of amyloid plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of α-synuclein in affected brain regions. This may indicate that these disorders partially share common pathogenic mechanisms. Recent data provide first insights into the physiological function of α-synuclein and support the concept of an essential role of α-synuclein in neurodegeneration. Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration and of the pathophysiological function of α-synuclein in particular may influence future development of therapeutic strategies in neurodegenerative disorders. Received April 9, 1999; accepted June 16, 1999     

Parkinson's disease and α-synuclein expression

Genetic studies of Parkinson's disease over the last decade or more have revolutionized our understanding of this condition. α-Synuclein was the first gene to be linked to Parkinson's disease, and is arguably the most important: the protein is the principal constituent of Lewy bodies, and variation at its locus is the major genetic risk factor for sporadic disease. Intriguingly, duplications and triplications of the locus, as well as point mutations, cause familial disease. Therefore, subtle alterations of α-synuclein expression can manifest with a dramatic phenotype. We outline the clinical impact of α-synuclein locus multiplications, and the implications that this has for Parkinson's disease pathogenesis. Finally, we discuss potential strategies for disease-modifying therapies for this currently incurable disorder.     

Cerebrospinal fluid/plasma quotients of essential and non-essential metals in patients with Alzheimer’s disease

In this study, the quotients (Q) between metal concentrations in cerebrospinal fluid (CSF) and plasma were studied in subjects with Alzheimer’s disease (AD) and referents to investigate if the leakage through the blood–CSF barrier (BCB) increased with increased duration and severity of the disease. Concentrations of 18 metals (Mg, Ca, Mn, Fe, Co, Ni, Cu, Zn, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Hg, and Pb) were determined by ICP-MS in plasma and cerebrospinal fluid in 264 patients with AD, and in 54 healthy referents. The quotients Q _Mn, Q _Rb, Q _Sb, Q _Pb and Q _Hg were significantly lower (p ≤ 0.003) and Q _Co significantly higher (p ≤ 0.001) in subjects with AD as compared with the controls. Subjects in a subgroup with more severe AD, showed the same pattern. The metal leakage into CSF did not increase with increased duration and/or severity of the disease. The permeability of BCB varied considerably between the studied metals with low median quotients (Q ≤ 0.02) for Cd, Cu, Sb, Se and Zn and higher median quotients for Ca (Q ~ 0.5) and Mg (Q ~ 1.3), probably partly depending on differences in size and lipophilicity of metal–carrier complexes and specific carrier mechanisms.     

Reduced bowel sounds in Parkinson’s disease and multiple system atrophy patients

Digital auscultation of bowel sounds was performed in newly diagnosed, drug-naïve patients with Parkinson’s disease (PD) (n = 10), multiple system atrophy (MSA) (n = 12), progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) (n = 7), and control subjects (n = 18). The number of bowel sounds per minute and the integrated time of bowel sounds were significantly lower in PD and MSA patients than in control subjects. Reduced bowel sounds may herald compromised gastrointestinal motility in patients with PD and MSA.     

Neuronal to oligodendroglial α-synuclein redistribution in a double transgenic model of multiple system atrophy

Multiple system atrophy is a sporadic, progressive, neurodegenerative disease characterized by an oligodendroglial accumulation of alpha-synuclein (α-syn). The mechanisms underlying the oligodendroglial accumulation of α-syn in the brains of patients with multiple system atrophy have attracted a great deal of interest, given the primarily neuronal role reported for this protein. We examined the interactions between neuronal and oligodendroglial α-syn in the progeny of crosses between parental transgenic (tg) mouse lines that express α-syn either under the oligodendroglial-specific myelin-basic protein promoter (MBP1-hα-syn tg) or under the neuronal platelet-derived growth factor promoter (PDGF-hα-syn tg). Our results demonstrate that progeny from the cross [hα-syn double (dbl) tg mice] displayed a robust redistribution of α-syn accumulation, with a relocalization from a neuronal or a mixed neuronal/oligodendroglial α-syn expression to a more oligodendroglial pattern in both the neocortex and the basal ganglia that closely resembled the parental MBP-hα-syn tg line. The hα-syn dbl tg mice also displayed motor deficits, concomitant with reduced levels of tyrosine hydroxylase and augmented neuropathological alterations in the basal ganglia. These results suggest that the central nervous system milieu in the hα-syn dbl tg mice favors an oligodendroglial accumulation of α-syn. This model represents an important tool to examine the interactions between neuronal and oligodendrocytic α-syn in diseases such as multiple system atrophy.     

Sleep disturbances and brain MRI morphometry in Parkinson's disease,multiple system atrophy and progressive supranuclear palsy – a comparative study

Despite common reports in Parkinson's disease (PD), in other parkinsonian syndromes, sleep disturbances have been less frequently described. This study evaluated and compared sleep disturbances in patients with PD, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and analyzed associations with brain magnetic resonance imaging (MRI) morphometry. This was a cross-sectional study of 16 PD cases, 13 MSA, 14 PSP and 12 control. Sleep disturbances were evaluated by Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI), Restless Legs Scale and Berlin questionnaire. Pons area, midbrain area, medial cerebellar peduncle (MCP) width, and superior cerebellar peduncle width were measured using MRI. Poor quality sleep, risk of obstructive sleep apnea (OSA) and restless legs syndrome (RLS) were detected in all groups. Patients with MSA showed higher risk of OSA and less frequent RLS. In MSA, a correlation between PSQI scores and Hoehn and Yahr stage was observed (p < 0.05). In PSP, RLS was frequent (57%) and related with reduced sleep duration and efficiency. In PD, excessive daytime sleepiness was related to atrophy of the MCP (p = 0.01). RLS was more frequent in PD and PSP, and in PSP, was associated with reduced sleep efficiency and sleep duration. Brain morphometry abnormalities were found in connection with excessive daytime sleepiness and risk of OSA in PD and PSP suggesting widespread degeneration of brainstem sleep structures on the basis of sleep abnormalities in these patients.     

Comparison of smooth pursuit eye movement deficits in multiple system atrophy and Parkinson’s disease

Because of the large overlap and quantitative similarity of eye movement alterations in Parkinson’s disease (PD) and multiple system atrophy (MSA), a measurement of eye movement is generally not considered helpful for the differential diagnosis. However, in view of the pathophysiological differences between MSA and PD as well as between the cerebellar (MSA-C) and Parkinsonian (MSA-P) subtypes of MSA, we wondered whether a detailed investigation of oculomotor performance would unravel parameters that could help to differentiate between these entities. We recorded eye movements during sinusoidal pursuit tracking by means of video-oculography in 11 cases of MSA-P, 8 cases of MSA-C and 27 cases of PD and compared them to 23 healthy controls (CTL). The gain of the smooth pursuit eye movement (SPEM) component exhibited significant group differences between each of the three subject groups (MSA, PD, controls) but not between MSA-P and MSA-C. The similarity of pursuit impairment in MSA-P and in MSA-C suggests a commencement of cerebellar pathology in MSA-P despite the lack of clinical signs. Otherwise, SPEM gain was of little use for differential diagnosis between MSA and PD because of wide overlap. However, inspection of the saccadic component of pursuit tracking revealed that in MSA saccades typically correct for position errors accumulated during SPEM epochs (“catch-up saccades”), whereas in PD, saccades were often directed toward future target positions (“anticipatory saccades”). The differences in pursuit tracking between PD and MSA were large enough to warrant their use as ancillary diagnostic criteria for the distinction between these disorders.     

Co-localization of α-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration

Neuronal and glial cytoplasmic inclusions (NCIs and GCIs), which contain alpha-synuclein as a major component, are characteristic cytopathological features of multiple system atrophy (MSA). We report MSA of 19 years' duration in a 73-year-old woman. Her initial symptom was parkinsonism, with dementia appearing about 8 years later. Postmortem examination showed marked atrophy of the frontal and temporal white matter and limbic system, in addition to the pathology typical of MSA. In the limbic system, severe neuronal loss and astrocytosis were observed, and the remaining neurons often had lightly eosinophilic, spherical cytoplasmic inclusions. Interestingly, a double-labeling immunofluorescence study revealed that the NCIs in the dentate gyrus and amygdaloid nucleus, and the GCIs in the frontal and temporal white matter often expressed both alpha-synuclein NACP-5 and phosphorylated tau AT8 epitopes. Double-immunolabeling electron microscopy of the NCIs in the dentate gyrus and the GCIs in the temporal white matter clearly revealed labeling of their constituent granule-associated filaments with NACP-5, and some of them were also labeled with AT8. These findings strongly suggested that some alpha-synuclein filaments were decorated with phosphorylated tau without formation of fibrils such as paired helical filaments. Immunoblotting of sarkosyl-insoluble tau indicated that the accumulated tau consisted mainly of four-repeat tau isoforms of 383 amino acids and 412 amino acids. We consider that the limbic system can be a major site of neurodegeneration in MSA of long duration. The mechanisms of such abnormal tau accumulation in the NCIs and GCIs are unknown.