Female sexual dysfunction in multiple system atrophy: a prospective cohort study.

PURPOSE: The diagnosis of probable multiple system atrophy relies on the presence of severe cardiovascular or urogenital autonomic failure. Erectile dysfunction is required to fulfil the latter criterion in men, whereas no corresponding item is established for women. In this study, we aimed to investigate sexual dysfunction in women with multiple system atrophy. METHODS: We administered the Female Sexual Function Index questionnaire and interviewed women with multiple system atrophy and age-matched controls regarding the presence of "genital hyposensitivity." RESULTS: We recruited 25 women with multiple system atrophy and 42 controls. Female Sexual Function Index scores in sexually active women with multiple system atrophy were significantly lower (multiple system atrophy = 10; 15.4, 95% CI [10.1, 22.1], controls = 37; 26.1 [24.1, 28.1], p = 0.0004). The lowest scores concerned the domains of desire, arousal and lubrication. Genital hyposensitivity was reported by 56% of the patients with multiple system atrophy and 9% controls (p < 0.0001). CONCLUSIONS: Sexual dysfunction is highly prevalent in women with multiple system atrophy. Screening for disturbances in specific sexual domains should be implemented in the clinical evaluation of women with suggestive motor symptoms.

Behavioral and histological analysis of a partial double-lesion model of parkinson-variant multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease with progressive autonomic failure, cerebellar ataxia (MSA-C), and parkinsonism (MSA-P) resulting from neuronal loss in multiple brain areas associated with oligodendroglial cytoplasmic α-synuclein inclusion bodies. No effective treatments exists, and MSA-P patients often fail to respond to L-DOPA because of the loss of striatal dopaminergic receptors. Rendering MSA-P patients sensitive to L-DOPA administration following striatal tissue transplantation has been proposed as a possible novel therapeutic strategy to improve the clinical condition. Here we describes simple, skilled, and sensorimotor behavior deficits in a unilateral partial double-lesion (DL) rat model of MSA-P. The sequential striatal double-lesion model mimicks early MSA-P pathology by combining partial 6-hydroxydopamine (6-OHDA) followed by striatal quinolinic acid (QA) lesion. Animals were tested on spontaneous, learned, or drug-induced behavioral tasks on multiple occasions pre- and postsurgery. The data show robust, lateralized deficits, and the partial 6-OHDA and the double-lesioned animals were most impaired. Importantly, this study identified a behavioral deficit profile unique to the double-lesion animals and distinctive from the single 6-OHDA- or the QA-lesioned animals. Histology confirmed an approximately 40% dopamine loss in the striatum in the 6-OHDA and double-lesion animals as well as a similar loss of striatal projection neurons in the QA and double-lesion animals. In summary, we have established the behavioral deficit profile of a partial double-lesion rat model mimicking the early stage of MSA-P.

Urodynamic Evaluation in Multiple System Atrophy: A Retrospective Cohort Study.

BACKGROUND: Urological dysfunction in patients with multiple system atrophy (MSA) is one of the main manifestations of autonomic failure. Urodynamic examination is clinically relevant since underlying pathophysiology of lower urinary tract (LUT) dysfunction can be variable. OBJECTIVE: Evaluation of the pathophysiology of urological symptoms and exploration of differences in urodynamic patterns of LUT dysfunction between MSA-P and MSA-C. METHODS: Retrospective study of patients with possible and probable MSA who were referred for urodynamic studies between 2004 and 2019. Demographic data, medical history, physical examination and urodynamic studies assessing storage and voiding dysfunction were obtained. RESULTS: Seventy-four patients were included in this study (MSA-P 64.9% n = 48; median age 62.5 (IQR 56.8-70) years). Detrusor overactivity during filling phase was noted in 58.1% (n = 43) of the patients. In the voiding phase, detrusor sphincter dyssynergia and detrusor underactivity were observed in 24.6% (n = 17) and in 62.1% (n = 41) of the patients, respectively. A postmicturition residual volume of over 100 ml was present in 71.4% (n = 50) of the patients. Comparison of MSA subtypes showed weaker detrusor contractility in MSA-P compared to MSA-C [pdetQmax 26.2 vs. 34.4 cmH20, P = 0.04]. In 56.2% (n = 41) of patients pathophysiology of LUT dysfunction was deemed to be neurogenic and consistent with the diagnosis of MSA. In 35.6% (n = 26) urodynamic pattern suggested other urological co-morbidities. CONCLUSION: Urodynamic evaluation is an important tool to analyze the pattern of LUT dysfunction in MSA. Impaired detrusor contractility was seen more in MSA-P which needs to be investigated in further studies.

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

BACKGROUND: Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls. OBJECTIVES: We compared gait variability at different walking velocities between and within groups of patients with Parkinson-variant multiple system atrophy, idiopathic Parkinson's disease, and a control group of older adults. METHODS: Gait metrics were recorded in 11 multiple system atrophy, 12 Parkinson's disease patients, and 18 controls using sensor-based gait analysis. Gait variability was analyzed for stride, swing and stance time, stride length and gait velocity. Values were compared between and within the groups at self-paced comfortable, fast and slow walking speed. RESULTS: Multiple system atrophy patients displayed higher gait variability except for stride time at all velocities compared with controls, while Parkinson's patients did not. Compared with Parkinson's disease, multiple system atrophy patients displayed higher variability of swing time, stride length and gait velocity at comfortable speed and at slow speed for swing and stance time, stride length and gait velocity (all P < 0.05). Stride time variability was significantly higher in slow compared to comfortable walking in patients with multiple system atrophy (P = 0.014). Variability parameters significantly correlated with the postural instability/gait difficulty subscore in both disease groups. Conversely, significant correlations between variability parameters and MDS-UPDRS III score was observed only for multiple system atrophy patients. CONCLUSION: This analysis suggests that gait variability parameters reflect the major axial impairment and postural instability displayed by multiple system atrophy patients compared with Parkinson's disease patients and controls.

Association of transient orthostatic hypotension with falls and syncope in patients with Parkinson disease.

OBJECTIVES: To assess the frequency of transient orthostatic hypotension (tOH) and its clinical impact in Parkinson disease (PD), we retrospectively studied 173 patients with PD and 173 age- and sex-matched controls with orthostatic intolerance, who underwent cardiovascular autonomic function testing under continuous noninvasive blood pressure (BP) monitoring. METHODS: We screened for tOH (systolic BP fall ≥20 mm Hg or diastolic ≥10 mm Hg resolving within the first minute upon standing) and classic OH (cOH, sustained systolic BP fall ≥20 mm Hg or diastolic ≥10 mm Hg within 3 minutes upon standing). In patients with PD, we reviewed the medical records of the 6 months preceding and following autonomic testing for history of falls, syncope, and orthostatic intolerance. RESULTS: tOH occurred in 24% of patients with PD and 21% of controls, cOH in 19% of patients with PD and in none of the controls, independently of any clinical-demographic or PD-specific characteristic. Forty percent of patients with PD had a history of falls, in 29% of cases due to syncope. Patients with PD with history of orthostatic intolerance and syncope had a more severe systolic BP fall and lower diastolic BP rise upon standing, most pronounced in the first 30-60 seconds. CONCLUSIONS: tOH is an age-dependent phenomenon, which is at least as common as cOH in PD. Transient BP falls when changing to the upright position may be overlooked with bedside BP measurements, but contribute to orthostatic intolerance and syncope in PD. Continuous noninvasive BP monitoring upon standing may help identify a modifiable risk factor for syncope-related falls in parkinsonian patients.

Cognition in multiple system atrophy: a single-center cohort study.

OBJECTIVE: Cognitive impairment in multiple system atrophy (MSA) is common, but remain poorly characterized. We evaluated cognitive and behavioral features in MSA patients and assessed between-group differences for MSA subtypes and the effect of orthostatic hypotension (OH) on cognition. METHODS: This retrospective study included 54 patients with clinical diagnosis of possible and probable MSA referred to the Department of Neurology at Medical University of Innsbruck between 2000 and 2018. Neurological work-up included comprehensive neuropsychological testing including Consortium to Establish a Registry for Alzheimer's Disease (CERAD-plus) test battery, Frontal Assessment Battery (FAB), digit span test (DST), clock drawing task (CLOX1), and Hospital Anxiety and Depression Scale (HADS-D). RESULTS: The mean MMSE score was 27.6 points. Overall, slight to moderate cognitive impairment was noted in up to 40% of patients, with predominant impairment of executive function and verbal memory. Patients with the cerebellar variant performed significantly worse than patients with the parkinsonian type (P < 0.05) in a screening of executive functions (FAB) and in phonemic verbal fluency. Depression and anxiety scores were elevated in 28% and 22% of MSA patients, respectively. Cognitive profile, depression, and anxiety levels were comparable between patients with and without OH. INTERPRETATION: Cognitive deficits are relatively frequent in MSA and primarily affect executive functions and verbal memory. Future comparative studies including Parkinson dementia, Lewy body disease, and MSA cases with and without OH are required to elucidate disease-specific cognitive profiles in these synucleinopathies and to examine the influence of cardiovascular autonomic dysfunction on cognitive function in MSA.

Iron in Neurodegeneration - Cause or Consequence?

Iron dyshomeostasis can cause neuronal damage to iron-sensitive brain regions. Neurodegeneration with brain iron accumulation reflects a group of disorders caused by iron overload in the basal ganglia. High iron levels and iron related pathogenic triggers have also been implicated in sporadic neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple system atrophy (MSA). Iron-induced dyshomeostasis within vulnerable brain regions is still insufficiently understood. Here, we summarize the modes of action by which iron might act as primary or secondary disease trigger in neurodegenerative disorders. In addition, available treatment options targeting brain iron dysregulation and the use of iron as biomarker in prodromal stages are critically discussed to address the question of cause or consequence.

L-dopa response pattern in a rat model of mild striatonigral degeneration.

BACKGROUND: Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined striatonigral degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure. METHODS AND RESULTS: Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p<0.001). Response to L-dopa treatment declined in both MSA-P/SND groups reflecting striatal damage of lateral motor areas in contrast to the 6-OHDA only lesioned animals (p<0.01). The remaining striatal volume correlated strongly with contralateral apomorphine induced rotation behaviour and contralateral paw use during L-dopa treatment in cylinder and stepping test (p<0.001). CONCLUSION: Our novel L-dopa response data suggest that L-dopa failure can be induced by restricted lateral striatal lesions combined with dopaminergic denervation. We propose that this sequential striatal double-lesion model replicates a mild stage of MSA-P/SND and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness.

Physiotherapy improves motor function in patients with the Parkinson variant of multiple system atrophy: A prospective trial.

BACKGROUND AND OBJECTIVES: Gait impairment and reduced mobility are disabling symptoms of multiple system atrophy. While physiotherapy is increasingly recognized as a valuable supplement to pharmacotherapy for patients with Parkinson's disease, data on the efficacy of physiotherapy for multiple system atrophy are lacking. This study aimed to explore the feasibility of two consecutive exercise-based interventions in patients with multiple system atrophy. SUBJECTS AND METHODS: We included 10 patients with the parkinsonian variant of multiple system atrophy and 10 patients with Parkinson's disease, matched for gender and Hoehn & Yahr stage (≤3). Interventions consisted of a five-day inpatient physiotherapy program followed by a five-week unsupervised home-based exercise program. Outcomes included instrumented gait analysis, patient questionnaires, clinical rating scales and physical tests. Patients were examined at baseline, after the first inpatient treatment and again after the home-based intervention. Additionally, a structured telephone interview was performed immediately after the second intervention period. RESULTS: Both patient groups exhibited a similar improvement of gait after the interventions, as measured by instrumented gait analysis. These effects reached their maximum level after inpatient physiotherapy and remained stable following the home-based exercise program. Patient questionnaires also showed improvements after the interventions, but motor clinical rating scales did not. CONCLUSION: Our pilot results suggest that a short-term bout of physiotherapy is feasible, safe and improves gait performance in patients with multiple system atrophy. This highlights the potential of physiotherapy for this disabling condition where pharmacotherapy typically achieves poor effects. The present findings warrant a larger controlled study.

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint.

Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a ß-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.

Failure of Neuroprotection Despite Microglial Suppression by Delayed-Start Myeloperoxidase Inhibition in a Model of Advanced Multiple System Atrophy: Clinical Implications.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease. Post-mortem hallmarks of MSA neuropathology include oligodendroglial α-synuclein (αSYN) inclusions, striatonigral degeneration, olivopontocerebellar atrophy, and increased microglial activation that accompanies the wide spread neurodegeneration. Recently, we demonstrated upregulation of myeloperoxidase (MPO) in activated microglia and provided evidence for the role of microglial MPO in the mediation of MSA-like neurodegeneration (Stefanova et al. Neurotox Res 21:393-404, 2015). The aim of the current study was to assess the therapeutic potency of MPO inhibition (MPOi) in a model of advanced MSA. We replicated the advanced pathology of MSA by intoxicating transgenic PLP-α-synuclein transgenic mice with 3-nitropropionic acid (3NP). After onset of the full-blown pathology, MSA mice received either MPOi or vehicle over 3 weeks. Motor phenotype and neuropathology were analyzed to assess the therapeutic efficacy of MPOi compared to vehicle treatment in MSA mice. MPOi therapy initiated after the onset of severe MSA-like neuropathology in mice failed to attenuate motor impairments and neuronal loss within the striatum, substantia nigra pars compacta, inferior olives, pontine nuclei, and cerebellar cortex. However, we observed a significant reduction of microglial activation in degenerating brain areas. Further, nitrated αSYN accumulation was reduced in the striatonigral region. In summary, delayed-start MPOi treatment reduced microglial activation and levels of nitrated αSYN in a mouse model of advanced MSA. These effects failed to impact on motor impairments and neuronal loss in contrast to previously reported disease modifying efficacy of early-start therapy with MPOi in MSA.

Tremor in Multiple System Atrophy - a review.

BACKGROUND: Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by a rapidly progressive course. The clinical presentation can include autonomic failure, parkinsonism, and cerebellar signs. Differentiation from Parkinson's disease (PD) is difficult if there is levodopa-responsive parkinsonism, rest tremor, lack of cerebellar ataxia, or mild/delayed autonomic failure. Little is known about tremor prevalence and features in MSA. METHODS: We performed a PubMed search to collect the literature on tremor in MSA and considered reports published between 1900 and 2013. RESULTS: Tremor is a common feature among MSA patients. Up to 80% of MSA patients show tremor, and patients with the parkinsonian variant of MSA are more commonly affected. Postural tremor has been documented in about half of the MSA population and is frequently referred to as jerky postural tremor with evidence of minipolymyoclonus on neurophysiological examination. Resting tremor has been reported in about one-third of patients but, in contrast to PD, only 10% show typical parkinsonian "pill-rolling" rest tremor. Some patients exhibit intention tremor associated with cerebellar dysmetria. In general, MSA patients can have more than one tremor type owing to a complex neuropathology that includes both the basal ganglia and pontocerebellar circuits. DISCUSSION: Tremor is not rare in MSA and might be underrecognized. Rest, postural, action and intention tremor can all be present, with jerky tremulous movements of the outstretched hands being the most characteristic. However, reviewing the data on tremor in MSA suggests that not every shaky movement satisfies tremor criteria; therefore, further studies are needed.